Losartan potassium/Hydrochlorothiazide

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, with a molecular formula of C22H22ClKN6O. It is classified as a white to off-white powder and has a molecular weight of 461.01. Losartan potassium is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents such as acetonitrile and methyl ethyl ketone.

Hydrochlorothiazide is identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular formula of C7H8ClN3O4S2. This compound appears as a white or practically white, practically odorless, crystalline powder with a molecular weight of 297.74. Hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.

Losartan potassium and hydrochlorothiazide are available for oral administration in three tablet combinations. The formulations include losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg, which contain 50 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP; losartan potassium and hydrochlorothiazide tablets USP, 100 mg/12.5 mg, containing 100 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP; and losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25 mg, which include 100 mg of losartan potassium USP and 25 mg of hydrochlorothiazide USP.

Inactive ingredients in these formulations consist of colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinised starch (maize), and titanium dioxide. Additionally, losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg and 100 mg/25 mg also contain D&C yellow No. 10 aluminum lake. The potassium content in the tablets is as follows: losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg contains 4.24 mg (0.108 mEq) of potassium; losartan potassium and hydrochlorothiazide tablets USP, 100 mg/12.5 mg contains 8.48 mg (0.217 mEq) of potassium; and losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25 mg also contains 8.48 mg (0.217 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 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 extend 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/12.5 mg administered once daily. Healthcare professionals may titrate the dosage as needed, with a maximum allowable dose of 100 mg/25 mg.

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

It is essential to monitor the patient's response to therapy and adjust the dosage accordingly to achieve optimal blood pressure control.

Contraindications

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

Patients with a known 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.

Warnings and Precautions

When pregnancy is detected, losartan potassium and hydrochlorothiazide tablets should be discontinued as soon as possible due to the risk of fetal toxicity. Medications that act directly on the renin-angiotensin system have the potential to cause injury or death to the developing fetus.

Prior to initiating treatment with losartan potassium and hydrochlorothiazide, it is essential to correct any volume or salt depletion to mitigate the risk of hypotension. Healthcare professionals should closely monitor renal function and serum potassium levels in patients who may be susceptible to these complications.

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

Furthermore, the use of losartan potassium and hydrochlorothiazide may exacerbate systemic lupus erythematosus, and patients should be monitored for any worsening of symptoms associated with this autoimmune disorder.

Side Effects

Patients receiving losartan potassium and hydrochlorothiazide 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 the use of this medication include the potential for fetal toxicity. Drugs that act directly on the renin-angiotensin system, such as losartan potassium and hydrochlorothiazide, can cause injury and death to the developing fetus. Therefore, it is imperative to discontinue the medication as soon as pregnancy is detected.

Additional adverse reactions of clinical significance 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, hypersensitivity to any component of the medication, and anuria. Coadministration with aliskiren is contraindicated in patients with diabetes.

In cases of overdosage, the most likely manifestations include hypotension and tachycardia, with bradycardia potentially occurring due to parasympathetic (vagal) stimulation. Supportive treatment should be initiated if symptomatic hypotension occurs. Common signs and symptoms associated with overdosage may include those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia, as well as dehydration due to excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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 these medications, if oliguria or hypotension occurs, it is crucial to direct attention toward supporting blood pressure and renal perfusion. In such cases, exchange transfusion or dialysis may be necessary 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 no overall differences in effectiveness between elderly patients and their younger counterparts. However, it is important to note that adverse events were reported more frequently 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

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, which can lead to 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 for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Hypertension in pregnancy poses additional risks, including increased maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications such as the need for cesarean section and post-partum hemorrhage. Furthermore, hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death, necessitating careful monitoring and management of pregnant women with hypertension.

The use of drugs that act on the renin-angiotensin system during the second and third trimesters can result in oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and death. In cases where there is no appropriate alternative to therapy with these drugs, 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.

Thiazides, including hydrochlorothiazide, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. Hydrochlorothiazide may cause placental hypoperfusion and can accumulate in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. The use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since thiazides do not alter the course of pre-eclampsia, they should not be used to treat hypertension in pregnant women, and the use of hydrochlorothiazide for other indications during pregnancy should be avoided.

Neonates with a history of in utero exposure to losartan potassium and hydrochlorothiazide should be closely observed for hypotension, oliguria, and hyperkalemia. In cases where oliguria or hypotension occurs, supportive measures for blood pressure and renal perfusion may be necessary, and exchange transfusions or dialysis may be required to reverse hypotension and restore renal function.

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 impact on breastfed infants is not established. 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. 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 observed in animal studies following oral administration of high doses of the compound, 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 on a mg/m² basis, respectively.

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 removed through hemodialysis, which limits the options for decontamination in cases of overdose.

In the context of hydrochlorothiazide overdosage, 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, including 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 studies involving losartan potassium-hydrochlorothiazide. The combination, 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 conducted in rat hepatocytes or in the in vitro chromosomal aberration assay in Chinese hamster ovary cells at noncytotoxic concentrations.

In terms of fertility, losartan potassium, when coadministered with 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, 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. Toxic dosage levels in females (300/200 mg/kg/day) were associated with a significant decrease in the number of corpora lutea, implants, and live fetuses at C-section, while at 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 in studies where these species were exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

Carcinogenicity studies have not been conducted with the losartan potassium-hydrochlorothiazide combination. However, two-year feeding studies conducted by the National Toxicology Program (NTP) 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 NTP did find equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay across various Salmonella typhimurium strains or in the Chinese Hamster Ovary test for chromosomal aberrations. In vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also showed no genotoxicity. Positive results were only observed in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. The maximally tolerated dosages (270 mg/kg/day in rats and 200 mg/kg/day in mice) resulted in 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

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 therapy with losartan potassium and hydrochlorothiazide and each time they receive a refill, as there may be new information. It is important for patients to understand that this leaflet does not replace discussions with their healthcare provider regarding their condition and treatment.

For female patients of childbearing age, it is essential to discuss the potential consequences of exposure to losartan potassium and hydrochlorothiazide during pregnancy. Healthcare providers should encourage these patients to explore alternative treatment options if they are planning to become pregnant and to report any pregnancies to their physician as soon as possible.

Patients should be informed about the possibility of experiencing symptomatic hypotension, particularly during the initial days of therapy. They should be advised to report any lightheadedness to their healthcare provider. Additionally, patients should be made aware that dehydration due to inadequate fluid intake, excessive perspiration, vomiting, or diarrhea may lead to a significant drop in blood pressure. In the event of syncope, patients must be instructed to contact their healthcare provider immediately.

It is crucial to advise patients against using potassium supplements or salt substitutes containing potassium without prior consultation with their healthcare provider. Furthermore, patients should be informed about the risk of acute myopia and secondary angle-closure glaucoma. They must be instructed to discontinue the medication and seek immediate medical attention if they experience symptoms associated with these conditions.

For those taking hydrochlorothiazide, it is important to emphasize the need for sun protection and regular skin cancer screenings due to the increased risk of non-melanoma skin cancer. Patients should discuss with their healthcare provider strategies for protecting their skin from sun exposure and the recommended frequency of skin cancer screenings.

Patients should maintain an updated list of all medications they are taking and share this list with their healthcare provider and pharmacist whenever they receive a new medication. This practice will help ensure safe and effective management of their treatment regimen.

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 range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from light to ensure its stability and effectiveness.

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 Losartan Potassium and Hydrochlorothiazide as submitted by NorthStar Rx LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)