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Mechanism of Action
US Drug Names
NOTE: Hyzaar is available as losartan 50 mg/hydrochlorothiazide 12.5 mg, losartan 100 mg/hydrochlorothiazide 12.5 mg, losartan 100 mg/hydrochlorothiazide 25 mg dosage strengths, respectively. Individualize dosage by titration of the separate components. If the optimal dose corresponds to the ratio contained in the combination formulation, Hyzaar can be substituted.
Patients whose blood pressure is not adequately controlled with losartan or hydrochlorothiazide (HCTZ) monotherapy may be switched to losartan 50 mg/hydrochlorothiazide 12.5 mg PO once daily. Hyzaar is not intended as first-line therapy, except when the hypertension is severe enough that the value of achieving prompt blood pressure control exceeds the risk of initiating combination therapy. The dosage for Hyzaar is best determined by individual titration with the separate components. Adjust dosage based on clinical response after 3 weeks or more. Dosage may be increased to 2 tablets of losartan 50 mg/hydrochlorothiazide 12.5 mg once daily or 1 tablet of losartan 100 mg/hydrochlorothiazide 25 PO once daily. The maximum dosage is 100 mg/day of losartan combined with 25 mg/day of hydrochlorothiazide. The usual starting dose of losartan monotherapy is 50 mg PO once daily, with 25 mg PO recommended for patients with intravascular volume depletion (e.g., patients treated with diuretics) or a history of hepatic impairment. The addition of a diuretic has a greater effect on lowering blood pressure than increasing the losartan dosage beyond 50 mg/day. The addition of hydrochlorothiazide 12.5 mg to losartan 50 mg once daily results in an additional 50% reduction in DBP and SBP.
See adult dosage. Greater sensitivity in some older individuals is possible. Adjust dosage based on clinical response.
Hyzaar is not intended as first-line therapy, except when the hypertension is severe enough that the value of achieving prompt blood pressure control exceeds the risk of initiating combination therapy. Initiate therapy with losartan 50 mg/hydrochlorothiazide 12.5 mg PO once daily. Adjust dosage based on clinical response after 2 to 4 weeks. Dosage may be increased to 1 tablet of losartan 100 mg/hydrochlorothiazide 25 PO once daily. The maximum dosage is 100 mg/day of losartan combined with 25 mg/day of hydrochlorothiazide.
NOTE: There is evidence that this benefit does not apply to Black patients.
Initially, 50 mg PO losartan once daily. Maximal antihypertensive effects generally occur within 3 to 6 weeks. If needed for blood pressure (BP) reduction, add hydrochlorothiazide (HCTZ) 12.5 mg PO once daily. If additional blood pressure reduction is needed, increase the losartan dose to 100 mg, or losartan 100mg/hydrochlorothiazide 12.5 mg PO once daily may be substituted. The maximum daily dosage is losartan 100 mg and hydrochlorothiazide 25 mg. This FDA-approved indication is based on the findings of the LIFE trial which compared losartan versus atenolol in patients with hypertension and LVH. In this trial, losartan reduced the risk of stroke (nonfatal and fatal) by 25% compared to atenolol. The overall findings demonstrate that losartan is more effective than atenolol in reducing total mortality and cardiovascular morbidity and mortality, and is associated with less drug-related adverse events. In a pre-specified subanalysis of the LIFE study in diabetic hypertensives with LVH, similar findings are reported.
100 mg/day PO losartan and 25 mg/day PO hydrochlorothiazide.
Safety and efficacy have not been established.
The fixed combination product, Hyzaar, is not recommended for initial titration in patients with hepatic impairment since the appropriate 25 mg starting dose of losartan cannot be administered. See Losartan monograph for dosing in patients with hepatic impairment. Hydrochlorothiazide should be used with caution in patients with hepatic disease since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
CrCl more than 30 mL/min: No dosage adjustment is necessary.
CrCl is 30 mL/min or less: Combination therapy with losartan and hydrochlorothiazide is not recommended. Thiazide diuretics are not effective in this setting.
Combination therapy with hydrochlorothiazide is not recommended in patients with CrCl is 30 mL/min or less. Thiazide diuretics are generally not effective in this setting.
