1.1 Hypertension

Losartan potassium and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal 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 and hydrochlorothiazide.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 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 Treatment of High Blood 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 can be concluded that it is blood pressure 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 have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit 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 benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

This fixed dose combination is not indicated for initial therapy of hypertension, except when the hypertension is severe enough that the value of achieving prompt blood pressure control exceeds the risk of initiating combination therapy in these patients [see Clinical Studies (14)and Dosage and Administration (2.1)].

Losartan potassium and hydrochlorothiazide tablets may be administered with other antihypertensive agents.

1.2 Hypertensive Patients with Left Ventricular Hypertrophy

Losartan potassium and hydrochlorothiazide tablets areindicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients[see Use in Specific Populations (8.6) ,Clinical Pharmacology (12.3) , and  Dosage and Administration (2.2) ].

2.1 Hypertension

The usual starting dose of losartan potassium and hydrochlorothiazide tablets is 50 mg/12.5 mg (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily. The dosage can be  increased  after  3  weeks  of  therapy  to  a  maximum  of  100 mg/25 mg  (losartan 100 mg/hydrochlorothiazide 25 mg) once daily as needed to control blood pressure [see Clinical Studies (14.2)].

Initiate a patient whose blood pressure is not adequately controlled with losartan 50 mg monotherapy with losartan potassium and hydrochlorothiazide tablets 50 mg/12.5 mg once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dosage may be increased to two tablets of losartan potassium and hydrochlorothiazide 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide 100 mg/25 mg once daily.

Initiate a patient whose blood pressure is not adequately controlled with losartan 100 mg monotherapy with losartan potassium and hydrochlorothiazide tablets 100 mg/12.5 mg  once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, increase the dose to two tablets of losartan potassium and hydrochlorothiazide 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide 100 mg/25 mg once daily.

Initiate a patient whose blood pressure is inadequately controlled with hydrochlorothiazide 25 mg once daily, or is controlled but who experiences hypokalemia with this regimen, on losartan potassium and hydrochlorothiazide tablets 50 mg/12.5 mg once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response. Evaluate the clinical response to losartan potassium and hydrochlorothiazide tablets 50 mg/12.5 mg and, if blood pressure remains uncontrolled after about 3 weeks of therapy, increase the dose to two tablets of losartan potassium and hydrochlorothiazide 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide 100 mg/25 mg once daily.

2.2 Hypertensive Patients with Left Ventricular Hypertrophy

In patients whose bloodpressure is not adequately controlled on 50 mg losartan potassium, initiate treatment with losartan potassium and hydrochlorothiazide tablets 50 mg/12.5 mg. If additional blood pressure reduction isneeded, increase the dose to losartan potassium and hydrochlorothiazide tablets 100 mg/12.5 mg,followed by losartan potassium and hydrochlorothiazide tablets 100 mg/25 mg. For further blood pressure reduction add other antihypertensives [seeClinical Studies (14) ] .

5.1 Fetal Toxicity

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal 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 losartan potassium and hydrochlorothiazide as soon as possible.

Thiazidescross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice, thrombocytopenia [seeUse in Specific Populations (8.1) ].

5.2 Hypotension in Volume- or Salt-Depleted Patients

In patients with anactivated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with losartan potassium and hydrochlorothiazide. Correct volume or salt depletion prior to administration of losartan potassium and hydrochlorothiazide. Do not use losartan potassium and hydrochlorothiazide as initial therapy in patients with intravascular volume depletion.

5.3 Impaired Renal Function

Changes inrenal function including acute renal failure can be caused by drugs that inhibit the renin­angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on losartan potassium and hydrochlorothiazide . Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on losartan potassium and hydrochlorothiazide [see  Drug Interactions (7.3) and Use in Specific Populations (8.8)].

5.4 Hypersensitivity

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchialasthma, but are more likely in patients with such a history.

5.5 Electrolyte and Metabolic Effects

In double-blind clinical trials of various doses of losartan potassium and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 6.7% versus 3.5% for placebo; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4% versus 0% for placebo.

