Full Prescribing Info
Contents
Losartan potassium, hydrochlorothiazide.
Description
Each tablet contains losartan potassium 50 mg or 100 mg and hydrochlorothiazide 12.5 mg.
Action
Hyzaar (losartan potassium and hydrochlorothiazide) is the first combination of an angiotensin II receptor (type AT1) antagonist and a diuretic.
Pharmacology: Pharmacodynamics: Losartan: Losartan inhibits systolic and diastolic pressor responses to angiotensin II infusions. At peak, losartan potassium 100 mg inhibits these responses by approximately 85%; 24 hrs after single and multiple-dose administration, inhibition is about 26-39%.
During losartan administration, removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. Increases in plasma renin activity lead to increases in angiotensin II in plasma. During chronic (6 weeks) treatment of hypertensive patients with losartan 100 mg/day, approximately 2- to 3-fold increases of plasma angiotensin II were observed at time of peak plasma drug concentrations. In some patients, greater increases were observed, particularly during short-term (2 weeks) treatment. However, antihypertensive activity and suppression of plasma aldosterone concentration were apparent at 2 and 6 weeks, indicating effective angiotensin II receptor blockade. After discontinuation of losartan, plasma renin activity and angiotensin II levels declined to untreated levels within 3 days. Effects of Hyzaar on PRA and angiotensin II levels were similar to those observed with losartan 50 mg.
Since losartan is a specific antagonist of the angiotensin II receptor type AT1, it does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. In a study which compared the effects of 20 mg and 100 mg of losartan potassium and an ACE inhibitor on responses to angiotensin I, angiotensin II and bradykinin, losartan was shown to block responses to angiotensin I and angiotensin II without affecting responses to bradykinin. This finding is consistent with losartan's specific mechanism of action. In contrast, the ACE inhibitor was shown to block responses to angiotensin I and enhance responses to bradykinin without altering the response to angiotensin II, thus providing a pharmacodynamic distinction between losartan and ACE inhibitors.
Plasma concentrations of losartan and its active metabolite and the antihypertensive effect of losartan increase with increasing dose. Since losartan and its active metabolite are both angiotensin II receptor antagonists, they both contribute to the antihypertensive effect.
In a single-dose study in normal males, the administration of losartan potassium 100 mg, under dietary high- and low-salt conditions, did not alter glomerular filtration rate, effective renal plasma flow or filtration fraction. Losartan had a natriuretic effect which was more pronounced on a low-salt diet and did not appear to be related to inhibition of early proximal reabsorption of sodium. Losartan also caused a transient increase in urinary uric acid excretion.
In nondiabetic hypertensive patients with proteinuria (≥2 g/24 hrs) treated for 8 weeks, the administration of losartan potassium 50 mg titrated to 100 mg significantly reduced proteinuria by 42%. Fractional excretion of albumin and IgG was also significantly reduced. In these patients, losartan maintained glomerular filtration rate and reduced filtration fraction.
In postmenopausal hypertensive women treated for 4 weeks, losartan potassium 50 mg had no effect on renal or systemic prostaglandin levels.
Losartan has no effect on autonomic reflexes and no sustained effect on plasma norepinephrine.
Losartan potassium, administered in doses of up to 150 mg once daily, did not cause clinically important changes in fasting triglycerides, total cholesterol or HDL-cholesterol in patients with hypertension. The same doses of losartan had no effect on fasting glucose levels.
Generally, losartan caused a decrease in serum uric acid (usually <0.4 mg/dL) which was persistent with chronic therapy. In controlled clinical trials in hypertensive patients, no patients were discontinued due to increases in serum creatinine or serum potassium.
In a 12-week, parallel-design study in patients with left ventricular failure (New York Heart Association Functional Classes II-IV), most of whom were receiving diuretics and/or digitalis, losartan potassium administered in once-daily doses of 2.5, 10, 25 and 50 mg was compared to placebo. The 25- and 50-mg doses produced positive hemodynamic and neurohormonal effects which were maintained for the length of the study. Hemodynamic responses were characterized by an increase in cardiac index and decreases in: Pulmonary capillary wedge pressure, systemic vascular resistance, mean systemic arterial pressure and heart rate. The occurrence of hypotension was dose related in these heart failure patients. Neurohormonal results were characterized by a reduction in circulating levels of aldosterone and norepinephrine.
Mechanism of Action: Losartan-Hydrochlorothiazide: The components of Hyzaar have been shown to have an additive effect on blood pressure reduction, reducing blood pressure to a greater degree than either component alone. This effect is thought to be a result of the complimentary actions of both components. Further, as a result of its diuretic effect, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, decreases serum potassium, and increases the levels of angiotensin II. Administration of losartan blocks all the physiologically relevant actions of angiotensin II and through inhibition of aldosterone could tend to attenuate the potassium loss associated with the diuretic.