Losartan and hydrochlorothiazide (HCTZ) are used together in a once daily oral preparation to manage hypertension. Hydrochlorothiazide is a thiazide diuretic. Losartan and its metabolite (E-3174) are specific and selective angiotensin II antagonists. Because AT1 receptors are nearly saturated at the starting dose for most angiotensin II antagonists, the antihypertensive dose-response curve of these drugs are nonlinear, with proportionally small decreases in blood pressure attained with increased dosage. Greater antihypertensive efficacy is achieved by adding a small dose of a diuretic to the angiotensin II antagonist. Losartan is associated with dose-related antiproteinuric and uricosuric effects. Losartan tends to reverse the potassium loss and blunts the rise in serum uric acid levels associated with hydrochlorothiazide. Because losartan does not inhibit angiotensin converting enzyme (ACE), it does not result in bradykinin accumulation which is theorized to cause the cough and angioedema associated with ACE inhibitors. However, angioedema has been rarely associated with losartan or other angiotensin II antagonists. Hyzaar (50 mg losartan and 12.5 mg hydrochlorothiazide) was originally approved on April 28, 1995; the subsequent dosage strength (100 mg losartan and 25 mg hydrochlorothiazide) was approved on October 13, 1998.
For storage information, see the specific product information within the How Supplied section.
Cough was reported in 2.6% of losartan; hydrochlorothiazide-treated patients compared to 2.3% of placebo-treated patients in controlled clinical trials. The incidence of cough appears to be lower with losartan than with an angiotensin converting enzyme inhibitor (ACEI); losartan does not inhibit angiotensin converting enzyme (kinase II), which is thought to be responsible for the ACEI-induced cough. In comparative studies, the incidence of cough in losartan-treated patients with a prior history of ACEI-induced cough was 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.
Dizziness was reported in 5.7% of losartan; hydrochlorothiazide-treated patients in clinical trials compared to 2.9% of placebo-treated patients. Asthenia/fatigue and headache were also reported in 1% or more of losartan; hydrochlorothiazide-treated patients, but were as or more common in the placebo group. Nervous system/psychiatric events reported in patients treated with losartan monotherapy without regard to causality include: anxiety, ataxia, confusion, depression, dream abnormality, hypoesthesia, insomnia, libido decrease, memory impairment, migraine, nervousness, panic disorder, paresthesias, peripheral neuropathy, sleep disorder, drowsiness, tremor, and vertigo. Restlessness and weakness have been reported during hydrochlorothiazide monotherapy.
Impotence (erectile dysfunction) has been reported in patients taking losartan monotherapy and is possible in patients taking losartan; hydrochlorothiazide.
Adverse reactions reported in losartan; hydrochlorothiazide-treated patients in clinical trials and more frequently than placebo include: edema/swelling (1.3% vs. 1.2%) and palpitations (1.4% vs. 0%). Patients treated with diuretics may become intravascularly volume-depleted (hypovolemia), and symptomatic hypotension may occur after initiation of therapy with losartan; hydrochlorothiazide. Chest pain (unspecified), orthostatic effects (e.g., orthostatic hypotension), syncope, angina pectoris, arrhythmia exacerbation (including atrial fibrillation, sinus bradycardia, sinus tachycardia, ventricular tachycardia and ventricular fibrillation), CVA (stroke), myocardial infarction, and second degree AV block have been reported with losartan.
Anaphylactic reactions (anaphylactoid reactions) and angioedema have been reported rarely with losartan and may occur during therapy with losartan; hydrochlorothiazide. Theoretically, angiotensin II receptor antagonists (ARBs) should be less likely than angiotensin converting enzyme inhibitors (ACEIs) to precipitate angioedema because ARBs do not cause accumulation of kinins. However, angioedema (swelling of lips and eyelids, facial rash) has been reported in patients receiving ARBs, including in patients with a prior history of angioedema during ACE inhibitor therapy (see Contraindications). Some of these patients previously experienced angioedema with other drugs including ACEIs. One patient receiving losartan also had a history of aspirin and penicillin allergies. Facial edema has also been reported with losartan.
Hypersensitivity reactions may occur during therapy with losartan; hydrochlorothiazide. Vasculitis, including Henoch-Schoenlein purpura, has been reported with losartan. Necrotizing angiitis (vasculitis and cutaneous vasculitis) has been reported with hydrochlorothiazide.