Losartan potassium and hydrochlorothiazide contains hydrochlorothiazide which can cause hypokalemia, hyponatremia and hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Losartan potassium and hydrochlorothiazide also contains losartan which can cause hyperkalemia. Monitor serum electrolytes periodically [see Drug Interactions (7.1)].

Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

Hyperuricemia may occur or frank gout may be precipitated in patients receiving thiazide therapy. Because losartan decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.

Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.

5.6 Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide,a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

5.7 Systemic Lupus Erythematosus

Thiazidediuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

5.8 Postsympathectomy Patients

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.

6.1 Clinical Trials Experience

Because clinical  trials  are  conducted  under  widely varying  conditions,  adverse  reaction rates  observed  in  the clinical  trials  of a drug  cannot  be directly compared to  rates  in the clinical  trials  of another drug  and  may  not reflect the  rates observed  in  practice.

Losartan  potassium  and  hydrochlorothiazide has been  evaluated for safety  in 858  patients  treated for  essential hypertension and 3889  patients  treated for hypertension and left ventricular  hypertrophy. Most  adverse  reactions  have been mild  and  transient in  nature and  have  not required discontinuation  of  therapy.  Incontrolled clinical trials, discontinuation  of therapy due  to clinical adverse  events  was required  in  only 2.8%  and  2.3%  of  patients  treated with the combination and  placebo,  respectively.

In these  double-blind  controlled clinical  trials,  adverse  reactions occurring  in  greater than  2%  of  subjects  treated with  losartan  and  hydrochlorothiazide  and  at a greater rate than placebo  were:  back  pain (2.1%  vs  0.6%),  dizziness (5.7%  vs  2.9%), and  upper respiratory  infection (6.1% vs 4.6%).

The  following additional adverse  reactions have been  reported  in clinical  trials  with  losartan potassium and hydrochlorothiazide  and/or  the  individual  components:

Blood and  the  lymphatic system  disorders: Anemia,  aplastic  anemia,  hemolytic  anemia,  leukopenia,  agranulocytosis.

Metabolism and  nutrition  disorders:  Anorexia, hyperglycemia,  hyperuricemia,  electrolyte  imbalance  including hyponatremia  and hypokalemia.

Psychiatric disorders: Insomnia,  restlessness.

Nervous system disorders:  Dysgeusia, headache, migraine, paraesthesias.

Eye disorders:  Xanthopsia,  transient  blurred vision.

Cardiac disorders: Palpitation,  tachycardia.

Vascular disorders: Dose-related  orthostatic effects,  necrotizing angiitis (vasculitis,  cutaneous vasculitis).

Respiratory,  thoracic and mediastinal disorders: Nasal congestion, pharyngitis,  sinus  disorder, respiratory  distress  (including  pneumonitis  and pulmonary edema).

Gastrointestinal disorders:  Dyspepsia, abdominal pain,  gastric  irritation, cramping,  diarrhea, constipation,  nausea,  vomiting,  pancreatitis, sialoadenitis.

Hepato-biliary disorders: Jaundice  (intrahepatic  cholestatic  jaundice).

Skin and  subcutaneous tissue disorders:  Rash, pruritus,  purpura,  toxic epidermal necrolysis,  urticaria,  photosensitivity, cutaneous  lupus erythematosus.

Musculoskeletal and connective  tissue disorders: Muscle cramps, muscle spasm,  myalgia,  arthralgia.

Renal and  urinary disorders:  Glycosuria, renal  dysfunction,  interstitial nephritis, renal  failure.

Reproductive system  and breast disorders:  Erectile  dysfunction/impotence.

General  disorders  and  administration site conditions:  Chest  pain,  edema/swelling, malaise, fever, weakness.

Investigations: Liver function  abnormalities.

Cough

Persistent dry cough  has  been  associated  with  ACE-inhibitor use  and in practice can  be a cause  of  discontinuation  of  ACE-inhibitor therapy. Two  prospective,parallel-group, 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  50  mg,  lisinopril  20  mg,  or  either  placebo  (one  study, n=97)  or  25  mg  hydrochlorothiazide (n=135). The double-blind  treatment  period  lasted  up  to 8 weeks. The  incidence  of  cough  is  shown  in Table 1  below.

