Losartan potassium/Hydrochlorothiazide

Description

Losartan potassium and hydrochlorothiazide tablets USP are available in three formulations: 50 mg/12.5 mg, 100 mg/12.5 mg, and 100 mg/25 mg. Each formulation combines losartan potassium, an angiotensin II receptor blocker, with hydrochlorothiazide, a diuretic.

Losartan potassium, USP is a non-peptide molecule with the chemical designation 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 461.00. Losartan potassium appears as a white to off-white powder, which is freely soluble in water, sparingly soluble in isopropyl alcohol, and slightly soluble in acetonitrile.

Hydrochlorothiazide, USP 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, practically odorless, and exhibits very slight solubility in methanol, sparing solubility in acetonitrile, and is soluble in 1% NaOH solution. Hydrochlorothiazide is practically insoluble or insoluble in water, ethanol, and buffer solutions with a pH range of 4.5 to 8.0.

The tablets are formulated for oral administration and contain the following amounts of potassium: 4.24 mg (0.108 mEq) in the 50 mg/12.5 mg formulation, and 8.48 mg (0.216 mEq) in both the 100 mg/12.5 mg and 100 mg/25 mg formulations. Inactive ingredients include hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and titanium dioxide. The 50 mg/12.5 mg and 100 mg/25 mg formulations also contain iron oxide yellow.

Uses and Indications

This drug is indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of both 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 mg of the primary component combined with 12.5 mg of the secondary component, administered once daily. Healthcare professionals may titrate the dosage as necessary, with a maximum allowable dose of 100 mg of the primary component and 25 mg of the secondary component.

In hypertensive patients with left ventricular hypertrophy who are not adequately controlled on monotherapy, treatment should also begin with a dose of 50 mg of the primary component and 12.5 mg of the secondary component, taken once daily. Similar to the general hypertension population, titration may be performed as needed, up to a maximum dose of 100 mg of the primary component and 25 mg of the secondary component.

Contraindications

Use of losartan potassium and hydrochlorothiazide tablets is contraindicated in the following situations:

Patients with hypersensitivity to any component of the formulation should not use this medication due to the risk of severe allergic reactions.

Anuria is a contraindication, as the medication may exacerbate renal function impairment.

Coadministration with aliskiren is contraindicated in patients with diabetes, as this combination may increase the risk of adverse effects related to renal function.

Warnings and Precautions

When pregnancy is detected, losartan potassium and hydrochlorothiazide tablets should be discontinued immediately. Medications that act directly on the renin-angiotensin system have the potential to cause injury or death to the developing fetus, necessitating prompt cessation of therapy.

General precautions must be observed prior to the administration of losartan potassium and hydrochlorothiazide. It is essential to correct any volume or salt depletion to mitigate the risk of hypotension. Healthcare professionals should monitor renal function and potassium levels in patients who are susceptible to these changes. Additionally, vigilance for clinical signs of fluid or electrolyte imbalance is advised.

Patients should be aware of the risk of acute angle-closure glaucoma, which may occur with the use of this medication. Furthermore, there is a potential for exacerbation of systemic lupus erythematosus, and healthcare providers should remain alert to this possibility.

Regular laboratory tests to monitor renal function and potassium levels are recommended for patients at risk, ensuring that any adverse effects can be identified and managed promptly.

Side Effects

Patients receiving losartan potassium and hydrochlorothiazide may experience a range of adverse reactions. The most commonly reported adverse reactions include dizziness, upper respiratory infection, cough, and back pain.

Serious warnings associated with the use of this medication include Fetal Toxicity. It is imperative that losartan potassium and hydrochlorothiazide tablets be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can lead to injury or death of the developing fetus.

Additional adverse reactions that may occur include hypotension, which necessitates the 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 notable adverse reactions include acute angle-closure glaucoma, exacerbation of systemic lupus erythematosus, and hypersensitivity to any component of losartan potassium and hydrochlorothiazide tablets. Anuria has also been reported. Coadministration with aliskiren is contraindicated in patients with diabetes due to the potential for serious adverse effects.

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. Caution is advised when prescribing NSAIDs to patients on this medication.

• 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. Regular monitoring of blood glucose levels is advised to maintain optimal control.

• Cholestyramine and Colestipol: The absorption of thiazides may be reduced when administered with cholestyramine or colestipol. It is advisable to separate the dosing of these agents to minimize the impact on thiazide absorption.

Packaging & NDC

The table below lists all NDC Code configurations of 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 losartan potassium and hydrochlorothiazide in pediatric patients have not been established. In neonates with a history of in utero exposure to losartan potassium and hydrochlorothiazide, 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. Specifically, 2,857 patients (62%) were aged 65 years and older, and 808 patients (18%) were 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 occurred somewhat more frequently in the elderly population compared to non-elderly patients, for 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 may be warranted, and consideration should be given to potential dose adjustments based on individual patient factors, including age and overall health status.