Losartan has been shown to have a mild and transient uricosuric effect. Hydrochlorothiazide has been shown to cause modest increases in uric acid; the combination of losartan and hydrochlorothiazide tends to attenuate the diuretic-induced hyperuricemia.
Pharmacokinetics: Absorption: Losartan: Following oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hr and in 3-4 hrs, respectively. There was no clinically significant effect on the plasma concentration profile of losartan when the drug was administered with a standardized meal.
Distribution: Losartan: Both losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 L. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.
Hydrochlorothiazide: Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Metabolism: Losartan: About 14% of an IV- or orally-administered dose of losartan is converted to its active metabolite. Following oral and IV administration of 14C-labeled losartan potassium, circulating plasma radioactivity is primarily attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was seen in about 1% of individuals studied.
In addition to the active metabolite, inactive metabolites are formed, including 2 major metabolites formed by hydroxylation of the butyl side chain and a minor metabolite, an N-2 tetrazole glucuronide.
Elimination: Losartan: Plasma clearance of losartan and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is about 74 mL/min and 26 mL/min, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.
Following oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal half-life of about 2 hrs and 6-9 hrs, respectively. During once-daily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.
Both biliary and urinary excretion contribute to the elimination of losartan and its metabolites. Following an oral dose of 14C-labeled losartan in man, about 35% of radioactivity is recovered in the urine and 58% in the feces. Following an IV dose of 14C-labeled losartan in man, about 43% of radioactivity is recovered in the urine and 50% in the feces.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hrs, the plasma half-life has been observed to vary between 5.6 and 14.8 hrs. At least 61% of the oral dose is eliminated unchanged within 24 hrs.
Characteristics in Patients: Losartan-Hydrochlorothiazide: The plasma concentrations of losartan and its active metabolite and the absorption of hydrochlorothiazide in elderly hypertensives are not significantly different from those in young hypertensives.
Losartan: The plasma concentrations of losartan and its active metabolite in elderly hypertensives are not significantly different from those in young hypertensives.
Plasma concentrations of losartan were up to 2-fold higher in female hypertensives as compared to male hypertensives. Concentrations of the active metabolite were not different in males and females. This apparent pharmacokinetic difference is not judged to be of clinical significance.
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-fold and 1.7-fold greater than those seen in young male volunteers.
Plasma concentrations of losartan are not altered in patients with creatinine clearance above 10 mL/min. Compared to patients with normal renal function, the AUC for losartan is approximately 2-fold greater in hemodialysis patients. Plasma concentrations of the active metabolite are not altered in patients with renal impairment or in hemodialysis patients. Neither losartan nor the active metabolite can be removed by hemodialysis.
Indications/Uses
Hypertension: Hyzaar is indicated for the treatment of hypertension, for patients in whom combination therapy is appropriate.
Hypertensive Patients with Left Ventricular Hypertrophy: Hyzaar is indicated 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 Pharmacology: Pharmacodynamics and Clinical Effects, Losartan Potassium, Reduction in the Risk of Stroke, Race under Actions, Dosage & Administration and Precautions: Race).
Dosage/Direction for Use
Hyzaar may be administered with other antihypertensive agents.
Hyzaar may be administered with or without food.
Fixed-dose combination is not indicated for initial therapy.
Hypertension: The usual starting and maintenance dose of Hyzaar is 1 tab of Hyzaar 50/12.5 (losartan potassium 50 mg/hydrochlorothiazide 12.5 mg) once daily. For patients who do not respond adequately to Hyzaar 50/12.5, the dosage may be increased to 1 tab of Fortzaar (losartan potassium 100 mg/hydrochlorothiazide 25 mg) once daily or 2 tabs of Hyzaar 50/12.5 once daily. The maximum dose is 1 tab of Fortzaar once daily or 2 tabs of Hyzaar 50/12.5 once daily. In general, the antihypertensive effect is attained within 3 weeks after initiation of therapy. Hyzaar 100/12.5 (losartan potassium 100 mg/hydrochlorothiazide 12.5 mg) is available for those patients titrated to 100 mg of Cozaar who require additional blood pressure control.
Hyzaar should not be initiated in patients who are intravascularly volume-depleted (eg, those treated with high-dose diuretics).
Hyzaar is not recommended for patients with severe renal impairment (creatinine clearance ≤30 mL/min) or for patients with hepatic impairment.