Clinically significant laboratory abnormalities are rarely reported with losartan. Small decreases in hemoglobin (0.14 grams percent) and hematocrit (0.72 volume percent) occurred frequently during losartan; hydrochlorothiazide therapy; no patient discontinued due to anemia. However, anemia has been reported with losartan monotherapy. Elevated hepatic enzymes and elevated bilirubin concentrations (hyperbilirubinemia) have been reported occasionally during antihypertensive therapy with losartan; hydrochlorothiazide; without requiring discontinuation from therapy. Hepatitis is rarely reported with losartan. Thiazide diuretics have been associated with intrahepatic cholestatic jaundice.
Rash (unspecified) was reported in 1.4% of losartan; hydrochlorothiazide-treated patients compared to 0% of placebo-treated patients in clinical trials. Superficial peeling of the palms with hemolysis has been reported in one patient receiving losartan monotherapy. Erythroderma (exfoliative dermatitis) has been reported during losartan postmarketing experience. Alopecia, dermatitis, dry skin (xerosis), ecchymosis, erythema, flushing, photosensitivity, pruritus, diaphoresis, and urticaria have also been reported in patients treated with losartan. Adverse dermatologic reactions to hydrochlorothiazide and other thiazide diuretics are uncommon but may occur. These reactions include photosensitivity, urticaria, erythema multiforme including Stevens-Johnson syndrome, and exfoliative dermatitis including toxic epidermal necrolysis (TEN)..
Hydrochlorothiazide has been associated with hyperglycemia and glycosuria without regard to causality. Diabetic patients receiving losartan; hydrochlorothiazide may require dosage adjustment of insulin or oral hypoglycemic agents.
While serious hematological reactions are rare; aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia have been reported with hydrochlorothiazide therapy. Thrombocytopenia has also been reported during postmarketing experience with losartan; hydrochlorothiazide.
Hyperuricemia may occur in patients receiving thiazide diuretics. In predisposed individuals, frank gout or nephrolithiasis may be precipitated. Diuretic-induced acute gouty arthritis and nephrolithiasis are extremely rare in patients with no prior history of gout. Losartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia. Although gout has been reported in losartan-treated patients, in a single dose study of losartan, there was a small uricosuric effect leading to a mean decrease in serum uric acid of less than 0.4 mg/dL during chronic oral administration. If some manifestation of gout occurs in a patient who requires diuretic therapy for effective treatment of hypertension, allopurinol or a uricosuric agent can be given to prevent recurrent gouty attacks without diminishing the antihypertensive effect of losartan; hydrochlorothiazide.
Thiazide diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Thiazides may also decrease urinary calcium excretion and may cause intermittent and slight elevations of serum calcium in the absence of known disorders of calcium metabolism. The development of marked hypercalcemia may be evidence of hidden hyperparathyroidism. If hypercalcemia occurs, losartan; hydrochlorothiazide should be discontinued before carrying out tests for parathyroid function.
Although hypercholesterolemia and/or hypertriglyceridemia have been associated with thiazide diuretic therapy, data from long-term studies suggest that diuretic-induced lipid abnormalities are not clinically significant. After approximately one year of treatment, total serum cholesterol concentrations will subside to baseline or lower, suggesting that diuretic therapy does not increase coronary heart disease risk. Nevertheless, it would be prudent to monitor serum cholesterol and triglyceride concentrations periodically in hypertensive patients receiving losartan; hydrochlorothiazide.
Abdominal pain was reported in 1.2% of losartan; hydrochlorothiazide-treated patients vs. 0.6% of placebo-treated patients in clinical trials. Diarrhea and nausea were also reported in 1% or more of losartan; hydrochlorothiazide-treated patients, but were as, or more common in the placebo group. Anorexia, constipation, dental pain, xerostomia, dyspepsia, flatulence, gastritis, and vomiting have been reported with losartan. Sialadenitis, cramping, and gastric irritation have been reported with hydrochlorothiazide.
Back pain was reported in 2.1% of losartan; hydrochlorothiazide-treated patients in clinical trials compared to 0.6% of placebo-treated patients. Muscle spasm has been reported with hydrochlorothiazide. Arm pain, arthralgia, arthritis, fibromyalgia, hip pain, joint swelling, knee pain, leg pain, muscle cramps, myasthenia (muscle weakness), musculoskeletal pain, myalgia, shoulder pain, and stiffness have been reported with losartan. Rare cases of rhabdomyolysis have been reported during postmarketing experience with angiotensin II receptor antagonists.
Dysgeusia has been reported in patients taking losartan; hydrochlorothiazide therapy.
