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Fetal Toxicity: HYZAAR, HYZAAR PLUS, or HYZAAR FORTE can cause fetal harm when administered to a pregnant woman. 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 HYZAAR, HYZAAR PLUS, or HYZAAR FORTE as soon as possible.
Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice, thrombocytopenia [see Pregnancy under Use in Pregnancy & Lactation].
Hypotension in Volume- or Salt-Depleted Patients: In patients with an activated 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 HYZAAR, HYZAAR PLUS, or HYZAAR FORTE. Correct volume or salt depletion prior to administration of HYZAAR, HYZAAR PLUS, or HYZAAR FORTE. Do not use HYZAAR, HYZAAR PLUS, or HYZAAR FORTE as initial therapy in patients with intravascular volume depletion.
Impaired Renal Function: Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin 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 HYZAAR, HYZAAR PLUS, or HYZAAR FORTE. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on HYZAAR, HYZAAR PLUS, or HYZAAR FORTE [see Renal Impairment as follows and Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS) under Interactions].
Hypersensitivity: Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history [see Postmarketing Experience under Adverse Reactions].
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.
HYZAAR, HYZAAR PLUS, and HYZAAR FORTE contain hydrochlorothiazide which can cause hypokalemia, hyponatremia and hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. HYZAAR, HYZAAR PLUS, and HYZAAR FORTE also contain losartan which can cause hyperkalemia. Monitor serum electrolytes periodically [see Agents Increasing Serum Potassium under Interactions].
Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia [see Agents Increasing Serum Potassium under Interactions].
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.
Choroidal Effusion, Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion, 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.
Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Race: In the Losartan Intervention 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 [see Pharmacology: Pharmacokinetics under Actions].
Hepatic Impairment: Initiation of HYZAAR, HYZAAR PLUS, or HYZAAR FORTE is not recommended for patients with hepatic impairment because the appropriate starting dose of losartan, 25 mg, is not available.
Renal Impairment: Changes in renal function have been reported in susceptible individuals [see Impaired Renal Function as previously mentioned, Hypertension under Dosage & Administration, and Pharmacology: Pharmacokinetics under Actions]. Safety and effectiveness of HYZAAR, HYZAAR PLUS, and HYZAAR FORTE in patients with severe renal impairment (creatinine clearance <30 mL/min) have not been established.
Use in Children: Safety and effectiveness of HYZAAR, HYZAAR PLUS, and HYZAAR FORTE in pediatric patients have not been established.
Neonates with a history of in utero exposure to HYZAAR, HYZAAR PLUS, or HYZAAR FORTE: 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.
Use in the Elderly: In a 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 [see Pharmacology: Pharmacokinetics under Actions].
