Losartan potassium/Hydrochlorothiazide

Description

Losartan Potassium and Hydrochlorothiazide Tablets USP are formulated in three strengths: 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 weight of 461.01 and a structural formula of C22H22ClKN6O. It appears as a white to off-white free-flowing crystalline powder, which is freely soluble in water and alcohols, and slightly soluble in common organic solvents such as acetonitrile and methyl ethyl ketone.

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

The tablets are intended for oral administration, with the following compositions: the 50 mg/12.5 mg tablets contain 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide; the 100 mg/12.5 mg tablets contain 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide; and the 100 mg/25 mg tablets contain 100 mg of losartan potassium and 25 mg of hydrochlorothiazide. Each tablet strength contains varying amounts of potassium: 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 lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol-part hydrolyzed, pregelatinized corn starch, talc, and titanium dioxide. The 50 mg/12.5 mg tablets also contain D&C Yellow #10 (Aluminum Lake) and FD&C Blue #1 (Aluminum Lake), while the 100 mg/25 mg tablets contain D&C Yellow #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 necessary, with a maximum allowable dose of 100/25 mg.

In patients with hypertension who also present with left ventricular hypertrophy and are not adequately controlled on monotherapy, treatment should be initiated with 50/12.5 mg once daily. Similar to the general hypertension population, titration may be performed as needed, 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 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 impairment in these patients.

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

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of losartan potassium and hydrochlorothiazide tablets. It is imperative that these medications be discontinued as soon as pregnancy is detected. Agents that directly affect the renin-angiotensin system have the potential to cause serious injury or death to the developing fetus.

Prior to initiating treatment with losartan potassium and hydrochlorothiazide tablets, 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 effects. Additionally, vigilance for clinical signs of fluid or electrolyte imbalance is recommended throughout the course of therapy.

The use of losartan potassium and hydrochlorothiazide tablets may also pose risks for patients with acute angle-closure glaucoma and those with a history of systemic lupus erythematosus, as exacerbation of this condition has been observed.

Regular laboratory tests to monitor renal function and potassium levels are advised for patients at risk, ensuring timely identification and management of any potential complications.

Side Effects

Patients receiving losartan potassium and hydrochlorothiazide tablets 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 fetal toxicity. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. Therefore, it is imperative to discontinue losartan potassium and hydrochlorothiazide tablets 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. 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, anuria, and the coadministration with aliskiren 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 are primarily those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, hyponatremia, and dehydration due to excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias.

Fetal and neonatal adverse reactions are particularly concerning when losartan potassium and hydrochlorothiazide tablets are used during the second and third trimesters of pregnancy. Potential outcomes include oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and even death.

In pediatric use, neonates with a history of in utero exposure to losartan potassium and hydrochlorothiazide tablets should be closely monitored. If oliguria or hypotension occurs, immediate attention should be directed toward supporting blood pressure and renal perfusion, with exchange transfusion or dialysis considered as necessary interventions.

Geriatric patients may experience adverse events more frequently than their non-elderly counterparts, as observed in both the losartan-hydrochlorothiazide and control groups during clinical trials.

Drug Interactions

The use of this medication may result in several significant drug interactions, categorized primarily into pharmacodynamic and pharmacokinetic interactions.

Pharmacodynamic Interactions

• Agents Increasing Serum Potassium: Concurrent use may elevate the risk of hyperkalemia. Monitoring of serum potassium levels is advised.

• Lithium: There is an increased risk of lithium toxicity when used in conjunction with this medication. Regular monitoring of lithium levels is recommended to avoid toxicity.

• Dual Inhibition of the Renin-Angiotensin System: The combination of this medication with agents that inhibit the renin-angiotensin system may lead to an increased risk of renal impairment, hypotension, syncope, and hyperkalemia. Close monitoring of renal function and blood pressure is warranted.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The concomitant use of NSAIDs may increase the risk of renal impairment and diminish the diuretic, natriuretic, and antihypertensive effects of this medication. Caution is advised, and renal function should be monitored.

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used with this medication. Blood glucose levels should be closely monitored to ensure effective glycemic control.

Pharmacokinetic Interactions

• 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 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 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 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, 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 factors, particularly in those aged 65 years and older.

Pregnancy

Losartan potassium and hydrochlorothiazide tablets 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 oligohydramnios, fetal lung hypoplasia, skeletal deformations, hypotension, and increased fetal and neonatal morbidity and mortality. Therefore, when pregnancy is detected, losartan potassium and hydrochlorothiazide tablets should be discontinued 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.