No initial dosage adjustment of Hyzaar is necessary for elderly patients. Fortzaar should not be used as initial therapy in elderly patients.
Hypertensive Patients with Left Ventricular Hypertrophy: The usual starting dose is losartan 50 mg once daily. If goal blood pressure is not reached with losartan 50 mg, therapy should be titrated using a combination of losartan and a low dose of hydrochlorothiazide (12.5 mg) and, if needed, the dose should then be increased to losartan 100 mg and hydrochlorothiazide 12.5 mg once daily. If necessary, the dose should be increased to losartan 100 mg and hydrochlorothiazide 25 mg once daily. Hyzaar 50/12.5, Hyzaar 100/12.5 and Fortzaar are suitable alternative formulations in patients who would otherwise be treated concomitantly with losartan plus hydrochlorothiazide.
Overdosage
No specific information is available on the treatment of overdosage with Hyzaar. Treatment is symptomatic and supportive. Therapy with Hyzaar should be discontinued and the patient observed closely. Suggested measures include induction of emesis if ingestion is recent, and correction of dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures.
Losartan: Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.
Neither losartan nor the active metabolite can be removed by hemodialysis.
Hydrochlorothiazide: The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.
The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.
Contraindications
Hyzaar is contraindicated in patients who are hypersensitive to any component of this product, patients with anuria and patients who are hypersensitive to other sulfonamide-derived drugs.
Special Precautions
Losartan-Hydrochlorothiazide: Hypersensitivity: Angioedema. (See Side Effects.)
Hepatic and Renal Impairment: Hyzaar is not recommended for patients with hepatic impairment or severe renal impairment (creatinine clearance ≤30 mL/min) (see Dosage & Administration).
Losartan: Renal Function Impairment: As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported in susceptible individuals; these changes in renal function may be reversible upon discontinuation of therapy.
Other drugs that affect the renin-angiotensin system may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Similar effects have been reported with losartan; these changes in renal function may be reversible upon discontinuation of therapy.
Hydrochlorothiazide: Hypotension and Electrolyte/Fluid Imbalance: As with all antihypertensive therapy, symptomatic hypotension may occur in some patients. Patients should be observed for clinical signs of fluid or electrolyte imbalance eg, volume depletion, hyponatremia, hypochloremic alkalosis, hypomagnesemia or hypokalemia which may occur during intercurrent diarrhea or vomiting. Periodic determination of serum electrolytes should be performed at appropriate intervals in such patients.
Metabolic and Endocrine Effects: Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required (see Interactions).
Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Thiazide therapy may precipitate hyperuricemia and/or gout in certain patients. Because losartan decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.
Others: In patients receiving thiazides, hypersensitivity reactions may occur with or without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.
Race: Based on the LIFE (Losartan Intervention For Endpoint reduction in hypertension) study, the benefits of losartan on cardiovascular morbidity and mortality compared to atenolol do not apply to Black patients with hypertension and left ventricular hypertrophy although both treatment regimens effectively lowered blood pressure in Black patients. In the overall LIFE study population (n=9193), treatment with losartan resulted in a 13% risk reduction (p=0.021) as compared to atenolol for patients reaching the primary composite endpoint of the combined incidence of cardiovascular death, stroke and myocardial infarction. In this study, losartan decreased the risk of cardiovascular morbidity and mortality compared to atenolol in non-Black, hypertensive patients with left ventricular hypertrophy (n=8660) as measured by the primary endpoint of the combined incidence of cardiovascular death, stroke and myocardial infarction (p=0.003). In this study, however, Black patients treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with losartan (p=0.03). 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%, 25.9 per 1000 patient-years) and 46 primary endpoints among 270 patients (17%, 41.8 per 1000 patient-years) on losartan.
Use in pregnancy: When used in pregnancy during the 2nd and 3rd trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, Hyzaar should be discontinued as soon as possible.
Although there is no experience with the use of Hyzaar in pregnant women, animal studies with losartan potassium have demonstrated fetal and neonatal injury and death, the mechanism of which is believed to be pharmacologically mediated through effects on the renin-angiotensin system. In humans, fetal renal perfusion, which is dependent upon the development of the renin-angiotensin system, begins in the 2nd trimester; thus, risk to the fetus increases if Hyzaar is administered during the 2nd or 3rd trimesters of pregnancy.
Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and fetus to unnecessary hazard including fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.
Use in lactation: It is not known whether losartan is excreted in human 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.
Use in children: Safety and effectiveness in children have not been established.
Use in the elderly: In clinical studies, there were no clinically significant differences in the efficacy and safety profiles of losartan-hydrochlorothiazide in older (≥65 years) and younger patients (<65 years).
