Hyzaar

Diuretic potentiation of orthostatic hypotension may occur.

Rifampin, an inducer of drug metabolism, decreases the concentrations of the active metabolite of losartan. In humans, two inhibitors of P450 3A4 have been studied. Ketoconazole did not affect the conversion of losartan to the active metabolite after intravenous administration of losartan, and erythromycin had no clinically significant effect after oral losartan administration. Fluconazole, an inhibitor of P450 2C9, decreased active metabolite concentration. The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined.

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. 0.72-0.88), while AUC of the active metabolite, E-3174, was 0.80 (90% C.I. 0.78-0.82).

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. 1.10-1.27), while AUC of the active metabolite, E-3174, was 1.00 (90% C.I. 0.92-1.08).

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.

Concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in 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.

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 C_max ratios, relative to placebo, were found to be 1.06 (90% C.I. 0.98-1.14) and 1.12 (90% C.I. 0.97-1.28), 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.

In some patients, the administration of a non-steroidal anti-inflammatory agent including a selective cyclooxygenase-2 inhibitor can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when HYZAAR and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Non-steroidal anti-inflammatory drugs (NSAIDs) including indomethacin and 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 non-steroidal 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.

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.

Intensified electrolyte depletion, particularly hypokalemia, may occur when given concomitantly with diuretics.

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.

In the presence of diuretics possible decreased response to pressor amines may be seen but not sufficient to preclude their use.

Thiazide drugs may increase the responsiveness to tubocurarine.

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 potassium. The possibility of symptomatic hypotension with losartan potassium can be minimized by discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with losartan potassium (see Warnings and precautions, Cardiovascular,Hypotension and Dosage and Administration).

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.

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 Warnings and Precautions, Geriatrics (>65 years of age)).

The usual starting dose of losartan monotherapy is 50 mg once daily.

Dosage should be adjusted according to blood pressure response. The maximal antihypertensive effect is attained 3-6 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 and Precautions, Hypotension and Drug Interactions).

The starting dose of HYZAAR for initial treatment of severe hypertension is one tablet of HYZAAR 50 mg/12.5 mg once daily. For patients who do not respond adequately to HYZAAR 50 mg/12.5 mg after 2 to 4 weeks of therapy, the dosage may be increased to one tablet of HYZAAR DS 100 mg/25 mg once daily. The maximum dose is one tablet of HYZAAR DS 100 mg/25 mg once daily.

HYZAAR may be administered with or without food, however it should be taken consistently with respect to food intake.

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.

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 two to three days prior to the administration of losartan, to reduce the likelihood of hypotension (see Warnings and Precautions, Hypotension and Drug Interactions, Diuretics). 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.

If a dose is missed, an extra dose should not be taken. The usual schedule should be resumed.

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 Warnings and Precautions, Patients with Liver Impairment).

Once the patient has been stabilized on the individual components as described below, either one tablet HYZAAR 50 mg/12.5 mg or 100 mg/12.5 mg, or one tablet HYZAAR DS 100 mg/25 mg once daily may be substituted if the doses on which the patient was stabilized are the same as those in the fixed combination. The maximum dose is one tablet HYZAAR DS 100 mg/25 mg once daily (see Indications and Clinical Use).

Dosage must be individualized.

The following additional adverse reactions have been reported in post-marketing experience:

Thrombocytopenia and Adult Respiratory Distress Syndrome have been reported rarely in post-marketing experience.

The adverse experience profile for patients with severe hypertension (SiDBP ≥110 mmHg) treated with losartan/hydrochlorothiazide as initial therapy was similar to the adverse experience profile in patients treated with losartan monotherapy at the time of first dose, at 4 weeks of therapy, and at 6 weeks of therapy. Additionally, the adverse experience rates for hypotension, syncope, dizziness, and increased serum creatinine (all of which are signs and symptoms of hypoperfusion) did not differ between the treatment groups.

Angioedema (involving swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, and/or tongue and pharynx, requiring therapeutic intervention in some cases) has been reported rarely in patients treated with losartan. Some patients previously experienced angioedema with ACE inhibitors. Vasculitis, including Henoch-Schoenlein purpura, has been reported rarely.