Respiratory-related adverse events that occurred more frequently in losartan; hydrochlorothiazide-treated patients in clinical trials than in placebo-treated patients include: sinusitis (1.2% vs. 0.6%) and upper respiratory infection (6.1% vs. 4.6%). Bronchitis and pharyngitis were reported in 1% or more of losartan; hydrochlorothiazide-treated patients but were as, or more, common in the placebo group. Fever, malaise, dyspnea, epistaxis, nasal congestion, pharyngeal discomfort, respiratory congestion, rhinitis, and sinus disorder have been reported with losartan. Fever and respiratory distress including pneumonitis and pulmonary edema have been reported with hydrochlorothiazide.
Pancreatitis has been reported rarely in patients receiving thiazide diuretics. Clinical manifestations frequently include pain in the abdomen, abdominal distention, nausea, vomiting, and low-grade fever. Pancreatitis can occur within 2 weeks of initiation of therapy or after several months of therapy. If signs and/or symptoms suggestive of pancreatitis develop in a patient receiving losartan; hydrochlorothiazide, drug therapy should be discontinued.
Due to the potential for teratogenesis, losartan; hydrochlorothiazide should not be used during pregnancy. Drugs that affect the renin-angiotensin system have been associated with fetal and neonatal abnormalities when administered to women during the second or third trimesters of pregnancy. Adverse fetal and neonatal effects have included hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, oligohydramnios, and death. Oligohydramnios has been associated with craniofacial deformation and hypoplastic lung development. If oliguria or hypotension occurs in a neonate with a history of in utero exposure to losartan; hydrochlorothiazide, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function.
Losartan; hydrochlorothiazide may result in ophthalmic and otic adverse reactions. Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in 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. Discontinue hydrochlorothiazide as rapidly as possible and consider prompt medical or surgical treatment if the ocular hypertension remains uncontrolled. Transient blurred vision and xanthopsia have also been reported during hydrochlorothiazide monotherapy. Blurred vision, ocular irritation (i.e., burning/stinging in the eye), conjunctivitis, visual impairment (i.e., decrease in visual acuity), and tinnitus have been reported with losartan.
Minor increases in blood urea nitrogen or serum creatinine were observed in 0.6% and 0.8%, respectively, of patients treated with losartan; hydrochlorothiazide for hypertension. Treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure (unspecified) and/or death in patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure). Similar outcomes have been reported with losartan. In the ELITE study, renal dysfunction (defined as a persistent increase in serum creatinine of 0.3 mg/dl) occurred in 10.5% of elderly heart failure patients treated with losartan and in 10.5% of patients treated with an ACE inhibitor (captopril). Nocturia, increased urinary frequency, and urinary tract infection have also been reported with losartan. Renal failure, renal dysfunction, and interstitial nephritis have been reported with hydrochlorothiazide.
Hypokalemia (serum potassium less than 3.5 mEq/L) has been observed in 6.7% patients; whereas hyperkalemia (serum potassium greater than 5.7 mEq/L) has been observed in 0.4% of patients receiving losartan; hydrochlorothiazide. No patients required discontinuation of therapy from the combination product in controlled clinical trials due to changes in serum potassium. Hyponatremia has also been reported with losartan monotherapy. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer. An FDA Sentinel Initiative study found that increased risk was mostly for squamous cell carcinoma and in White patients taking large cumulative doses. The increased risk for the overall population was approximately 1 additional case per 16,000 patients per year. For White patients taking a cumulative dose more than 50,000 mg, the risk increased to approximately 1 additional case per 6,700 patients per year.
Thiazide diuretics such as hydrochlorothiazide have been associated with a slight increase in serum cholesterol and triglyceride concentrations. Data from long-term studies, however, suggest diuretic-induced cholesterol changes are not clinically significant and do not contribute to coronary heart disease risk.
