Losartan Potassium – Hydrochlorothiazide
Angiotensin II Receptor Antagonist – Diuretic
Action And Clinical Pharmacology: Hyzaar combines the actions of losartan potassium, an angiotensin II receptor antagonist, and that of a thiazide diuretic, hydrochlorothiazide.
Losartan: Losartan antagonizes angiotensin II by blocking the angiotensin type 1 (AT1) receptor.
Angiotensin II is the primary vasoactive hormone of the renin-angiotensin system. Its effects include vasoconstriction and the stimulation of aldosterone secretion by the adrenal cortex.
Losartan, and its active metabolite, E-3174, block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to AT1 receptors found in many tissues, including vascular smooth muscle. A second type of angiotensin II receptor has been identified as the AT2 receptor, but it plays no known role in cardiovascular homeostasis to date. Both losartan and its active metabolite do not exhibit any agonist activity at the AT1 receptor, and have much greater affinity, in the order of 1 000-fold, for the AT1 receptor than for the AT2 receptor. In vitro binding studies indicate that losartan itself is a reversible, competitive antagonist at the AT1 receptor, while the active metabolite is 10 to 40 times more potent than losartan, and is a reversible, non-competitive antagonist of the AT1 receptor.
Neither losartan nor its active metabolite inhibits angiotensin converting enzyme (ACE), also known as 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 diuretic and antihypertensive which interferes with the renal tubular mechanism of electrolyte reabsorption. It increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. While this compound is predominantly a saluretic agent, in vitro studies have shown that it has a carbonic anhydrase inhibitory action which seems to be relatively specific for the renal tubular mechanism. It does not appear to be concentrated in erythrocytes or the brain in sufficient amounts to influence the activity of carbonic anhydrase in those tissues.
Hydrochlorothiazide is useful in the treatment of hypertension. It may be used alone or as an adjunct to other antihypertensive drugs. Hydrochlorothiazide does not affect normal blood pressure.
Pharmacokinetics: Losartan: 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, E-3174, that is responsible for most of the angiotensin II receptor antagonism that follows oral losartan administration.
The terminal half-life of losartan itself is about 2 hours, and that of the active metabolite, about 6 to 9 hours. The pharmacokinetics of losartan and this metabolite are linear with oral losartan doses up to 200 mg and do not change over time. Neither losartan nor its metabolite accumulate in plasma upon repeated once-daily administration.
Following oral administration, losartan is well absorbed, with systemic bioavailability of losartan approximately 33%. About 14% of an orally-administered dose of losartan is converted to the active metabolite, although about 1% of subjects did not convert losartan efficiently to the active metabolite.
Mean peak concentrations of losartan occur at about 1 hour, and that of its active metabolite at about 3 to 4 hours. Although maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times greater than that of losartan.
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.
Various losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, E-3174, several inactive metabolites are formed. In vitro studies indicate that the cytochrome P450 isoenzymes 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites.
The volume of distribution of losartan is about 34 L, and that of the active metabolite is about 12 L.
Total plasma clearance of losartan is about 600 mL/min, with about 75 mL/min accounted for by renal clearance. Total plasma clearance of the active metabolite is about 50 mL/min, with about 25 mL/min accounted for by renal clearance. Both biliary and urinary excretion contribute substantially to the elimination of losartan and its metabolites.
Following oral 4-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an i.v. dose of 4-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. The plasma half-life is 5.6 to 14.8 hours when the plasma levels can be followed for at least 24 hours. At least 61% 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.
Pharmacodynamics: Losartan: Losartan inhibits the pressor effect of angiotensin II. A dose of 100 mg inhibits this 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 2- to 3- fold rise in plasma renin activity, and a consequent rise in angiotensin II plasma concentration, in hypertensive patients.
Maximum blood pressure lowering, following oral administration of a single dose of losartan, as seen in hypertensive patients, occurs at about 6 hours.
In losartan-treated patients during controlled trials, there was no meaningful change in heart rate.