Other adverse reactions reported rarely with losartan potassium alone in open-label studies or post-marketing use, regardless of drug relationship, include anemia, hepatitis, liver function tests abnormalities, drug induced cough, asthenia, diarrhea, migraine, arthralgia, pruritus, dysgeusia, taste disorder, urticaria, erythroderma, vomiting, malaise and erectile dysfunction/impotence. Photosensitivity has been reported with both losartan potassium- and hydrochlorothiazide. Cases of muscle pain, muscle weakness, myositis and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Minor increases in blood urea nitrogen (1.0%) and serum creatinine (1.0%) 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 Warnings and Precautions).

Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.1 percent of patients with essential hypertension treated with losartan potassium alone. In clinical studies, no patient discontinued taking losartan potassium 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.

In these controlled clinical trials for essential hypertension, 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 potassium-hydrochlorothiazide-treated (3.3%) than placebo-treated (2.1%) patients.

HYZAAR has been evaluated for safety in 2498 patients treated for essential hypertension. Of these, 1088 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 with losartan potassium 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.

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.

Rarely, elevations of liver enzymes and/or serum bilirubin have occurred.

No data are available.

No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see Dosage and Administration).

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.

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.

Each light yellow, oval shaped, film-coated tablet, with code 747 on one side and plain on the other, contains: losartan potassium 100 mg and hydrochlorothiazide 25 mg. Nonmedicinal ingredients: hydroxypropylcellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch and titanium dioxide. May contain carnauba wax and quinoline yellow aluminum lake. Potassium as losartan potassium: 8.48 mg (<1 mmol). Push-through blister packages of 30. Bottles of 100.

Each white to off-white, oval shaped, film-coated tablet, with code 745 on one side and plain on the other, contains: losartan potassium 100 mg and hydrochlorothiazide 12.5 mg. Nonmedicinal ingredients: hydroxypropylcellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch and titanium dioxide. May contain carnauba wax. Potassium as losartan potassium: 8.48 mg (<1 mmol). Push-through blister packages of 30. Bottles of 100.

Each yellow, oval shaped, film-coated tablet, marked with code 717 on one side and plain on the other, contains: losartan potassium 50 mg and hydrochlorothiazide 12.5 mg. Nonmedicinal ingredients: hydroxypropylcellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch and titanium dioxide. May contain carnauba wax and quinoline yellow aluminum lake. Potassium as losartan potassium: 4.24 mg (<1 mmol). Push-through blister packages of 30. Bottles of 100.

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.

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.

Drugs that act directly on the renin-angiotensin-aldosterone-system (RAAS) 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 ARB is not recommended during pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to angiotensin converting enzyme inhibitors (another class of therapeutic products interfering with the RAAS) during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Given the current evidence available on the risk with ARB, similar risks may exist for this class of drugs. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

The use of ARBs during the second and third trimesters is known to induce human fetotoxicity (decreased renal function; oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

Infants with a history of in utero exposure to ARB 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 or dialysis may be required as means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit. 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.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal functions have been reported 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 ≤30 mL/min).

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.

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.

Losartan potassium 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.

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.

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.

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan and its active metabolite in cirrhotic patients after administration of COZAAR (losartan potassium), a lower dose should be considered for patients with hepatic impairment, or a history of hepatic impairment (see Dosage and Administration).

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.

HYZAAR has not been studied in children, therefore use in this age group is not recommended.

It is not known whether losartan or its active metabolite are excreted in human milk, but significant levels of both of these compounds have been found in the milk of lactating rats. Thiazides appear in human milk. Because many drugs are excreted in human milk and because of their potential for affecting the nursing infant adversely, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

HYZAAR combines the actions of losartan potassium, an angiotensin II receptor antagonist, and that of a thiazide diuretic, 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 one 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.

Hydrochlorothiazide is eliminated rapidly by the kidney. The plasma half-life is 5.6-14.8 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.

The terminal half-life of losartan itself is about 2 hours, and that of the active metabolite, about 6-9 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.

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 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.