Thiazide diuretics are contraindicated in patients with known thiazide diuretic hypersensitivity. According to the manufacturer, hydrochlorothiazide is specifically contraindicated in patients with sulfonamide hypersensitivity. Hypersensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma; however, reactions are more likely to occur in patients with such history. Although thiazide diuretics are sulfonamide derivatives, sulfonamide cross-sensitivity has rarely been documented.   Until further data are available, thiazide diuretics should be used with caution in patients with sulfonamide hypersensitivity. Thiazide diuretics do not contain the N4-aromatic amine or the N1-substituent which are present in sulfonamide antibiotics. Non-arylamine sulfonamide derivatives, such as thiazide diuretics, have been proposed to have a lower risk of allergic reactions in patients with sulfonamide allergy, presumably due to lack of an arylamine group at the N4 position (a proposed structural site of action for sulfonamide allergy).  One large retrospective cohort study has reported that in patients with the presence of an allergic reaction after exposure to a sulfonamide antibiotic, 9.9% had an allergic reaction after receiving a non-antibiotic sulfonamide derivative, while in patients who lacked an allergic reaction after sulfonamide antibiotic exposure, 1.6% had an allergic reaction after administration of a non-antibiotic sulfonamide derivative (adjusted odds ratio 2.8; 95% CI, 2.1 to 3.7). A causal relationship between sulfonamide hypersensitivity and allergic reactions with non-arylamine sulfonamide derivatives has not been definitively established and remains controversial.    In general, patients with a documented sulfonamide allergy are considered to be predisposed for development of allergic drug reactions.  Also, patients with a history of sulfonamide hypersensitivity or penicillin hypersensitivity who receive hydrochlorothiazide may also be at increased risk for the development of an idiosyncratic reaction resulting in transient myopia and acute angle-closure glaucoma. Discontinue hydrochlorothiazide promptly if this reaction occurs.
Losartan; hydrochlorothiazide is contraindicated in patients with anuria since thiazide diuretics are considered ineffective when the creatinine clearance is less than 30 ml/minute. Hydrochlorothiazide should be used cautiously in patients with renal disease resulting in renal failure or severe renal impairment because the drug decreases the glomerular filtration rate and may precipitate azotemia in these patients. Losartan should be used with caution in patients whose renal function is critically dependent on the activity of the renin-angiotensin-aldosterone system (RAS) (e.g., patients with heart failure). Changes in renal function have been reported in susceptible individuals receiving losartan, with these changes reversible upon discontinuation of therapy in some patients. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor antagonists affect the RAS system and have caused increases in serum creatinine in susceptible individuals. Although serum creatinine returns to baseline or stabilizes in most patients with continued use, oliguria, progressive azotemia, and rarely, acute renal failure have occurred. In addition, ACEIs have been associated with azotemia in patients with unilateral or bilateral renal artery stenosis. Although losartan has not been studied in renal artery stenosis, similar effects to the ACEIs might be anticipated due to losartan's pharmacology. Renal function should be monitored in patients receiving losartan; hydrochlorothiazide.
Losartan; hydrochlorothiazide is not recommended for titration in patients with hepatic impairment since the appropriate 25 mg starting dose of losartan cannot be administered. Losartan requires dosage adjustment in patients with hepatic disease. Patients with mild to moderate alcoholic cirrhosis demonstrated significantly increased losartan and active metabolite plasma concentrations which were 5 and 1.7 times higher, respectively, compared to normal subjects. Hydrochlorothiazide should be used with caution in patients with hepatic disease since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Losartan; hydrochlorothiazide should be used with caution in patients who have hypovolemia. Intravascular volume depletion increases the risk of symptomatic hypotension during therapy. When initiating therapy in these patients, lower doses are recommended. Losartan; hydrochlorothiazide should be used with great care in patients who exhibit signs of hypotension. Volume depletion should be corrected prior to the administration of losartan; hydrochlorothiazide. Orthostatic hypotension may occur during treatment with thiazide diuretics. Orthostatic hypotension can be exacerbated by concurrent use of alcohol, narcotics, or antihypertensive drugs. Excessive hypotension during thiazide diuretic therapy can result in syncope. An increased risk of falls has been reported for elderly patients receiving thiazide diuretics.  In addition, the antihypertensive effects of thiazides may be enhanced in other patients predisposed for orthostatic hypotension, including the post-sympathectomy patient.
Anaphylactic reactions (anaphylactoid reactions) and angioedema have been reported with angiotensin II receptor antagonists. Theoretically, angiotensin II receptor antagonists should be less likely than angiotensin converting enzyme inhibitors (ACEIs) to precipitate angioedema because angiotensin II receptor antagonists do not cause accumulation of kinins. However, angioedema (swelling of lips and eyelids, facial rash) has rarely been reported in patients receiving angiotensin II receptor antagonists, including in patients with a prior history of ACE-inhibitor induced angioedema. While angiotensin II receptor antagonists have been suggested as potential alternatives to ACE inhibitors for patients who experience angioedema due to a lower frequency of associated angioedema  , the safety of angiotensin II receptor antagonists in patients with a prior history of ACE-inhibitor induced angioedema has not been definitively established.    It is prudent to use substantial caution when prescribing losartan; hydrochlorothiazide in patients with a history of ACE-inhibitor induced angioedema. Some authors have recommended that angiotensin II receptor antagonists should be avoided in patients with a history of angioedema, especially those with ACE-inhibitor induced angioedema.