These  studies  demonstrate  that the  incidence  of cough associated  with  losartan  therapy,  in a  population  that all had  cough associated  with ACE inhibitor  therapy, is similar  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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of losartan potassium and hydrochlorothiazide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

Digestive: Hepatitis has been reported rarely in patients treated with losartan.

Hematologic: Thrombocytopenia.

Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, 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 with losartan. Anaphylactic reactions have been reported.

Musculoskeletal: rhabdomyolysis

Skin: Erythroderma

7.1 Agents Increasing Serum Potassium

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

7.2 Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of angiotensin II receptor antagonists or thiazide diuretics. Monitor lithium levels in patients receiving losartan potassium and hydrochlorothiazide andlithium.

7.3 Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors

Losartan Potassium

In patients who are elderly, volume-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 result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving losartan and NSAID therapy.

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

Hydrochlorothiazide

The administration of a non-steroidal anti-inflammatory agent including a selective COX-2 inhibitor can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when losartan potassium and hydrochlorothiazide and non-steroidal anti-inflammatory agents including selective COX-2 inhibitors are used concomitantly, observe closely to determine if the desired effect of the diuretic is obtained.

In patients receiving diuretic therapy, coadministration of NSAIDs with angiotensin receptor blockers, including losartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving hydrochlorothiazide, losartan, and NSAID therapy.

7.4 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 additional benefit compared to monotherapy for the combined endpoint of decline in GFR, end-stage renal disease, or death, but experienced an increased incidence of hyperkalemia and acute kidney injury compared with the monotherapy group.

Closely monitor blood pressure, renal function, and electrolytes in patients on losartan potassium and hydrochlorothiazide and other agents that affect the RAS.

Do not coadminister aliskiren with losartan potassium and hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with losartan potassium and hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min).

7.5 The Use of Hydrochlorothiazide with Other Drugs

When administered concurrently, the following drugs may interact with thiazide diuretics [see Clinical Pharmacology (12.3)]:

Antidiabetic drugs (oral agents and insulin) — dosage adjustment of the antidiabetic drug may be required.

Cholestyramine and colestipol resins — Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively. Stagger the dosage of hydrochlorothiazide and the resin such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of the resin.

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal 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 losartan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not 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 appropriate alternative to therapy with drugs affecting the renin­angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue losartan potassium and hydrochlorothiazide, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to losartan potassium and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].

There was no evidence of teratogenicity in rats or rabbits treated with a maximum losartan potassium dose of 10 mg/kg/day in combination with 2.5 mg/kg/day of hydrochlorothiazide. At these dosages, respective exposures (AUCs) of losartan, its active metabolite, and hydrochlorothiazide in rabbits were approximately 5, 1.5, and 1 times those achieved in humans with 100 mg losartan in combination with 25 mg hydrochlorothiazide. AUC values for losartan, its active metabolite and hydrochlorothiazide, extrapolated from data obtained with losartan administered to rats at a dose of 50 mg/kg/day in combination with 12.5 mg/kg/day of hydrochlorothiazide, were approximately 6, 2, and 2 times greater than those achieved in humans with 100 mg of losartan in combination with 25 mg of hydrochlorothiazide. Fetal toxicity in rats, as evidenced by a slight increase in supernumerary ribs, was observed when females were treated prior to and throughout gestation with 10 mg/kg/day losartan in combination with 2.5 mg/kg/day hydrochlorothiazide. As also observed in studies with losartan alone, adverse fetal and neonatal effects, including decreased body weight, renal toxicity, and mortality, occurred when pregnant rats were treated during late gestation and/or lactation with 50 mg/kg/day losartan in combination with 12.5 mg/kg/day hydrochlorothiazide. Respective AUCs for losartan, its active metabolite and hydrochlorothiazide at these dosages in rats were approximately 35, 10 and 10 times greater than those achieved in humans with the administration of 100 mg of losartan in combination with 25 mg hydrochlorothiazide. When hydrochlorothiazide was administered without losartan to pregnant mice and rats during their respective periods of major organogenesis, at doses up to 3000 and 1000 mg/kg/day, respectively, there was no evidence of harm to the fetus.

