Hydrochlorothiazide/Losartan potassium

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, a non-peptide molecule, is chemically defined as 2-butyl-4-chloro-1-p-(o-1H-tetrazol-5-ylphenyl)benzylimidazole-5-methanol monopotassium salt, with a molecular formula of C22H22ClKN6O and a molecular weight of 461.01. It appears as a white to off-white free-flowing crystalline powder, freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents. The active metabolite of losartan is formed through the oxidation of the 5-hydroxymethyl group on the imidazole ring.

Hydrochlorothiazide is characterized 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 a white or practically white crystalline powder, slightly soluble in water, but freely soluble in sodium hydroxide solution.

The tablets are formulated for oral administration, with the following active ingredient content: 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide in the 50 mg/12.5 mg formulation; 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide in the 100 mg/12.5 mg formulation; and 100 mg of losartan potassium and 25 mg of hydrochlorothiazide in the 100 mg/25 mg formulation. Each formulation contains potassium as follows: 4.24 mg (0.108 mEq) in the 50 mg/12.5 mg tablets, and 8.48 mg (0.216 mEq) in both the 100 mg/12.5 mg and 100 mg/25 mg tablets.

Inactive ingredients include microcrystalline cellulose, lactose monohydrate, pregelatinized starch, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol, and D&C yellow No. 10 aluminum lake.

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 50/12.5 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 begin with a dose of 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 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 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. Medications that act directly on the renin-angiotensin system have the potential to cause serious injury or death to the developing fetus.

General precautions must be observed prior to the administration of losartan potassium and hydrochlorothiazide tablets. 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 recommended.

Patients should be aware of the risk of acute angle-closure glaucoma and the potential exacerbation of systemic lupus erythematosus. Regular laboratory tests to monitor renal function and potassium levels are advised for those at risk.

In the event of any concerning symptoms or adverse effects, patients should seek immediate medical assistance.

Side Effects

Most common adverse reactions observed in clinical trials, with an incidence of 2% or greater than placebo, include dizziness, upper respiratory infection, cough, and back pain.

Patients receiving losartan potassium and hydrochlorothiazide tablets should be made aware of the serious risk of fetal toxicity. Drugs that act directly on the renin-angiotensin system, including this combination, 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 correction of volume or salt depletion prior to administration. It is also recommended to monitor renal function and potassium levels in susceptible patients, as well as to observe for clinical signs of fluid or electrolyte imbalance. Other noted adverse reactions include acute angle-closure glaucoma, exacerbation of systemic lupus erythematosus, hypersensitivity to any component of the medication, and anuria. Coadministration with aliskiren in patients with diabetes is contraindicated.

In cases of overdosage, the most likely manifestations include hypotension and tachycardia, with bradycardia potentially occurring due to parasympathetic (vagal) stimulation. If symptomatic hypotension occurs, supportive treatment should be initiated. Common signs and symptoms associated with overdosage are primarily 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

The following drug interactions have been identified, categorized by their pharmacodynamic and pharmacokinetic effects.

Pharmacodynamic Interactions

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

• Lithium: Co-administration may elevate the risk of lithium toxicity. Regular monitoring of lithium levels is recommended to avoid 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 advised to ensure effective glycemic control.

• Cholestyramine and Colestipol: These agents may reduce the absorption of thiazides. It is recommended to separate the administration of thiazides from these medications to minimize interaction effects.

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 tablets in pediatric patients have not been established.

In neonates with a history of in utero exposure to losartan potassium and hydrochlorothiazide tablets, 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

In a controlled clinical study aimed at reducing the combined risk of cardiovascular death, stroke, and myocardial infarction, 62% of participants were aged 65 years and older, with 18% being 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 somewhat more frequently in elderly patients compared to non-elderly patients across both the losartan-hydrochlorothiazide and control groups. Given this increased incidence of adverse events, healthcare providers should exercise caution when prescribing this medication to geriatric patients. Close monitoring for potential side effects is recommended, and consideration should be given to possible dose adjustments based on the individual patient's health status and response to treatment.

Pregnancy

Losartan potassium and hydrochlorothiazide tablets 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 tablets 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 approximately 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. 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 and perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, losartan potassium and hydrochlorothiazide tablets should be discontinued unless deemed lifesaving for the mother.

Fetal testing may be appropriate based on gestational age, and it is important for patients and physicians 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 tablets 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, and exchange transfusions or dialysis could be required.

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 risks of fetal or neonatal jaundice or thrombocytopenia, and thiazides do not alter the course of preeclampsia; therefore, they should not be used to treat hypertension in pregnant women. Additionally, the use of hydrochlorothiazide for other indications during pregnancy should be avoided.

Lactation

There are no specific statements regarding nursing mothers or lactation in the provided text. Therefore, the effects of this medication on lactating mothers and breastfed infants are not established. Healthcare professionals should consider the absence of data when advising lactating mothers on the use of this 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, with mice and rats exhibiting severe outcomes following oral administration of 1000 mg/kg and 2000 mg/kg, respectively. These dosages 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 managing cases of overdosage.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, losartan potassium-hydrochlorothiazide 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 was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. However, female rats given the highest dose of 270 mg/kg/day exhibited 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 showed 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 NTP found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay or in the Chinese Hamster Ovary 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 in the Mouse Lymphoma Cell (mutagenicity) assays.

The systemic exposures 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. AUC values for losartan, its active metabolite, and hydrochlorothiazide, extrapolated from data obtained with losartan administered to rats at a dose of 50 mg/kg/day in combination with 12.5 mg/kg/day of hydrochlorothiazide, were approximately 6, 2, and 2 times greater than those achieved in humans with 100 mg of losartan in combination with 25 mg of hydrochlorothiazide.

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 discuss with their healthcare provider strategies for protecting their skin from sun exposure and the appropriate frequency of skin cancer screenings.

Additionally, eye problems have been reported in patients taking losartan potassium and hydrochlorothiazide tablets. These issues may manifest within hours to weeks of initiating treatment and, if left untreated, could potentially lead to vision loss. Patients should promptly inform their healthcare provider if they experience any decrease in vision or eye pain.

Furthermore, there have been reports of increased sensitivity of the skin to sunlight, which may contribute to the risk of skin cancer.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) prior to initiating therapy with losartan potassium and hydrochlorothiazide tablets and each time they receive a refill, as there may be new information. Additional patient information leaflets can be obtained by contacting Unichem at 1-866-562-4616.

Healthcare providers should discuss the implications of losartan potassium and hydrochlorothiazide tablets during pregnancy with female patients of childbearing age. It is important to inform these patients about the potential consequences of exposure during pregnancy and to 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.

Patients may experience lightheadedness, particularly during the initial days of therapy, and should be advised to report this symptom to their healthcare provider. It is essential to inform patients that dehydration due to inadequate fluid intake, excessive perspiration, vomiting, or diarrhea can lead to significant drops in blood pressure. In the event of syncope, patients should be instructed 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. Additionally, if patients experience symptoms of acute myopia or secondary angle-closure glaucoma, they should discontinue the medication and seek immediate medical attention.

For those taking hydrochlorothiazide, it is crucial to instruct patients to protect their skin from sun exposure and to undergo regular skin cancer screenings, as there is an increased risk of non-melanoma skin cancer associated with this medication.

Patients should be encouraged 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. Furthermore, discussions regarding skin protection from sun exposure and the frequency of skin cancer screenings should be held with their healthcare provider.

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 in these patients to ensure safety and efficacy during treatment.

FDA Insert (PDF)

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

View full prescribing information (PDF)