Losartan potassium/Hydrochlorothiazide

Description

Losartan potassium is chemically described as 2-butyl-4-chloro-1-p-(o-1H-tetrazol-5-ylphenyl)benzylimidazole-5-methanol monopotassium salt, with an empirical formula of C22H22ClKN6O. It is a white to off-white free-flowing crystalline powder with 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 an empirical formula of C7H8ClN3O4S2. It appears as a white or practically white 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: 50/12.5, 100/12.5, and 100/25. The 50/12.5 tablet contains 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide, while the 100/12.5 tablet contains 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide. The 100/25 tablet contains 100 mg of losartan potassium and 25 mg of hydrochlorothiazide.

Inactive ingredients in these tablets include microcrystalline cellulose, lactose monohydrate, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose, titanium dioxide, and carnauba wax. The 50/12.5 tablet contains 4.24 mg (0.108 mEq) of potassium, while both the 100/12.5 and 100/25 tablets contain 8.48 mg (0.216 mEq) of potassium.

Uses and Indications

Losartan potassium and hydrochlorothiazide is indicated for the treatment of hypertension to lower blood pressure. Effective blood pressure reduction is associated with a decreased risk of both fatal and nonfatal cardiovascular events, including strokes and myocardial infarctions.

This combination therapy is also indicated for the reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy. It is important to note that the evidence supporting this benefit does not extend to Black patients.

There are no teratogenic or nonteratogenic effects mentioned in the provided data.

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 hypertensive patients with left ventricular hypertrophy who are not adequately controlled on monotherapy, treatment should also be initiated with 50/12.5 mg once daily. Similar to the general hypertension protocol, 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 losartan potassium and hydrochlorothiazide 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 another contraindication, as the medication may exacerbate renal function issues in these patients.

Additionally, 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 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.

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.

Patients should be observed for clinical signs indicative of fluid or electrolyte imbalance, as these may arise during treatment. Additionally, there is a risk of acute angle-closure glaucoma associated with this medication, which requires vigilance in monitoring for symptoms.

Exacerbation of systemic lupus erythematosus has been reported, and healthcare providers should be aware of this potential reaction in susceptible individuals.

In the event of a serious allergic reaction, characterized by symptoms such as rash, itching or swelling, severe dizziness, or difficulty breathing, immediate medical assistance should be sought. Patients are advised to discontinue use and contact their healthcare provider if they experience persistent dry cough, signs of kidney dysfunction (e.g., changes in urine output), or any other unusual symptoms.

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 this medication include a significant risk of fetal toxicity. It is imperative that losartan potassium and hydrochlorothiazide 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 the medication. Anuria has also been reported, as well as concerns regarding the coadministration of losartan potassium and hydrochlorothiazide with aliskiren in patients with diabetes.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there are no known 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 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 occurred somewhat more frequently in the elderly population 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 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, 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 for the indicated population is unknown; however, all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. 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, as well as increased fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

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, it is essential to 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.

Hydrochlorothiazide can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. It 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, and thiazides 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.

Neonates with a history of in utero exposure to losartan potassium and hydrochlorothiazide should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs in these neonates, it is important to support blood pressure and renal perfusion.

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, healthcare professionals should consider the importance of the drug to the lactating mother when making a decision to either discontinue nursing or discontinue 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 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 on a mg/m² basis.

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 from the body through hemodialysis, which limits the options for intervention in cases of overdose.

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 have been observed in studies involving losartan potassium-hydrochlorothiazide. The combination, tested at a weight ratio of 4:1, yielded 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 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 mating behavior or fertility 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. Furthermore, the administration of toxic dosage levels in females (300/200 mg/kg/day) was 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. In contrast, hydrochlorothiazide did not exhibit adverse effects on the fertility of mice and rats of either sex when administered 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, losartan potassium was not found to be carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Notably, female rats receiving the highest dose of 270 mg/kg/day exhibited a slightly higher incidence of pancreatic acinar adenoma.

Hydrochlorothiazide was not genotoxic in vitro, as demonstrated in the Ames mutagenicity assay using various Salmonella typhimurium strains and in the Chinese Hamster Ovary test for chromosomal aberrations. In vivo assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also showed no genotoxic effects. 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.

The maximally tolerated dosages of losartan potassium (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

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 treatment 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 exposure to losartan potassium and hydrochlorothiazide during pregnancy with female patients of childbearing age. Providers should encourage these patients to report any pregnancies to their physicians as soon as possible and to consider alternative treatment options if they are planning to become pregnant.

Patients should be informed about the potential for symptomatic hypotension, particularly during the initial days of therapy. They should be advised to report any occurrences of 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 should be instructed to contact their healthcare provider immediately.

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

For those taking hydrochlorothiazide, healthcare providers should emphasize the importance of protecting the skin from sun exposure and the necessity of regular skin cancer screenings, particularly due to the association with non-melanoma skin cancer.

Patients should be encouraged to discuss all medical conditions with their healthcare provider, including any plans for pregnancy. Providers should also discuss alternative methods for managing blood pressure for patients who are planning to become pregnant and advise on appropriate skin protection measures 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 its integrity. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature guidelines. Additionally, the product must be protected from light to ensure its efficacy. It is essential to keep this and all medications out of the reach of children to prevent accidental ingestion.

Additional Clinical Information

Patients receiving ACE-inhibitor therapy may experience persistent dry cough, which has been noted as a common reason for discontinuation of treatment. Clinicians should counsel patients regarding this potential side effect to ensure they are adequately informed.

In the context of postmarketing experience, there have been reported cases of cough associated with the use of losartan, including instances of positive re-challenges. Additionally, clinicians should monitor liver function abnormalities in patients, as these may occur during treatment.

FDA Insert (PDF)

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

View full prescribing information (PDF)