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

8.3 Nursing Mothers

It is notknown whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk. Thiazides appear in human milk. Because of the potential for adverse 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 mother.

8.4 Pediatric Use

Safety and effectiveness of losartan potassium and hydrochlorothiazide in pediatric patients have not been established.

Neonates witha history ofin uteroexposure to losartan potassium and hydrochlorothiazide: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

8.5 Geriatric Use

Ina controlled clinical study for the reduction in the combined risk 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. In an effort to control blood pressure in this study, patients were coadministered losartan and hydrochlorothiazide 74% of the total time they were on study drug. No overall differences in effectiveness were observed between these patients and younger patients. Adverse events were somewhat more frequent in the elderly compared to non-elderly patients for both the losartan-hydrochlorothiazide and the control groups [seeClinical Pharmacology (12.3) ] .

8.6 Race

In the LosartanIntervention For Endpoint reduction in hypertension (LIFE) study, Black patients with hypertension and left ventricular hypertrophy treated with atenolol had a lower risk of stroke, the primary composite endpoint, as compared with Black patients treated with losartan (both cotreated with hydrochlorothiazide in the majority of patients). In the subgroup of Black patients (n=533, 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 26 per 1000 patient-years) and 46 primary endpoints among 270 patients (17%, 42 per 1000 patient-years) on losartan. This finding could not be explained on the basis of differences in the populations other than race or on any imbalances between treatment groups. In addition, blood pressure reductions in both treatment groups were consistent between Black and non-Black patients. Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study provides no evidence that the benefits of losartan on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients [seeClinical Pharmacology (12.3) ] .

8.7 Hepatic Impairment

Initiation of losartan potassium and hydrochlorothiazide isnot recommended for patients with hepatic impairment because the appropriate starting dose of losartan, 25 mg, is not available.

8.8 Renal Impairment

Changesin renal function have been reported in susceptible individuals [seeDosage and Administration (2.1) ,Warnings and Precautions (5.4) , and Clinical Pharmacology (12.3) ]. Safety and effectiveness of losartan potassium and hydrochlorothiazide in patients with severe renal impairment (creatine clearance <30 mL/min) have not been established.

12.1 Mechanism of Action

Losartan Potassium

Angiotensin II [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 principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Neither losartan nor its principal active metabolite exhibits any partial agonist activity at the AT1 receptor, and both have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.

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

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity,  increases in aldosterone secretion,  increases in urinary potassium loss,  and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown.

12.2 Pharmacodynamics

LosartanPotassium

Losartan   inhibits   the pressor  effect of angiotensin   II (as   well as  angiotensin   I)  infusions. A dose of   100   mg   inhibits   the   pressor  effect   by   about   85%   at  peak   with   25 to 40%  inhibition  persisting  for   24  hours.   Removal   of   the   negative  feedback   of   angiotensin   II   causes  a   doubling   to  tripling  in  plasma   renin  activity  and   consequent  rise  in  angiotensin   II  plasma   concentration  in   hypertensive   patients.   Losartan  does  not  affect   the  response   to  bradykinin,   whereas  ACE   inhibitors  increase  the  response   to   bradykinin.   Aldosterone  plasma   concentrations  fall  following   losartan  administration.   In  spite   of   the  effect   of   losartan   on   aldosterone   secretion,  very   little  effect   on   serum   potassium   was   observed.

The  effect   of   losartan   is  substantially   present   within   one   week   but   in   some   studies  the  maximal  effect   occurred   in  3 to 6  weeks.   In   long-term   follow-up  studies   (without   placebo   control)   the  effect   of   losartan   appeared   to   be  maintained  for   up   to  a   year.  There   is   no  apparent  rebound  effect   after   abrupt  withdrawal   of   losartan.  There   was  essentially   no change in average  heart   rate   in  losartan-treated   patients   in   controlled  trials.

Hydrochlorothiazide

After   oral  administration   of   hydrochlorothiazide,  diuresis   begins   within  2  hours,  peaks   in  about  4  hours,   and   lasts   about  6   to   12  hours.

