Losartan potassium/Hydrochlorothiazide

Description

Losartan potassium and hydrochlorothiazide tablets are available in three formulations: 50/12.5 mg, 100/12.5 mg, and 100/25 mg. Each formulation combines losartan potassium, an angiotensin II receptor blocker, with hydrochlorothiazide, a diuretic.

Losartan potassium, USP, 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. Its empirical formula is C22H22ClKN6O, and it has a molecular weight of 461.01. This compound appears as a white to off-white free-flowing crystalline powder, which is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents such as acetonitrile and methyl ethyl ketone.

Hydrochlorothiazide, USP, is chemically defined as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.74. It is presented as 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 concentrations: 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide in the 50/12.5 mg tablets; 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide in the 100/12.5 mg tablets; and 100 mg of losartan potassium and 25 mg of hydrochlorothiazide in the 100/25 mg tablets. Each tablet formulation contains varying amounts of potassium: 4.24 mg (0.108 mEq) in the 50/12.5 mg tablets, and 8.48 mg (0.216 mEq) in both the 100/12.5 mg and 100/25 mg tablets.

Inactive ingredients include colloidal silicon dioxide, lactose monohydrate, macrogol/polyethylene glycol, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol-part hydrolyzed, pregelatinized starch, talc, and titanium dioxide. The 50/12.5 mg and 100/25 mg formulations also contain D&C yellow No. 10 aluminum lake and FD&C blue No. 1/brilliant blue FCF aluminum lake, while the 100/12.5 mg formulation includes lecithin.

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 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 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 impairment in these patients.

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, it is imperative to discontinue the use of losartan potassium and hydrochlorothiazide tablets as soon as possible. Medications that act directly on the renin-angiotensin system have the potential to cause injury or death to the developing fetus.

General precautions should 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. The use of these tablets may also exacerbate conditions such as acute angle-closure glaucoma and systemic lupus erythematosus.

Laboratory tests should include regular monitoring of renal function and potassium levels in susceptible patients to ensure safety during treatment.

Emergency medical assistance should be sought immediately in the event of angioedema, which may manifest as swelling of the larynx and glottis, leading to airway obstruction, or as swelling of the face, lips, pharynx, and/or tongue. Anaphylactic reactions can also occur, presenting as respiratory distress, which may include pneumonitis and pulmonary edema.

Patients are advised to discontinue the medication and contact their healthcare provider if they experience symptoms of angioedema or any severe allergic reactions.

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.

Serious adverse reactions associated with losartan potassium and hydrochlorothiazide tablets include hypotension, which necessitates 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. Additional serious reactions may include acute angle-closure glaucoma, exacerbation of systemic lupus erythematosus, and hypersensitivity to any component of the medication. Anuria has been reported, as well as concerns regarding coadministration with aliskiren in patients with diabetes.

A boxed warning highlights the risk of fetal toxicity, indicating that drugs acting 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.

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. The most common signs and symptoms resulting from overdosage are those related to 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 of the drug. 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.

• 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.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol: The absorption of thiazides, particularly hydrochlorothiazide, is significantly reduced in the presence of these anionic exchange resins. Single doses of cholestyramine or colestipol can decrease the absorption of hydrochlorothiazide by up to 85% and 43%, respectively. It is recommended to stagger the administration of hydrochlorothiazide and the resin, ensuring that hydrochlorothiazide is taken at least 4 hours before or 4 to 6 hours after the resin to minimize interaction.

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 in 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

There is no relevant information regarding the use of this medication during pregnancy, including safety concerns, dosage modifications, or special precautions. Healthcare professionals should consider the absence of data when prescribing this medication to pregnant patients and weigh the potential risks and benefits. Women of childbearing potential should be counseled accordingly.

Lactation

There are no specific statements regarding the use of this medication in lactating mothers or its effects on breastfed infants. Healthcare professionals should consider the absence of data when advising lactating mothers about 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 following oral administration of high doses of the drug, with mice exhibiting a lethal dose (LD50) of 1,000 mg/kg and rats showing an LD50 of 2,000 mg/kg. These doses 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. In some cases, bradycardia may occur due to parasympathetic (vagal) stimulation. Should symptomatic hypotension arise, it is imperative to initiate supportive treatment to manage the condition effectively.