In patients undergoing major surgery or during anesthesia with agents that lower blood pressure, losartan may enhance hypotensive effects via angiotensin II blockade. Therefore, losartan; hydrochlorothiazide should be used with caution prior to surgery. If hypotension occurs during surgery and/or anesthesia and is considered to be due to blockade of angiotensin II formation, it can be corrected by volume expansion.
When pregnancy is detected, discontinue losartan; hydrochlorothiazide therapy as soon as possible. Women of child-bearing age should be made aware of the potential risk and losartan; hydrochlorothiazide should only be given after careful counseling and consideration of risks and benefits. When used during the second and third trimesters, drugs that affect the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) reduce fetal renal function and increase fetal and neonatal morbidity and death. Use of drugs that affect the renin-angiotensin system during pregnancy can cause fetal death or injury such as hypotension, neonatal skull hypoplasia, reversible or irreversible renal failure and death. Anhydramnios and oligohydramnios have also been reported. Development of oligohydramnios may be associated with decreased fetal renal function leading to anuria and renal failure and results in fetal limb contractures, craniofacial deformation, hypotension, hypoplastic lung development, and death.  Retrospective data indicate that first trimester use of ACE inhibitors has been associated with a potential risk of birth defects. However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in infants exposed to ACE inhibitors during the first trimester, in infants exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated. Infants born to mothers with hypertension, either treated or untreated, had a higher risk of birth defects than those born to mothers without hypertension. The authors concluded that the presence of hypertension likely contributed to the development of birth defects rather than the use of medications. An observational cohort study evaluating the outcomes of angiotensin receptor blockers (ARBs) use during the first trimester of pregnancy found an increased rate of major birth defects compared to non-hypertensive pregnancies, 5.4% and 3%, respectively; the difference did not reach statistical significance. The authors noted that there was a higher risk of major birth defects with ARB therapy beyond 6 weeks of gestation compared to discontinuation of ARBs before week 6, 7.3% and 2.8%, respectively. The rates of prematurity and reduced birth weight were also increased in the ARB group. There were no statistically significant differences in the rates of major birth defects, spontaneous abortions, or preterm births between women with chronic hypertension treated with an ARB versus methyldopa. Thiazide diuretics can cross the placenta resulting in umbilical cord concentrations similar to maternal plasma concentrations and amniotic fluid concentrations that are up to 19 times greater than in the umbilical vein. Based on the results from one large study, first trimester use of thiazide and related diuretics may increase the risk for congenital defects. In addition to malformations, other fetal risks associated with thiazide use during pregnancy include hypoperfusion, fetal or neonatal jaundice, hypoglycemia, thrombocytopenia, hyponatremia, hypokalemia, and death from maternal complications. Once pregnancy is detected, ultrasound examination should be performed if losartan; hydrochlorothiazide exposure occurs beyond the first trimester. In rare cases when another antihypertensive agent cannot be used to treat a pregnant patient, serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, discontinue losartan; hydrochlorothiazide unless it is considered life-saving for the mother. It should be noted that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe newborns with histories of in utero exposure to losartan; hydrochlorothiazide for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function.
Patients with pre-existing significant hyponatremia, hyperkalemia, hypokalemia, hypomagnesemia, and/or hypercalcemia should have their electrolyte imbalances corrected before losartan; hydrochlorothiazide is initiated. Thiazide diuretics such as hydrochlorothiazide have been shown to increase the urinary excretion of magnesium and decrease urinary calcium excretion. Losartan; hydrochlorothiazide may reduce, elevate or leave potassium levels unchanged in individual patients. All patients should be monitored closely for clinical signs of fluid or electrolyte imbalance. Thiazides may worsen dilutional hyponatremia, especially in elderly individuals. Greater sensitivity to the usual dosage of hydrochlorothiazide may occur in some elderly patients. In general, drug dose selection for an elderly patient should be cautious, usually starting at the low end of the adult dosage range. Losartan and active metabolite plasma concentrations are similar in elderly and younger hypertensive adults. Plasma losartan concentrations are about twice as high in females versus males, but the plasma concentrations of the active metabolite are unchanged. However, blood pressure responses to losartan are similar, regardless of age or gender.