Drug Interactions

Hydrochlorothiazide

Alcohol, barbiturates, ornarcotics  —   potentiation   of   orthostatic  hypotension   may  occur.

Other antihypertensivedrugs  —  additive  effect   or   potentiation.

Skeletal musclerelaxants,   nondepolarizing   (e.g.,  tubocurarine)  —  possible  increased   responsiveness   to   the  muscle   relaxant.

Corticosteroids, ACTH, or glycyrrhizin(found  in   liquorice)  —  intensified  electrolyte   depletion,  particularly  hypokalemia.

Pressor amines (e.g., norepinephrine)—  possible   decreased  response   to  pressor   amines   but   not   sufficient   to   preclude   their  use.

12.3 Pharmacokinetics

Losartan Potassium

Absorption: Following oral administration, losartan is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of losartan is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3 to 4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC (area under the curve) of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its Cmax  but has only minor effects on losartan AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time.

Distribution: The volume of distribution of losartan and the active metabolite is about 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 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.

Metabolism: Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. About 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 indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites.

Elimination: Total plasma clearance of losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of losartan is about 2 hours and of the metabolite is about 6 to 9 hours. After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites. Following oral 14C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of 14C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither losartan nor its metabolite accumulate in plasma upon repeated once-daily dosing.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Special Populations

Geriatric and Gender

Losartan pharmacokinetics have been investigated in the elderly (65 to 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 active metabolite were similar in males and females.

Race

Pharmacokinetic differences due to race have not been studied [see also Use in Specific Populations (8.6)].

Hepatic Insufficiency

Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5 times and about 1.7 times those in young male volunteers. Compared to normal subjects, the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower, and the oral bioavailability was about doubled. The lower starting dose of losartan recommended for use in patients with hepatic impairment cannot be given using losartan potassium and hydrochlorothiazide. Its use in such patients as a means of losartan titration is, therefore, not recommended [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].

Renal Insufficiency

Losartan

Following oral administration, plasma concentrations and AUCs of losartan and its active metabolite are increased by 50 to 90% 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 to 85% for both losartan and its active metabolite in patients with mild or moderate renal insufficiency. Neither losartan nor its active metabolite can be removed by hemodialysis.

Hydrochlorothiazide

Following oral administration, the AUC for hydrochlorothiazide is increased by 70 and 700% for patients with mild and moderate renal insufficiency, respectively. In this study, renal clearance of hydrochlorothiazide decreased by 45 and 85% in patients with mild and moderate renal impairment, respectively.

Use the usual regimens of therapy with losartan potassium and hydrochlorothiazide as long as the patient's creatinine clearance is greater than 30 mL/min. Safety and effectiveness of losartan potassium and hydrochlorothiazide in patients with severe renal impairment (creatinine clearance less than 30 mL/min) have not been established [see Use in Specific Populations (8.8)].

Drug Interactions

Losartan Potassium

No clinically significant drug interactions have been found in studies of losartan potassium with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. However, rifampin has been shown to decrease the AUC of losartan and its active metabolite by 30% and 40%, respectively. Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by approximately 40%, but increased the AUC of losartan by approximately 70% following multiple doses. Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4.The AUC of active metabolite following oral losartan was not 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 active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of losartan to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Losartan Potassium-Hydrochlorothiazide

No carcinogenicity studies have been conducted with the losartan potassium-hydrochlorothiazide combination.

Losartan potassium and hydrochlorothiazide when tested at a weight ratio of 4:1, was negative in the Ames microbial mutagenesis assay and the V-79 Chinese hamster lung cell mutagenesis assay. In addition, there was no evidence of direct genotoxicity in the in vitro alkaline elution assay in rat hepatocytes and in vitro chromosomal aberration assay in Chinese hamster ovary cells at noncytotoxic concentrations.