Use In Pregnancy & Lactation
Use in pregnancy: When used in pregnancy during the 2nd and 3rd trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, Hyzaar should be discontinued as soon as possible.
Although there is no experience with the use of Hyzaar in pregnant women, animal studies with losartan potassium have demonstrated fetal and neonatal injury and death, the mechanism of which is believed to be pharmacologically mediated through effects on the renin-angiotensin system. In humans, fetal renal perfusion, which is dependent upon the development of the renin-angiotensin system, begins in the 2nd trimester; thus, risk to the fetus increases if Hyzaar is administered during the 2nd or 3rd trimesters of pregnancy.
Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and fetus to unnecessary hazard including fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.
Use in lactation: It is not known whether losartan is excreted in human 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.
Side Effects
In clinical trials with losartan potassium-hydrochlorothiazide, no adverse experiences peculiar to this combination drug have been observed. Adverse experiences have been limited to those that were reported previously with losartan potassium and/or hydrochlorothiazide. The overall incidence of adverse experiences reported with the combination was comparable to placebo. The percentage of discontinuations of therapy was also comparable to placebo.
In general, treatment with losartan potassium-hydrochlorothiazide was well tolerated. For the most part, adverse experiences have been mild and transient in nature and have not required discontinuation of therapy.
In controlled clinical trials for essential hypertension, dizziness was the only adverse experience reported as drug-related that occurred with an incidence greater than placebo in 1% or more of patients treated with losartan potassium-hydrochlorothiazide.
In a controlled clinical trial in hypertensive patients with left ventricular hypertrophy, losartan, often in combination with hydrochlorothiazide, was generally well tolerated. The most common drug-related side effects were dizziness, asthenia/fatigue and vertigo.
The following additional adverse reactions have been reported in post-marketing experience: Hypersensitivity: Anaphylactic reactions, angioedema including swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue have been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schoenlein purpura, has been reported rarely with losartan.
Gastrointestinal: Hepatitis has been reported rarely in patients treated with losartan, diarrhea.
Respiratory: Cough has been reported with losartan.
Skin: Urticaria, erythroderma have been reported with losartan. Photosensitivity has been reported with losartan potassium-hydrochlorothiazide.
Laboratory Test Findings: In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of losartan-hydrochlorothiazide. Hyperkalemia (serum potassium >5.5 mEq/L) occurred in 0.7% of patients, but in these trials, discontinuation of losartan-hydrochlorothiazide due to hyperkalemia was not necessary. Elevations of ALT occurred rarely and usually resolved upon discontinuation of therapy.
Drug Interactions
Losartan: In clinical pharmacokinetic trials, no drug interactions of clinical significance have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital (see Hydrochlorothiazide, Alcohol, Barbiturates or Narcotics as follows), ketoconazole and erythromycin. Rifampin and fluconazole have been reported to reduce levels of active metabolite. The clinical consequences of these interactions have not been evaluated.
As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride), potassium supplements or salt substitutes containing potassium may lead to increases in serum potassium.
As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.
Nonsteroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function who are being treated with nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists may result in a further deterioration of renal function. These effects are usually reversible.
Hydrochlorothiazide: When given concurrently, the following drugs may interact with thiazide diuretics: Alcohol, Barbiturates or Narcotics: Potentiation of orthostatic hypotension may occur.
Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustment of the antidiabetic drug may be required.
Other Antihypertensive Drugs: Additive effect.
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%, respectively.
Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.
Pressor Amines (eg, Adrenaline): Possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal Muscle Relaxants, Nondepolarizing (eg, Tubocurarine): Possible increased responsiveness to the muscle relaxant.
Lithium: Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity; concomitant use is not recommended. Refer to the package inserts for lithium preparations before use of such preparations.
Nonsteroidal Anti-Inflammatory Drugs Including Cyclooxygenase-2 Inhibitors: In some patients, the administration of a nonsteroidal anti-inflammatory agent including a selective cyclooxygenase-2 inhibitor can reduce the diuretic, natriuretic and antihypertensive effects of diuretics.
Drug/Laboratory Test Interactions: Because of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function (see Precautions).
Storage
Store below 30°C. Protect from light.
ATC Classification
C09DA01 - losartan and diuretics ; Belongs to the class of angiotensin II receptor blockers (ARBs) in combination with diuretics. Used in the treatment of cardiovascular disease.
Presentation/Packing
Tab 50/12.5 mg (yellow, oval-shaped, film-coated, plain on one side, the other side imprinted '717') x 30's. 100/12.5 mg (white to off-white, oval-shaped, film-coated, with '745' debossed on one side and plain on the other side) x 30's.
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