Hyzaar

Description

Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-p-(o-1H-tetrazol-5-ylphenyl)benzylimidazole-5-methanol monopotassium salt. Its empirical formula is C22H22ClKN6O, and it has a molecular weight of 461.01. Losartan potassium appears as a white to off-white free-flowing crystalline powder that is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents such as acetonitrile and methyl ethyl ketone.

Hydrochlorothiazide is chemically defined as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.74. It is a white or practically white crystalline powder that is slightly soluble in water but freely soluble in sodium hydroxide solution.

HYZAAR is available for oral administration in three tablet combinations of losartan and hydrochlorothiazide. The formulations include HYZAAR 50/12.5, which contains 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide; HYZAAR 100/12.5, which contains 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide; and HYZAAR 100/25, which contains 100 mg of losartan potassium and 25 mg of hydrochlorothiazide.

Inactive ingredients in these formulations include microcrystalline cellulose, lactose hydrous, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose, and titanium dioxide. HYZAAR 50/12.5 and HYZAAR 100/25 also contain D&C yellow No. 10 aluminum lake, and all three formulations may contain carnauba wax. Additionally, HYZAAR 50/12.5 contains 4.24 mg (0.108 mEq) of potassium, HYZAAR 100/12.5 contains 8.48 mg (0.216 mEq) of potassium, and HYZAAR 100/25 contains 8.48 mg (0.216 mEq) of potassium.

Uses and Indications

This drug is indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

Additionally, this drug is indicated for the reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy. It is important to note that evidence suggests this benefit does not apply to Black patients.

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

For the management of hypertension, the usual starting dose is 50/12.5 mg administered once daily. Healthcare professionals may titrate the dosage as needed, with a maximum allowable dose of 100/25 mg.

In patients with hypertension who also present with left ventricular hypertrophy and are not adequately controlled on monotherapy, treatment should be initiated with 50/12.5 mg once daily. Similar to the general hypertension population, titration may be performed as necessary, up to a maximum dose of 100/25 mg.

It is recommended that healthcare providers monitor patient response and adjust the dosage accordingly to achieve optimal blood pressure control.

Contraindications

Use of HYZAAR is contraindicated in the following situations:

Patients with hypersensitivity to any component of HYZAAR should not use this medication due to the risk of severe allergic reactions. Additionally, the use of HYZAAR is contraindicated in individuals with anuria, as it may exacerbate renal impairment. Coadministration with aliskiren is contraindicated in patients with diabetes, as this combination may increase the risk of adverse effects.

Warnings and Precautions

When pregnancy is detected, it is imperative to discontinue HYZAAR as soon as possible due to the risk of fetal toxicity. Medications that directly affect the renin-angiotensin system have the potential to cause serious injury or death to the developing fetus.

Prior to initiating treatment with HYZAAR, healthcare professionals should ensure that any volume or salt depletion is corrected to mitigate the risk of hypotension. It is essential to monitor renal function and serum potassium levels in patients who may be susceptible to these effects, as this can help prevent adverse outcomes.

Clinicians should remain vigilant for clinical signs of fluid or electrolyte imbalance during the course of treatment. Additionally, there is a risk of acute angle-closure glaucoma associated with the use of HYZAAR, which necessitates careful monitoring of patients with a history of this condition.

Furthermore, patients with systemic lupus erythematosus may experience exacerbation of their condition while on HYZAAR. Regular assessment and monitoring are recommended to manage these potential complications effectively.

Side Effects

Patients receiving HYZAAR may experience a range of adverse reactions. The most common adverse reactions reported include dizziness, upper respiratory infection, cough, and back pain.

Serious warnings associated with HYZAAR include the potential for fetal toxicity. It is imperative that HYZAAR be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can cause injury or death to the developing fetus.

Additional adverse reactions of clinical significance include hypotension, which necessitates correction of volume or salt depletion prior to administration. Patients should be monitored for renal function and potassium levels, particularly those who are susceptible. Clinical signs of fluid or electrolyte imbalance should also be observed. Other serious adverse reactions may include acute angle-closure glaucoma, exacerbation of systemic lupus erythematosus, hypersensitivity to any component of HYZAAR, and anuria. Coadministration with aliskiren is contraindicated in patients with diabetes.

In cases of overdosage, the most likely manifestations would be hypotension and tachycardia, although bradycardia may occur due to parasympathetic (vagal) stimulation. If symptomatic hypotension occurs, supportive treatment should be instituted.

Drug Interactions

The concomitant use of certain agents may lead to significant drug interactions that require careful consideration and monitoring.

Pharmacodynamic Interactions

• Agents Increasing Serum Potassium: The use of agents that elevate serum potassium levels may result in hyperkalemia. Monitoring of serum potassium is advised to mitigate this risk.

• Lithium: Co-administration with lithium may increase the risk of lithium toxicity. Regular monitoring of lithium levels is recommended to ensure safe therapeutic ranges.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs can lead to an increased risk of renal impairment and may diminish the diuretic, natriuretic, and antihypertensive effects of the drug. Renal function should be monitored, and NSAID use should be approached with caution.