Losartan potassium, coadministered with hydrochlorothiazide, had no effect on the fertility or mating behavior of male rats at dosages up to 135 mg/kg/day of losartan and 33.75 mg/kg/day of hydrochlorothiazide. These dosages have been shown to provide respective systemic exposures (AUCs) for losartan, its active metabolite and hydrochlorothiazide that are approximately 60, 60 and 30 times greater than those achieved in humans with 100 mg of losartan potassium in combination with 25 mg of hydrochlorothiazide. In female rats, however, the coadministration of doses as low as 10 mg/kg/day of losartan and 2.5 mg/kg/day of hydrochlorothiazide was associated with slight but statistically significant decreases in fecundity and fertility indices. AUC values for losartan, its active metabolite and hydrochlorothiazide, extrapolated from data obtained with losartan administered to rats at a dose of 50 mg/kg/day in combination with 12.5 mg/kg/day of hydrochlorothiazide, were approximately 6, 2, and 2 times greater than those achieved in humans with 100 mg of losartan in combination with 25 mg of hydrochlorothiazide.

Losartan Potassium

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).

Hydrochlorothiazide

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 mcg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.

14.1 Losartan Monotherapy

Reduction in the Risk of Stroke: The LIFE study was a multinational, double-blind study comparing losartan 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 once daily losartan 50 mg or atenolol 50 mg. If goal blood pressure (<140/90 mmHg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of losartan or atenolol was then increased to 100 mg once daily. If necessary, other antihypertensive treatments (e.g., increase in dose of hydrochlorothiazide therapy to 25 mg or addition of other diuretic therapy, calcium channel blockers, alpha-blockers, or centrally acting agents, but not ACE inhibitors, angiotensin II antagonists, or beta-blockers) were added to the treatment regimen to reach the goal blood pressure.

In efforts to control blood pressure, the patients in both arms of the LIFE study were coadministered hydrochlorothiazide the majority of time they were on study drug (73.9% and 72.4% of days in the losartan and atenolol arms, respectively).

Of the randomized patients, 4963 (54%) were female and 533 (6%) were Black. The mean age was 67 with 5704 (62%) age ≥65. At baseline, 1195 (13%) had diabetes, 1326 (14%) had isolated systolic hypertension, 1469 (16%) had coronary heart disease, and 728 (8%) had cerebrovascular disease. Baseline mean blood pressure 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 before a primary endpoint, 77% of the group treated with losartan and 73% of the group treated with atenolol were still taking study medication. Of the patients still taking study medication, the mean doses of losartan and atenolol were both about 80 mg/day, and 15% were taking atenolol or losartan as monotherapy, while 77% were also receiving hydrochlorothiazide (at a mean dose of 20 mg/day in each group). Blood pressure reduction measured at trough was similar for both treatment groups but blood pressure was not measured at any other time of the day. At the end of study or at the last visit before a primary endpoint, the mean blood pressures were 144.1/81.3 mmHg for the group treated with losartan and 145.4/80.9 mmHg for the group treated with atenolol [the difference in SBP of 1.3 mmHg was significant (p<0.001), while the difference of 0.4 mmHg in 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, so that there was also an examination of the first event of each type even if it was not the first event (e.g., a stroke following an initial myocardial infarction would be counted in the analysis of stroke). Treatment with losartan resulted in a 13% reduction (p=0.021) in risk of the primary endpoint compared to the atenolol group; this difference was primarily the result of an effect on fatal and nonfatal stroke. Treatment with losartan reduced the risk of stroke by 25% relative to atenolol (p=0.001).