There is no apparent rebound effect after abrupt withdrawal of losartan therapy.
Black hypertensive patients show a smaller average blood pressure response to losartan monotherapy than other hypertensive patients.
Hydrochlorothiazide: Onset of the diuretic action following oral administration occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6 to 12 hours.
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.
The antihypertensive effect of Hyzaar is sustained for a 24-hour period. In clinical studies of at least 1 year’s duration, the antihypertensive effect was maintained with continued therapy. Despite the significant decrease in blood pressure, administration of Hyzaar had no clinically significant effect on heart rate.
Indications And Clinical Uses: For the treatment of essential hypertension in patients for whom combination therapy is appropriate.
Hyzaar is not indicated for initial therapy (see Dosage).
Losartan should normally be used in those patients in whom treatment with diuretic or beta-blocker was found ineffective or has been associated with unacceptable adverse effects.
Contra-Indications: In patients who are hypersensitive to any component of this product. Because of the hydrochlorothiazide component, it is also contraindicated in patients with anuria, and in patients who are hypersensitive to other sulfonamide-derived drugs.
Manufacturers’ Warnings In Clinical States: Pregnancy: Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, Hyzaar should be discontinued as soon as possible.
The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.
Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of losartan potassium as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is observed, losartan should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion may be required as means of reversing hypotension and/or substituting for impaired renal function. Neither losartan nor the active metabolite can be removed by hemodialysis.
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 experiences 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.
Animal Data: Losartan has been shown to produce adverse effects in rat fetuses and neonates, which include decreased body weight, mortality and/or renal toxicity. Significant levels of losartan and its active metabolite were shown to be present in rat milk. Based on pharmacokinetic assessments, these findings are attributed to drug exposure in late gestation and during lactation.
Hypotension: Occasionally, symptomatic hypotension has occurred after administration of losartan, in some cases after the first dose. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In these patients, because of the potential fall in blood pressure, therapy should be started under close medical supervision. Similar considerations apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.
Azotemia: Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease the diuretic should be discontinued.
Hypersensitivity Reactions: Sensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported in patients treated with hydrochlorothiazide.
Precautions: Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal functions have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.
Use of losartan should include appropriate assessment of renal function.
Thiazides should be used with caution.
Because of the hydrochlorothiazide component, Hyzaar is not recommended in patients with severe renal impairment (creatinine clearance Â£30 mL/min).
Patients with Liver Impairment: Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan and its active metabolite in cirrhotic patients after administration of Cozaar, a lower dose should be considered for patients with hepatic impairment, or a history of hepatic impairment (see Dosage).
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Metabolism: Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazide therapy.
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Thiazides have been shown to increase excretion of magnesium; this may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Increases in cholesterol, triglyceride and glucose levels may be associated with thiazide diuretic therapy.
Valvular Stenosis: There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.
Lactation: It is not known whether losartan or its active metabolite are excreted in human milk, however significant levels of both of these compounds have been shown to be present in the milk of lactating rats. Thiazides appear in human milk. A decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Children: Hyzaar has not been studied in children, therefore use in this age group is not recommended.
Geriatrics: No overall differences in safety were observed between elderly patients and younger patients, but appropriate caution should nevertheless be used when prescribing to the elderly, as increased vulnerability to drug effect is possible in this patient population.
Drug Interactions: Diuretics: Patients on diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with losartan. The possibility of symptomatic hypotension with losartan can be minimized by discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with losartan potassium (see Warnings, Hypotension and Dosage).
Agents Increasing Serum Potassium: Since losartan decreases the production of aldosterone, potassium-sparing diuretics or potassium supplements should be given only for documented hypokalemia and with frequent monitoring of serum potassium when losartan therapy is instituted. Potassium-containing salt substitutes should also be used with caution. Concomitant thiazide diuretic use may attenuate any effect that losartan may have on serum potassium.
Lithium Salts: As with other drugs which eliminate sodium, lithium clearance may be reduced in the presence of losartan. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be administered with losartan.
Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.