• Dual Inhibition of the Renin-Angiotensin System: The combination of agents that inhibit the renin-angiotensin system may heighten the risk of renal impairment, hypotension, syncope, and hyperkalemia. Close monitoring of blood pressure and renal function is recommended.

Pharmacokinetic Interactions

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used concurrently. Blood glucose levels should be closely monitored to ensure effective glycemic control.

• Cholestyramine and Colestipol: The presence of cholestyramine or colestipol may reduce the absorption of thiazide diuretics. It is advisable to separate the administration of these agents to optimize therapeutic efficacy.

Packaging & NDC

The table below lists all NDC Code configurations of Hyzaar (losartan potassium and hydrochlorothiazide), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of HYZAAR in pediatric patients have not been established.

In neonates with a history of in utero exposure to HYZAAR, if oliguria or hypotension occurs, it is essential to direct attention toward supporting blood pressure and renal perfusion. In such cases, exchange transfusion or dialysis may be required to reverse hypotension and/or substitute for disordered renal function.

Geriatric Use

In a controlled clinical study aimed at reducing the combined risk of cardiovascular death, stroke, and myocardial infarction in hypertensive patients with left ventricular hypertrophy, a significant proportion of participants were elderly, with 62% (n=2857) aged 65 years and older and 18% (n=808) aged 75 years and older.

The findings indicated that there were no overall differences in effectiveness between elderly patients and their younger counterparts. However, it is important to note that adverse events were reported with somewhat greater frequency among elderly patients compared to non-elderly patients in both the losartan-hydrochlorothiazide and control groups.

Given these observations, healthcare providers should exercise caution when prescribing this medication to geriatric patients. Monitoring for adverse events is recommended, and consideration should be given to potential dose adjustments based on individual patient factors, particularly in those aged 75 years and older.

Pregnancy

HYZAAR can cause fetal harm when administered to a pregnant woman. The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy is associated with reduced fetal renal function, leading to oligohydramnios, increased fetal and neonatal morbidity, and potential death. Pregnant patients should be advised to discontinue HYZAAR as soon as pregnancy is detected.

The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2% to 4% and 15% to 20%, respectively. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. Hypertension in pregnancy poses additional risks, including increased maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, as well as fetal risks such as intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be closely monitored and managed accordingly.

In cases where there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, healthcare providers should inform the mother of the potential risks to the fetus. Serial ultrasound examinations are recommended to assess the intra-amniotic environment, and if oligohydramnios is observed, HYZAAR should be discontinued unless it is deemed lifesaving for the mother. It is important to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury.

Neonates with a history of in utero exposure to HYZAAR should be closely observed for hypotension, oliguria, and hyperkalemia. In cases of oliguria or hypotension, supportive measures for blood pressure and renal perfusion may be necessary, including potential exchange transfusions or dialysis.

Thiazides, including hydrochlorothiazide, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. Hydrochlorothiazide may accumulate in the amniotic fluid, with reported concentrations significantly higher than in umbilical vein plasma. The use of thiazides during pregnancy is associated with risks of fetal or neonatal jaundice and thrombocytopenia, and these agents do not alter the course of pre-eclampsia; therefore, they should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications during pregnancy should also be avoided.

Lactation

It is not known whether losartan is excreted in human milk; however, significant levels of losartan and its active metabolite have been detected in rat milk. Thiazides are known to appear in human milk.

Due to the potential for adverse effects on the nursing infant, lactating mothers should consider whether to discontinue breastfeeding or to discontinue the medication, weighing the importance of the drug to the mother against the potential risks to the breastfed infant.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored closely. This is particularly important for those with reduced kidney function, as they may be at increased risk for complications. Dosing adjustments may be necessary based on the degree of renal impairment to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Significant lethality has been documented in animal studies following oral administration of high doses of the drug, with mice exhibiting a lethal dose (LD50) of 1000 mg/kg and rats showing an LD50 of 2000 mg/kg. These doses correspond to approximately 44 and 170 times the maximum recommended human dose when adjusted for body surface area (mg/m²).

The primary manifestations of overdosage are likely to include hypotension and tachycardia. In some cases, bradycardia may occur due to parasympathetic (vagal) stimulation. Should symptomatic hypotension arise, it is imperative that supportive treatment be initiated promptly to manage the patient's condition effectively.

It is important to note that neither losartan nor its active metabolite can be eliminated from the body through hemodialysis, which limits the options for managing severe cases of overdosage.

In the case of hydrochlorothiazide, the oral LD50 is reported to be greater than 10 g/kg in both mice and rats. The most frequently observed signs and symptoms associated with hydrochlorothiazide overdosage are primarily due to electrolyte depletion, which may include hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis.