14.2 Losartan Potassium-Hydrochlorothiazide

The  3   controlled  studies   of   losartan   and   hydrochlorothiazide  included   over  1300   patients  assessing   the   antihypertensive  efficacy   of   various  doses   of   losartan   (25 mg,   50 mg  and   100   mg)   and   concomitant   hydrochlorothiazide   (6.25 mg,  12.5 mg  and   25  mg).  A   factorial  study  compared   the   combination   of   losartan/hydrochlorothiazide  50 mg/12.5   mg   with   its  components   and   placebo.  The   combination   of   losartan/hydrochlorothiazide  50 mg/12.5   mg   resulted   in   an  approximately  additive   placebo-adjusted   systolic/diastolic  response   (15.5/9   mmHg  for   the   combination  compared   to   8.5/5   mmHg  for   losartan   alone  and   7/3   mmHg   for   hydrochlorothiazide  alone).   Another  study  investigated   the  dose-response   relationship   of   various  doses   of   hydrochlorothiazide   (6.25 mg,  12.5 mg  and   25   mg)   or   placebo   on  a  background   of   losartan   (50   mg) in  patients   not  adequately   controlled  (Sitting Diastolic  Blood   Pressure  [SiDBP]  93 to 120   mmHg)   on   losartan   (50   mg)   alone.  The  third  study  investigated  the  dose-response  relationship   of   various   doses   of   losartan   (25 mg,   50 mg   and   100   mg)   or   placebo   on  a  background   of   hydrochlorothiazide   (25   mg)   in   patients  not  adequately  controlled  (SiDBP  93 to 120   mmHg)   on   hydrochlorothiazide   (25   mg) alone.  These   studies  showed   an   added  antihypertensive   response   at   trough   (24  hours   post-dosing)   of   hydrochlorothiazide  12.5 mg   or   25   mg   added   to   losartan   50   mg   of   5.5/3.5   and   10/6   mmHg,   respectively.   Similarly,  there   was   an   added  antihypertensive   response   at   trough   when   losartan   50 mg   or   100 mg   was   added   to  hydrochlorothiazide   25   mg   of 9/5.5   and  12.5/6.5   mmHg,   respectively.  There   was no   significant  effect   on   heart   rate.

There   was no  difference   in   response  for   men   and   women   or   in   patients   over   or   under   65 years   of   age.

Black   patients   had  a   larger   response   to   hydrochlorothiazide   than  non-Black   patients  and  a   smaller   response   to   losartan.  The   overall   response   to  the   combination   was  similar   for  Black   and  non-Black   patients.

SevereHypertension  (SiDBP  ≥110   mmHg)

The  safety and  efficacy of losartan potassium and hydrochlorothiazide   as  initial  therapy  for   severe   hypertension  (defined   as  a  mean  SiDBP ≥110   mmHg confirmed   on  2   separate   occasions  off   all   antihypertensive   therapy)   was   studied   in  a   6-week   double-blind,   randomized,   multicenter  study.   Patients   were   randomized   to   either   losartan   and   hydrochlorothiazide  (50 mg/12.5   mg,   once   daily)   or   to   losartan   (50   mg,   once   daily)   and  followed  for   blood   pressure   response.   Patients   were   titrated   at  2-week   intervals   if   their  SiDBP  did   not  reach   goal   (<90  mmHg).   Patients   on   combination  therapy   were   titrated  from losartan   50   mg/hydrochlorothiazide 12.5   mg   to   losartan   50   mg/hydrochlorothiazide  12.5 mg   (sham   titration   to   maintain  the  blind)   to   losartan  100  mg/hydrochlorothiazide   25   mg.   Patients   on  monotherapy   were  titrated   from   losartan   50   mg   to   losartan  100   mg   to losartan  150   mg,   as needed. The  primary   endpoint   was a  comparison   at 4  weeks of   patients   who  achieved  goal   diastolic   blood   pressure   (trough  SiDBP  <90  mmHg).

The  study   enrolled  585   patients,  including  264  (45%)  females,   124  (21%)  blacks,   and   21   (4%) ≥ 65   years   of   age.  The  mean  blood   pressure   at  baseline  for   the   total  population   was  171/113   mmHg. The  mean   age   was 53 years. After  4  weeks   of   therapy, the  mean  SiDBP   was 3.1   mmHg lower  and  the  mean  SiSBP   was 5.6   mmHg   lower  in   the  group   treated   with   losartan potassium and hydrochlorothiazide.   As  a  result,  a   greater   proportion   of   the   patients   on   losartan potassium and hydrochlorothiazide  reached  the   target   diastolic   blood  pressure   (17.6%  for   losartan potassium and hydrochlorothiazide,  9.4%  for   losartan;  p=0.006).   Similar   trends   were  seen   when  the   patients were  grouped  according   to   gender,  race   or   age   (<, ≥ 65).

After  6   weeks   of   therapy,  more   patients   who  received   the  combination  regimen   reached   target   diastolic   blood  pressure  than  those   who  received  the  monotherapy  regimen   (29.8%   versus   12.5%).