According to the manufacturer, because of the potential for adverse effects on the nursing infant, a decision should be made to discontinue breast-feeding or discontinue losartan; hydrochlorothiazide therapy. It is not known whether losartan is excreted into human milk. Hydrochlorothiazide has been detected in human breast milk. The American Academy of Pediatrics (AAP) has not evaluated the use of losartan in breast-feeding mothers; however, the AAP does consider hydrochlorothiazide to be usually compatible with breast-feeding. Thiazide diuretics distribute into breast milk, and it has been recommended by some manufacturers that women do not nurse while receiving selected thiazide diuretics. High doses of some thiazide diuretics have been used off-label to suppress lactation, and thus should be used with caution during establishment of breast-feeding. Some experts consider 50 mg or less to be compatible with breast-feeding. The ACE inhibitors captopril, enalapril, benazepril, and quinapril are excreted in human breast milk in very small quantities; therefore, a clinically significant risk to a breast-feeding infant is not expected unless high doses are required.     If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Safety and effectiveness of losartan; hydrochlorothiazide have not been established in neonates, infants, and children less than 18 years old.
Hyperglycemia or impaired glucose tolerance can occur during hydrochlorothiazide therapy. In patients with diabetes mellitus who are receiving losartan; hydrochlorothiazide, blood glucose levels should be monitored frequently. Adjustment of insulin and/or oral hypoglycemic agents may be required.
Thiazide diuretics have been reported to cause pancreatitis. Losartan; hydrochlorothiazide should be used with caution in patients with a history of pancreatitis.
Losartan; hydrochlorothiazide should be administered cautiously to patients with gout or hyperuricemia since thiazide diuretics such as hydrochlorothiazide have been reported to reduce the clearance of uric acid.
Hydrochlorothiazide has been reported to activate or exacerbate systemic lupus erythematosus (SLE).
Instruct patients taking hydrochlorothiazide to avoid excessive sunlight (UV) exposure and undergo regular skin cancer screening. Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer. An FDA Sentinel Initiative study found that increased risk was mostly for squamous cell carcinoma and in White patients taking large cumulative doses. The increased risk for the overall population was approximately 1 additional case per 16,000 patients per year. For White patients taking a cumulative dose more than 50,000 mg, the risk increased to approximately 1 additional case per 6,700 patients per year. Photosensitivity has also been reported with thiazide diuretics like hydrochlorothiazide; discontinue if phototoxicity occurs.
No overall differences in effectiveness were observed between geriatric patients and younger adults during clinical trials of losartan; hydrochlorothiazide; the reported adverse events were somewhat more frequent in the elderly compared to non-elderly patients for both the losartan; hydrochlorothiazide and control groups. Greater sensitivity to the usual dosage of hydrochlorothiazide or losartan may occur in some geriatric patients, and care should be taken in initial dose selection, usually starting at the low end of the usual adult dose range. Thiazides may worsen dilutional hyponatremia, especially in geriatric individuals. An increased risk of falls has been reported for older adult patients receiving thiazide diuretics.  Monitor renal function and for clinical signs of acid/base, fluid, or electrolyte imbalances. According to the Beers Criteria, diuretics such as hydrochlorothiazide are considered potentially inappropriate medications (PIMs) in geriatric patients and should be used with caution due to the potential for causing or exacerbating SIADH or hyponatremia. Sodium levels should be closely monitored when starting or changing dosages of diuretics in older adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. In addition, diuretics may cause fluid and electrolyte imbalances and may precipitate or exacerbate urinary incontinence.
The effects of losartan and hydrochlorothiazide on blood pressure are additive. Thiazide diuretics lower the blood pressure by increasing the excretion of sodium; whereas losartan and its principal metabolite lower blood pressure by selectively blocking the AT1 receptor to antagonize the actions of angiotensin II, the primary vasoactive hormone of the renin-angiotensin system. Losartan tends to reverse the hypokalemia caused by the hydrochlorothiazide; this effect is related to the dose of losartan. Due to the dose-related uricosuric effects of losartan, the combination of losartan with hydrochlorothiazide partially attenuates the rise in serum uric acid and the association with hydrochlorothiazide monotherapy.
Losartan; hydrochlorothiazide is administered orally. No pharmacokinetic drug interaction is observed between losartan and hydrochlorothiazide.
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