Digitalis: In 9 healthy volunteers, when a single oral dose of 0.5 mg digoxin was administered to patients receiving losartan for 11 days, digoxin AUC and digoxin Cmax ratios, relative to placebo, were found to be 1.06 (90% C.I. 0.98 to 1.14) and 1.12 (90% C.I. 0.97 to 1.28), respectively. The effect of losartan on steady-state pharmacokinetics of cardiac glycosides is not known.
Thiazide-induced electrolyte disturbances may predispose to digitalis-induced arrhythmias.
Warfarin: Losartan administered for 7 days did not affect the pharmacokinetics or pharmacodynamic activity of a single dose of warfarin. The effect of losartan on steady-state pharmacokinetics of warfarin is not known.
Drugs Affecting Cytochrome P450 System: When losartan was administered to 10 healthy male volunteers as a single dose in steady-state conditions of phenobarbital, a cytochrome P450 inducer, losartan AUC, relative to baseline, was 0.80 (90% C.I. 0.72 to 0.88), while AUC of the active metabolite, E-3174, was 0.80 (90% C.I. 0.78 to 0.82).
When losartan was administered to 8 healthy male volunteers as a single dose in steady-state conditions of cimetidine, a cytochrome P450 inhibitor, losartan AUC, relative to baseline, was 1.18 (90% C.I. 1.10 to 1.27), while AUC of the active metabolite, E-3174, was 1.00 (90% C.I. 0.92 to 1.08).
d-Tubocurarine: Thiazide drugs may increase the responsiveness to tubocurarine.
Insulin: Insulin requirements in diabetic patients treated with diuretics may be increased, decreased or unchanged. Diabetes mellitus which has been latent may become manifest during thiazide administration.
Alcohol, Barbiturates or Narcotics: Diuretic potentiation of orthostatic hypotension may occur.
Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur when given concomitantly with diuretics.
Pressor Amines (e.g., norepinephrine): In the presence of diuretics possible decreased response to pressor amines may be seen but not sufficient to preclude their use.
NSAIDs: In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Hyzaar and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
Adverse Reactions: Hyzaar has been evaluated for safety in 2 498 patients treated for essential hypertension. Of these, 1 088 were treated with Hyzaar monotherapy in controlled clinical trials. In open studies, 926 patients were treated with Hyzaar for a year or more.
The following potentially serious adverse reactions have been reported rarely with Hyzaar in controlled clinical trials: syncope, hypotension.
In controlled clinical trials, discontinuations of therapy due to clinical adverse experiences occurred in 2.4 and 2.1% of patients treated with Hyzaar and placebo, respectively.
In double-blind controlled clinical trials, the following adverse experiences were reported with losartan – hydrochlorothiazide in Â³1% of patients, regardless of drug relationship (see Table I).
In these controlled clinical trials, dizziness was the only adverse experience, occurring in more than 1% of cases, that was reported as drug-related, and that occurred at a greater incidence in losartan – hydrochlorothiazide-treated (3.3%) than placebo-treated (2.1%) patients.
Thrombocytopenia and Adult Respiratory Distress Syndrome have been reported rarely in postmarketing experience.
In double-blind, controlled clinical trials with losartan alone, the following adverse experiences were reported at an occurrence rate of less than 1%, regardless of drug relationship: orthostatic effects, somnolence, vertigo, epistaxis, tinnitus, constipation, malaise, rash.
Other adverse experiences reported with losartan alone in open-label studies or postmarketing use, regardless of drug relationship, include diarrhea, migraine, myalgia, pruritus, taste disorder and urticaria.
Angioedema (involving swelling of the face, lips, and/or tongue), has been reported rarely in postmarketing experience with losartan.
Laboratory Test Findings: Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred.
Hyperkalemia: In controlled hypertensive trials with losartan monotherapy and Hyzaar, a serum potassium >5.5 mEq/L occurred in 1.5 and 0.7% of patients, respectively. However, no patient discontinued losartan or Hyzaar therapy due to hyperkalemia.