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 tablets 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 risks of fetal or neonatal jaundice or thrombocytopenia, and since thiazides do not alter the course of pre-eclampsia, 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 tablets should be closely observed for hypotension, oliguria, and hyperkalemia. If 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 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, as they may be at increased risk for complications. Dosing adjustments may be necessary based on the degree of reduced kidney function 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 on a mg/m² basis, respectively.

In humans, data regarding overdosage are limited. The most likely clinical manifestations of an overdose 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.

It is important to note that neither losartan nor its active metabolite can be effectively removed through hemodialysis, which may complicate management in cases of overdose.

Regarding hydrochlorothiazide, the oral LD50 is greater than 10 g/kg in both mice and rats. The predominant signs and symptoms associated with hydrochlorothiazide overdosage are typically related to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has been co-administered, hypokalemia may exacerbate the risk of cardiac arrhythmias. The extent to which hydrochlorothiazide is removed by hemodialysis remains undetermined, necessitating careful monitoring and management of electrolyte levels in cases of overdose.

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 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, 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. 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, while a dose of 100 mg/kg/day only showed a decrease in the number of corpora lutea. Hydrochlorothiazide did not adversely affect 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.

Losartan potassium was not found to be carcinogenic 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 exhibited a slightly higher incidence of pancreatic acinar adenoma. No carcinogenicity studies have been conducted specifically on the losartan potassium-hydrochlorothiazide combination. 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 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 and Mouse Lymphoma Cell assays at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay.

In terms of animal pharmacology and toxicology, losartan potassium was not carcinogenic at maximally tolerated dosages in rats and mice. 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 significantly higher than those achieved in humans at the maximum recommended daily dosage of 100 mg. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure levels for losartan and its active metabolite were approximately 66 and 26 times, respectively, the exposure achieved in humans at the maximum recommended dosage.

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 tablets and each time they receive a refill, as there may be new information. It is important for female patients of childbearing age to understand the potential consequences of exposure to these medications during pregnancy. Healthcare providers should discuss alternative treatment options with women who are planning to become pregnant and instruct patients to report any pregnancies to their physician as soon as possible.

Inform patients that symptomatic hypotension, characterized by lightheadedness, may occur, particularly during the initial days of therapy. Patients should be encouraged to report this symptom to their healthcare provider. Additionally, advise patients that dehydration resulting from 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.

Counsel patients against the use of potassium supplements or salt substitutes containing potassium without prior consultation with their healthcare provider. Patients should be made aware of the risk of acute myopia and secondary angle-closure glaucoma; they must discontinue the medication and seek immediate medical attention if they experience symptoms indicative of these conditions.

For patients taking hydrochlorothiazide, it is essential to emphasize the importance of protecting their skin from sun exposure and undergoing regular skin cancer screenings, as there is an increased risk of non-melanoma skin cancer associated with this medication.

Encourage patients to discuss all medical conditions with their healthcare provider, including any plans for pregnancy, breastfeeding status, and any history of vomiting, diarrhea, excessive sweating, liver or kidney problems, systemic lupus erythematosus, diabetes, gout, allergies, or previous skin cancer. Patients should also be advised to report any new skin lesions that develop during treatment.

Healthcare providers should discuss strategies for skin protection from sun exposure and establish a schedule for skin cancer screening. Patients should maintain an updated list of all medications they are taking and present this list to their healthcare provider and pharmacist when receiving new prescriptions.

Storage and Handling

The product is supplied in a tightly closed container that is light-resistant, in accordance with USP guidelines, and features a child-resistant closure as required. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), adhering to USP Controlled Room Temperature standards. Additionally, the container must be protected from light to maintain the integrity of the product. It is crucial to keep this medication, along with all other medications, out of the reach of children.

Additional Clinical Information

Clinicians are advised to monitor renal function periodically in patients whose renal function may be influenced by the renin-angiotensin system. Additionally, it is important to periodically assess serum electrolytes and calcium levels in these patients.

Patients should be counseled to discontinue losartan potassium and hydrochlorothiazide tablets immediately upon detection of pregnancy. They should also be informed about the potential risk of acute transient myopia and acute angle-closure glaucoma, including the associated symptoms and the necessity for prompt medical attention. Furthermore, it is noted that thiazide diuretics may exacerbate or activate systemic lupus erythematosus based on postmarketing experience.

FDA Insert (PDF)

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

View full prescribing information (PDF)