Pregnancy

Losartan potassium and hydrochlorothiazide can cause fetal harm when administered to pregnant patients. 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, fetal lung hypoplasia, skeletal deformations, hypotension, and increased fetal and neonatal morbidity and mortality. Therefore, when pregnancy is detected, losartan potassium and hydrochlorothiazide should be discontinued as soon as possible.

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 pre-eclampsia, gestational diabetes, premature delivery, and complications during delivery, such as the need for cesarean section and post-partum hemorrhage. Furthermore, maternal hypertension increases the risk of intrauterine growth restriction and intrauterine death, necessitating careful monitoring and management of pregnant women with hypertension.

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 should be performed to assess the intra-amniotic environment, and if oligohydramnios is observed, losartan potassium and hydrochlorothiazide should be discontinued unless deemed lifesaving for the mother. Fetal testing may be warranted based on gestational age, but 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 losartan potassium and hydrochlorothiazide should be closely monitored 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. Hydrochlorothiazide, like other thiazides, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. The use of thiazides during pregnancy is associated with risks such as fetal or neonatal jaundice and thrombocytopenia, and these medications should not be used to treat hypertension in pregnant women, as they do not alter the course of pre-eclampsia. Additionally, the use of hydrochlorothiazide for other indications during pregnancy should be avoided.

Lactation

There is no specific information available regarding the use of this medication in nursing mothers or its effects on lactation. Consequently, healthcare professionals should exercise caution when prescribing this medication to lactating mothers, as the potential risks to breastfed infants are not well characterized. It is advisable to consider the benefits of breastfeeding alongside the potential risks associated with the medication.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored closely, particularly in those who are susceptible to changes in these parameters. It is essential to correct any volume or salt depletion prior to the administration of losartan potassium and hydrochlorothiazide to ensure optimal therapeutic outcomes and minimize the risk of adverse effects.

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 observed in animal studies, with mice and rats exhibiting fatal outcomes following oral administration of 1000 mg/kg and 2000 mg/kg, respectively. These doses correspond to approximately 44 and 170 times the maximum recommended human dose when adjusted for body surface area (mg/m²).

In humans, data regarding overdosage are limited. The most likely clinical manifestations of an overdose include hypotension and tachycardia. Additionally, bradycardia may occur due to parasympathetic (vagal) stimulation. In the event of symptomatic hypotension, 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 should be taken into consideration when planning management strategies for overdosage cases.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. Losartan potassium-hydrochlorothiazide, tested at a weight ratio of 4:1, demonstrated negative results 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 using rat hepatocytes or in the in vitro chromosomal aberration assay with Chinese hamster ovary cells at noncytotoxic concentrations.

In terms of fertility, the coadministration of losartan potassium and hydrochlorothiazide did not affect 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, doses as low as 10 mg/kg/day of losartan and 2.5 mg/kg/day of hydrochlorothiazide were associated with slight but statistically significant decreases in fecundity and fertility indices. The administration of toxic dosage levels in females (300/200 mg/kg/day) resulted in a significant decrease in the number of corpora lutea, implants, and live fetuses at C-section. Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex when exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

Losartan potassium was not found to be carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. No carcinogenicity studies have been conducted with the losartan potassium-hydrochlorothiazide combination. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains, the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were only obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays.

The maximally tolerated dosages of losartan (270 mg/kg/day in rats and 200 mg/kg/day in mice) provided systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160 and 90 times (in rats) and 30 and 15 times (in mice) the exposure of a 50 kg human receiving 100 mg per day. 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

In postmarketing experience, non-melanoma skin cancer has been reported in patients taking hydrochlorothiazide. It is advised that patients receiving this medication take precautions to protect their skin from sun exposure and participate in regular skin cancer screenings.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) to understand the medication's uses and potential risks.

Healthcare providers should specifically inform female patients of childbearing age about the risks associated with exposure to losartan potassium and hydrochlorothiazide during pregnancy. It is important to discuss alternative treatment options with women who are planning to become pregnant and to encourage patients to report any pregnancies to their healthcare provider as soon as possible.

Patients should be made aware that lightheadedness may occur, particularly during the initial days of therapy. They should be instructed to report this symptom to their healthcare provider. Additionally, patients should be informed that dehydration resulting from inadequate fluid intake, excessive perspiration, vomiting, or diarrhea can lead to a significant drop in blood pressure. In the event of syncope, patients should be advised to contact their healthcare provider immediately.

It is crucial to advise patients against using potassium supplements or salt substitutes that contain potassium without prior consultation with their healthcare provider.

Patients should also be instructed to discontinue losartan potassium and hydrochlorothiazide and seek immediate medical attention if they experience symptoms indicative of acute myopia or secondary angle-closure glaucoma.

For those taking hydrochlorothiazide, healthcare providers should emphasize the importance of protecting their skin from sun exposure and undergoing regular skin cancer screenings.

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 temperature of 25°C (77°F), with permissible excursions between 15-30°C (59-86°F) in accordance with USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from light to ensure its stability and efficacy.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Losartan Potassium and Hydrochlorothiazide as submitted by Granules Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)