Losartan potassium/Hydrochlorothiazide

Description

Losartan potassium and hydrochlorothiazide tablets are available in three formulations: 50 mg/12.5 mg, 100 mg/12.5 mg, and 100 mg/25 mg. Each tablet combines losartan potassium, an angiotensin II receptor blocker, with hydrochlorothiazide, a diuretic. Losartan potassium 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, having a molecular formula of C22H22ClKN6O and a molecular weight of 461.01. It appears as a white to off-white powder, is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents such as acetonitrile and methyl ethyl ketone. The active metabolite of losartan is formed through the oxidation of the 5-hydroxymethyl group on the imidazole ring.

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

Each formulation of losartan potassium and hydrochlorothiazide tablets contains specific amounts of potassium: the 50 mg/12.5 mg formulation contains 4.24 mg (0.108 mEq), while both the 100 mg/12.5 mg and 100 mg/25 mg formulations contain 8.48 mg (0.217 mEq) of potassium. Inactive ingredients include colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch (maize), and titanium dioxide. The 50 mg/12.5 mg and 100 mg/25 mg formulations also contain D&C yellow No. 10 aluminum lake. All formulations meet the USP Dissolution Test 2 criteria.

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 protocol, titration may be performed as necessary, up to a maximum dose of 100 mg/25 mg.

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 and blood pressure regulation.

Warnings and Precautions

When pregnancy is detected, losartan potassium and hydrochlorothiazide tablets should be discontinued immediately. This is critical as drugs 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 existing 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 indicative 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 this medication.

Patients with a history of systemic lupus erythematosus may experience exacerbation of their condition while on losartan potassium and hydrochlorothiazide. Therefore, careful consideration and monitoring are advised for this patient population.

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 in 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 due to the increased risk of adverse effects.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacological effects and mechanisms:

Pharmacodynamic Interactions

• Agents Increasing Serum Potassium: Concurrent use may lead to an increased risk of hyperkalemia. Monitoring of serum potassium levels is recommended.

• Lithium: Co-administration may elevate the risk of lithium toxicity. Regular monitoring of lithium levels is advised to prevent adverse effects.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs may increase the risk of renal impairment and 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: This combination may heighten the risk of renal impairment, hypotension, syncope, and hyperkalemia. Close monitoring of renal function and blood pressure is recommended.

Pharmacokinetic Interactions

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used concurrently. Regular monitoring of blood glucose levels is recommended to ensure effective glycemic control.

• Cholestyramine and Colestipol: These agents may reduce the absorption of thiazides. It is advisable to separate the administration of thiazides from these medications to minimize the risk of reduced efficacy.

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 the support of 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

Elderly patients, defined as those aged 65 years and older, comprised 62% of participants 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. Among these, 18% were aged 75 years and older.

The study 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 with somewhat greater frequency in the elderly population compared to non-elderly patients, observed in both the losartan-hydrochlorothiazide and control groups.

Given these considerations, healthcare providers should exercise caution when prescribing this medication to geriatric patients. Monitoring for adverse events may be warranted, and dose adjustments should be considered based on individual patient response and tolerability.

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, it is recommended to discontinue losartan potassium and hydrochlorothiazide 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 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. Pregnant women with hypertension should be closely monitored and managed accordingly.

The use of drugs that affect the renin-angiotensin system in 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.

Fetal testing may be warranted based on gestational age, and it is important for patients and healthcare providers to recognize 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 observed for hypotension, oliguria, and hyperkalemia. In cases of oliguria or hypotension, it may be necessary to support blood pressure and renal perfusion, with exchange transfusions or dialysis potentially required to reverse hypotension and restore renal function.

Thiazides, including hydrochlorothiazide, can cross the placenta, reaching concentrations in the umbilical vein that approach those in maternal plasma. Hydrochlorothiazide has been associated with 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 linked to risks of fetal or neonatal jaundice and thrombocytopenia. Furthermore, thiazides do not alter the course of pre-eclampsia and should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications during pregnancy should also 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. 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 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 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 on a mg/m² basis, respectively.

In humans, data regarding overdosage are limited. The most likely manifestations of an overdose include hypotension and tachycardia; however, bradycardia may also occur due to parasympathetic (vagal) stimulation. In the event of symptomatic hypotension, it is recommended that supportive treatment be initiated to manage the condition effectively.

It is important to note that neither losartan nor its active metabolite can be removed through hemodialysis, which limits the options for managing severe cases of overdosage. Additionally, the oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, indicating a high threshold for toxicity in these species.

The most common 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. If digitalis has been co-administered, hypokalemia may further exacerbate the risk of cardiac arrhythmias.

The extent to which hydrochlorothiazide is removed by hemodialysis remains undetermined, necessitating careful monitoring and management of patients presenting with signs 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) led to a significant decrease in the number of corpora lutea, implants, and live fetuses at C-section (p<0.05). At a dose 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 conducted 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. 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 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) found 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 obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays.

The relationship of findings related to drug treatment in females remains uncertain, as there were no effects at these dosage levels on implants in pregnant females, 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

Patients should be advised 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 healthcare providers to discuss the implications of using this medication during pregnancy with female patients of childbearing age. Providers should inform these patients about the potential consequences of exposure to losartan potassium and hydrochlorothiazide during pregnancy and explore alternative treatment options for those planning to conceive. Patients should be instructed to report any pregnancies to their healthcare provider as soon as possible.

Healthcare providers should inform patients about the risk of symptomatic hypotension, particularly during the initial days of therapy. Patients may experience lightheadedness and should be encouraged to report this symptom to their healthcare provider. Additionally, patients should be made aware that dehydration due to 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.

Patients should be cautioned against using potassium supplements or salt substitutes containing potassium without prior consultation with their healthcare provider. Furthermore, if patients experience symptoms indicative of acute myopia or secondary angle-closure glaucoma, they should discontinue the medication and seek immediate medical attention.

For those taking hydrochlorothiazide, it is essential to instruct patients on the importance of protecting their skin from sun exposure and to discuss the necessity of regular skin cancer screenings, particularly due to the association with non-melanoma skin cancer.

Patients should be reminded to maintain an updated list of all medications they are taking and to share this list with their healthcare provider and pharmacist whenever they receive a new prescription. It is also crucial for patients to communicate all medical conditions to their healthcare provider, including any current or planned pregnancies, and to discuss strategies for skin protection and the frequency of skin cancer screenings.

Storage and Handling

The product is supplied in a container that must be kept tightly closed to maintain 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 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 Aurobindo Pharma Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)