It is important to note that neither losartan nor its active metabolite can be eliminated from the body 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 studies involving losartan potassium-hydrochlorothiazide. In male rats, the combination did not affect fertility or mating behavior 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 with 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, 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. 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 administered via diet at doses 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 and 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 assays, including the microbial mutagenesis and V-79 mammalian cell mutagenesis assays, as well as in the in vitro alkaline elution and chromosomal aberration assays. The active metabolite demonstrated no evidence of genotoxicity in the same assays. Two-year feeding studies in mice and rats revealed no carcinogenic potential for hydrochlorothiazide in female mice or in male and female rats, although the NTP found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay and the Chinese Hamster Ovary test for chromosomal aberrations, with positive results only in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell 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 human 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 consult with their healthcare provider regarding appropriate measures to protect their skin from sun exposure and to determine the frequency of skin cancer screenings.

Adverse events and side effects can be reported to Solco Healthcare US, LLC at 1-866-257-2597 or to the FDA at 1-800-FDA-1088.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) that accompanies losartan potassium and hydrochlorothiazide tablets. 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 treatment options with women who are planning to become pregnant and encourage them to report any pregnancies to their physicians as soon as possible.

Patients should be informed that lightheadedness may occur, particularly during the initial days of therapy, and they should report this symptom to their healthcare provider. Additionally, patients should be made aware that dehydration resulting from inadequate fluid intake, excessive perspiration, vomiting, or diarrhea can lead to a significant drop in blood pressure. In the event of syncope, patients are advised to contact their healthcare provider immediately.

It is crucial to inform patients not to use potassium supplements or salt substitutes containing potassium without prior consultation with their healthcare provider. Patients should also be instructed to discontinue losartan potassium and hydrochlorothiazide tablets and seek immediate medical attention if they experience symptoms indicative of Acute Myopia or Secondary Angle-Closure Glaucoma.

For those taking hydrochlorothiazide, patients should be advised to protect their skin from sun exposure and to undergo regular skin cancer screenings. They should be reminded to read the Patient Information leaflet that comes with their medication before starting treatment and each time they receive a refill, as there may be new information. This leaflet is not a substitute for discussions with their doctor regarding their condition and treatment.

Patients planning to become pregnant should discuss alternative methods for lowering blood pressure with their doctor. If a patient becomes pregnant while taking losartan potassium and hydrochlorothiazide tablets, they should inform their doctor immediately. It is also important for patients to disclose all their medical conditions to their healthcare provider, including any current or planned pregnancies.

Lastly, patients should be encouraged to maintain an updated list of all medications they are taking and to share this list with their doctor and pharmacist whenever they receive a new medication.

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°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines. Additionally, the product must be protected from light to ensure its stability and efficacy.

Additional Clinical Information

Postmarketing experience has revealed several adverse reactions associated with the use of losartan potassium and hydrochlorothiazide tablets. Rare cases of hepatitis have been reported among patients treated with losartan. Hematologic concerns include thrombocytopenia. Clinicians should be aware of hypersensitivity reactions such as angioedema, which may involve swelling of the larynx and glottis, leading to airway obstruction, as well as facial, lip, pharyngeal, and/or tongue swelling. Additional hypersensitivity reactions include vasculitis, specifically Henoch-Schönlein purpura, and anaphylactic reactions that can manifest as respiratory distress, including pneumonitis and pulmonary edema.

Musculoskeletal adverse effects include rhabdomyolysis, while skin reactions may present as erythroderma. Furthermore, hydrochlorothiazide has been linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study in the Sentinel System indicated that the risk for SCC was notably higher in white patients receiving large cumulative doses, with an estimated increase of approximately one additional case per 16,000 patients per year in the overall population, and one additional case for every 6,700 patients per year among white patients taking a cumulative dose of ≥50,000 mg.

FDA Insert (PDF)

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

View full prescribing information (PDF)