Healthcare professionals should remain vigilant for these symptoms and manage them accordingly to mitigate the effects of overdosage.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted with losartan potassium-hydrochlorothiazide. In terms of non-teratogenic effects, the combination did not impact the fertility or mating behavior of male rats at dosages up to 135 mg/kg/day of losartan and 33.75 mg/kg/day of hydrochlorothiazide. However, in female rats, coadministration of doses as low as 10 mg/kg/day of losartan and 2.5 mg/kg/day of hydrochlorothiazide resulted in slight but statistically significant decreases in fecundity and fertility indices. Studies involving male rats receiving oral doses of losartan potassium up to approximately 150 mg/kg/day indicated no adverse effects on fertility and reproductive performance. Conversely, the administration of higher toxic dosage levels in females (300/200 mg/kg/day) was linked to a significant decrease in the number of corpora lutea, implants, and live fetuses at C-section (p<0.05). At a dosage of 100 mg/kg/day, only a decrease in the number of corpora lutea was noted. Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex when these species were exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

No carcinogenicity studies have been performed with the losartan potassium-hydrochlorothiazide combination. The combination was found to be negative in both the Ames microbial mutagenesis assay and the V-79 Chinese hamster lung cell mutagenesis assay. Additionally, there was no evidence of direct genotoxicity in the in vitro alkaline elution assay in rat hepatocytes or in the in vitro chromosomal aberration assay in Chinese hamster ovary cells at noncytotoxic concentrations. Losartan potassium did not exhibit carcinogenic properties when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. However, female rats receiving the highest dose of 270 mg/kg/day showed a slightly higher incidence of pancreatic acinar adenoma. Losartan potassium was also negative in various mutagenesis and genotoxicity assays, including the microbial mutagenesis, V-79 mammalian cell mutagenesis, in vitro alkaline elution, and chromosomal aberration assays. The active metabolite demonstrated no evidence of genotoxicity in similar assays.

Two-year feeding studies in mice and rats revealed no evidence of carcinogenic potential for hydrochlorothiazide in female mice at doses up to approximately 600 mg/kg/day or in male and female rats at doses up to approximately 100 mg/kg/day. The National Toxicology Program (NTP) reported equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay or the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, nor in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive results were only observed in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays.

The relationship of findings related to toxic dosage levels in females to drug treatment remains uncertain, as there were no effects at these dosage levels on implants, percent post-implantation loss, or live animals per litter at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were approximately 66 and 26 times the exposure achieved in humans at the maximum recommended daily dosage of 100 mg.

Postmarketing Experience

Treatment with hydrochlorothiazide has been associated with an increased risk of certain types of skin cancer, specifically non-melanoma skin cancer. Patients are advised to consult with their healthcare provider regarding appropriate measures to protect their skin from sun exposure and to determine the frequency of skin cancer screening.

Patient Counseling

Advise patients to read the FDA-approved patient labeling (Patient Information) prior to initiating treatment with HYZAAR and each time they receive a refill, as there may be new information. It is essential for patients to understand that HYZAAR can cause harm or death to an unborn baby; therefore, healthcare providers should discuss the implications of exposure during pregnancy with female patients of childbearing age. Patients planning to become pregnant should be informed about alternative methods for managing blood pressure and are encouraged to report any pregnancies to their healthcare provider immediately.

Inform patients that symptomatic hypotension, characterized by lightheadedness, may occur, particularly during the initial days of therapy. Patients should be advised to report any such symptoms to their healthcare provider. Additionally, dehydration resulting from inadequate fluid intake, excessive perspiration, vomiting, or diarrhea may lead to a significant drop in blood pressure. In the event of syncope, patients should be instructed to contact their healthcare provider without delay.

Counsel patients against the use of potassium supplements or salt substitutes containing potassium unless they have consulted their healthcare provider. Patients should also be made aware of the potential risk of acute myopia and secondary angle-closure glaucoma; they must discontinue HYZAAR and seek immediate medical attention if they experience symptoms indicative of these conditions.

For patients taking hydrochlorothiazide, it is important to discuss the increased risk of non-melanoma skin cancer. Advise patients to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Encourage patients to maintain an updated list of all medications they are taking and to share this list with their healthcare provider and pharmacist when receiving new prescriptions. Additionally, patients should inform their healthcare provider about any medical conditions, including instances of vomiting, diarrhea, excessive sweating, or inadequate fluid intake, as these factors could contribute to low blood pressure.

Storage and Handling

The product is supplied in a container that must be kept tightly closed to maintain its integrity. It should be stored at a controlled room temperature of 77°F (25°C), with permissible excursions between 59°F to 86°F (15°C to 30°C). Additionally, it is essential to protect the product from light to ensure its stability and efficacy.

Additional Clinical Information

Clinicians are advised to monitor renal function periodically in patients whose renal function may be influenced by the activity of the renin-angiotensin system. Additionally, it is important to periodically assess serum electrolytes and calcium levels to ensure patient safety and effective management.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Hyzaar as submitted by Organon LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)