Serum Creatinine, Blood Urea Nitrogen (BUN): Minor increases in blood urea nitrogen (1%) and serum creatinine (1%) were observed in patients with essential hypertension treated with Hyzaar. More marked increases have also been reported and were more likely to occur in patients with bilateral renal artery stenosis (see Precautions).
Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.1% of patients with essential hypertension treated with losartan alone. In clinical studies, no patient discontinued taking losartan alone due to increased BUN or serum creatinine.
No other adverse experiences have been reported with Hyzaar which have not been reported with losartan or hydrochlorothiazide individually.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: No specific information is available on the treatment of overdosage with Hyzaar. Treatment is symptomatic and supportive.
Losartan: Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia. If symptomatic hypotension should occur, supportive treatment should be instituted.
Neither losartan nor its 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.
Dosage And Administration: Dosage must be individualized. The fixed combination is not for initial therapy. The dose should be determined by the titration of the individual components.
Once the patient has been stabilized on the individual components as described below, either one 50/12.5 mg tablet or 2 tablets once daily may be substituted if the doses on which the patient was stabilized are the same as those in the fixed combination (see Indications).
Hyzaar may be administered with or without food, however it should be taken consistently with respect to food intake.
Losartan Monotherapy: The usual starting dose of monotherapy is 50 mg once daily.
Dosage should be adjusted according to blood pressure response. The maximal antihypertensive effect is attained 3 to 6 weeks after initiation of therapy.
The usual dose range for losartan is 50 to 100 mg once daily. A dose of 100 mg daily should not be exceeded, as no additional antihypertensive effect is obtained with higher doses.
In most patients taking losartan 50 mg once daily, the antihypertensive effect is maintained. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. This can be evaluated by measuring the blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either twice daily administration with the same total daily dosage, or an increase in the dose should be considered. If blood pressure is not adequately controlled with losartan alone, a non-potassium-sparing diuretic may be administered concomitantly.
For patients with volume-depletion, a starting dose of 25 mg once daily should be considered (see Warnings, Hypotension and Precautions, Drug Interactions).
Diuretic Treated Patients: In patients receiving diuretics, losartan therapy should be initiated with caution, since these patients may be volume-depleted and thus more likely to experience hypotension following initiation of additional antihypertensive therapy. Whenever possible, all diuretics should be discontinued 2 to 3 days prior to the administration of losartan, to reduce the likelihood of hypotension (see Warnings, Hypotension and Precautions, Drug Interactions). If this is not possible because of the patient’s condition, losartan should be administered with caution and the blood pressure monitored closely. Thereafter, the dosage should be adjusted according to the individual response of the patient.
Dosage Adjustment in Renal Impairment: No initial dosage adjustment in losartan is usually necessary for patients with renal impairment, including those requiring hemodialysis. However, appropriate monitoring of these patients is recommended.
The usual regimens of therapy with Hyzaar may be followed as long as the patient’s creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so Hyzaar is not recommended.
Patients with Liver Impairment: Since dosage adjustment of losartan is required in patients with liver impairment, and thiazide diuretics may precipitate hepatic coma, a fixed combination product such as Hyzaar is not advisable (see Precautions, Patients with Liver Impairment).
Geriatrics: No initial dosage adjustment is necessary for most elderly patients. Appropriate caution should nevertheless be used when prescribing to the elderly, as increased vulnerability to drug effect is possible in this patient population (see Precautions, Geriatrics).
Availability And Storage: Each yellow, teardrop-shaped, film-coated tablet, marked with code MRK 717 on one side and HYZAAR on the other, contains: losartan potassium 50 mg and hydrochlorothiazide 12.5 mg. Nonmedicinal ingredients: D&C yellow No. 10 aluminum lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose hydrous, magnesium stearate, microcrystalline cellulose, pregelatinized starch and titanium dioxide. Potassium:
HYZAAR® MSD Losartan Potassium – Hydrochlorothiazide Angiotensin II Receptor Antagonist – Diuretic