Losartan potassium/Hydrochlorothiazide

Description

Losartan potassium, USP is chemically described as 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 g/mol. Losartan potassium appears as a white to off-white free-flowing crystalline powder. It 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 identified 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 g/mol. Hydrochlorothiazide is a white, or practically white, crystalline powder that is slightly soluble in water but freely soluble in sodium hydroxide solution.

Losartan potassium and hydrochlorothiazide tablets, USP are available in three combinations: 50/12.5 mg, 100/12.5 mg, and 100/25 mg. The 50/12.5 mg tablets contain 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide, along with 4.24 mg (0.108 mEq) of potassium. The 100/12.5 mg tablets contain 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide, with 8.48 mg (0.216 mEq) of potassium. The 100/25 mg tablets contain 100 mg of losartan potassium and 25 mg of hydrochlorothiazide, also with 8.48 mg (0.216 mEq) of potassium.

Inactive ingredients in the tablets include colloidal silicon dioxide, lactose monohydrate, macrogol/polyethylene glycol, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol-part hydrolyzed, pregelatinized starch, talc, and titanium dioxide.

Uses and Indications

Losartan potassium and hydrochlorothiazide tablets are indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Additionally, these tablets are 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 apply to Black patients.

There are no teratogenic or nonteratogenic effects associated with this medication.

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 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 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 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. Patients should also be assessed for the risk of acute angle-closure glaucoma and the potential exacerbation of 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 present 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 manifest as respiratory distress, including 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

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. It is imperative that losartan potassium and hydrochlorothiazide tablets be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can cause injury or death to 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, hypersensitivity to any component of the medication, and anuria. Coadministration with aliskiren is contraindicated 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. If symptomatic hypotension occurs, supportive treatment should be initiated. The most common signs and symptoms associated with overdosage are 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 concomitant use of certain agents may lead to significant drug interactions that require careful consideration and monitoring.

Pharmacodynamic Interactions

• Agents Increasing Serum Potassium: The use of agents that elevate serum potassium levels may result in hyperkalemia. Monitoring of serum potassium is advised to mitigate this risk.

• Lithium: Co-administration with lithium may increase the risk of lithium toxicity. Regular monitoring of lithium levels is recommended to ensure safe therapeutic ranges.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs can lead to an increased risk of renal impairment and may diminish the diuretic, natriuretic, and antihypertensive effects. Patients should be monitored for renal function and blood pressure.

• 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 warranted.

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: The absorption of hydrochlorothiazide is impaired when administered with these resins. It is advised to administer hydrochlorothiazide at least 4 hours before or 4 to 6 hours after taking cholestyramine or colestipol to optimize absorption.

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, a significant proportion of participants were elderly, with 62% of patients aged 65 years and older and 18% aged 75 years and older. While no overall differences in effectiveness were observed between elderly patients and their younger counterparts, it is important to note that adverse events occurred somewhat more frequently in the elderly population compared to non-elderly patients for both the losartan-hydrochlorothiazide and control groups.

Given these findings, 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, including renal function and the presence of comorbidities, which are more prevalent in the elderly population.

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 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 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 documented in animal studies following oral administration of high doses of the drug, with mice exhibiting a lethal dose (LD50) at 1,000 mg/kg and rats at 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).

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

In the context 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 were observed in studies involving losartan potassium-hydrochlorothiazide. The combination, 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 conducted in rat hepatocytes or in the in vitro 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 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. The administration of higher 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. Hydrochlorothiazide alone had no 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.

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. The combination of losartan potassium and hydrochlorothiazide has not been evaluated for carcinogenicity. 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 various assays, including the Ames mutagenicity assay and the Chinese Hamster Ovary test for chromosomal aberrations, as well as in vivo assays using mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes. Positive results were only observed in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays at specific concentrations, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

In studies involving 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 the exposure achieved in humans at the maximum recommended daily dosage of 100 mg. The maximally tolerated dosages for losartan potassium were determined to be 270 mg/kg/day in rats and 200 mg/kg/day in mice, providing systemic exposures that were approximately 160 and 90 times (rats) and 30 and 15 times (mice) the exposure of a 50 kg human receiving 100 mg per day.

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

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 essential 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 planning to become pregnant and instruct 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, 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 contact their healthcare provider immediately.

It is important to counsel patients against using 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, advise them to protect their skin from sun exposure and to undergo regular skin cancer screenings. Patients should be reminded to inform their healthcare provider about all medical conditions, including pregnancy status or plans to become pregnant, as well as breastfeeding intentions, since losartan potassium and hydrochlorothiazide can pass into breast milk and may harm a nursing infant. A discussion with their doctor is necessary to determine whether to continue the medication or breastfeeding.

Patients should provide their healthcare provider with a comprehensive list of all medications they are taking, including prescription and non-prescription drugs, vitamins, and herbal supplements. They should be encouraged to maintain an updated list of their medications and present it to their doctor and pharmacist when obtaining new prescriptions.

Instruct patients to take losartan potassium and hydrochlorothiazide tablets exactly as prescribed, noting that their doctor may adjust the dosage as necessary. These tablets can be taken with or without food. If a dose is missed, patients should take it as soon as they remember, but if it is close to the time of their next scheduled dose, they should skip the missed dose and resume their regular dosing schedule.

In the case of an overdose, patients should be advised to contact their healthcare provider, the Poison Control Center, or proceed to the nearest hospital emergency room immediately. Regular blood tests may be conducted by the healthcare provider while the patient is on this medication. Finally, patients should be encouraged to report any side effects that are bothersome or persistent to 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°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as defined by USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from light to ensure its stability and effectiveness.

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 in 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 tongue swelling. Other hypersensitivity reactions may include vasculitis, such as 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. Additionally, 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 indicate that the overall risk for SCC is approximately 1 additional case per 16,000 patients per year, with a significantly higher risk for white patients receiving cumulative doses of ≥50,000 mg, estimated at 1 additional case per 6,700 patients per year.

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)