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 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. 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 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 apply to Black patients.

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

Dosage and Administration

The usual starting dose for the management of hypertension is 50/12.5 mg administered orally once daily. Healthcare professionals may titrate the dosage as needed, with a maximum allowable dose of 100/25 mg.

For hypertensive patients with left ventricular hypertrophy who are not adequately controlled on monotherapy, treatment should also be initiated with 50/12.5 mg orally once daily, with titration to a maximum of 100/25 mg as necessary.

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.

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 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, clinicians should remain vigilant for clinical signs indicative of fluid or electrolyte imbalance. There is also a risk of acute angle-closure glaucoma and exacerbation of systemic lupus erythematosus associated with the use of this medication.

Laboratory tests should include regular monitoring of renal function and potassium levels in susceptible patients to ensure safety and efficacy 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 the potential for 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, and hypersensitivity to any component of the medication. Anuria has also been reported. Coadministration with aliskiren is contraindicated in patients with diabetes due to the increased risk of adverse effects.

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 of the drug. Caution is advised when prescribing NSAIDs to patients on this medication.

• Dual Inhibition of the Renin-Angiotensin System: The combination of agents that inhibit the renin-angiotensin system 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. Monitoring of blood glucose levels is advised to ensure effective glycemic control.

• Cholestyramine and Colestipol: The use of cholestyramine or colestipol may reduce the absorption of thiazide diuretics. It is recommended to separate the administration of these agents to minimize the impact on thiazide 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, 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 drug during pregnancy, including safety concerns, dosage modifications, or special precautions. Healthcare professionals should consider the lack 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 any lactation considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to lactating mothers, as the effects on breastfed infants are not established. It is advisable to weigh the potential benefits against any unknown risks when considering treatment options for lactating patients.

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

In cases of overdosage, significant lethality has been observed in animal studies, with oral administration of 1,000 mg/kg in mice and 2,000 mg/kg in rats resulting in mortality rates approximately 44 and 170 times the maximum recommended human dose on a mg/m² basis, respectively.

Limited data regarding human overdosage are available. The most likely clinical manifestations include hypotension and tachycardia; however, bradycardia may occur due to parasympathetic (vagal) stimulation. In instances of symptomatic hypotension, it is imperative to initiate supportive treatment promptly.

It is important to note that neither losartan nor its active metabolite can be effectively removed through hemodialysis.

For hydrochlorothiazide, the oral LD50 is greater than 10 g/kg in both mice and rats. The predominant signs and symptoms associated with overdosage are typically those resulting from electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration due to 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.

Healthcare professionals should remain vigilant for these symptoms and manage the patient accordingly, ensuring appropriate monitoring and supportive care as needed.

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 impact on fertility or 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 (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 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. In mutagenicity assessments, losartan potassium-hydrochlorothiazide, tested at a weight ratio of 4:1, was 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 receiving the highest dose of 270 mg/kg/day exhibited a slightly higher incidence of pancreatic acinar adenoma. Losartan potassium was consistently 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 also showed no evidence of genotoxicity in these 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 National Toxicology Program (NTP) found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay or the Chinese Hamster Ovary (CHO) 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.

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

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) prior to initiating treatment with losartan potassium and hydrochlorothiazide tablets and each time they receive a refill, as there may be new information.

For female patients of childbearing age, it is essential to discuss the potential consequences of exposure to losartan potassium and hydrochlorothiazide during pregnancy. Providers should encourage these patients to report any pregnancies to their healthcare provider as soon as possible and to discuss alternative treatment options if they are planning to become pregnant.

Patients should be informed about the risk of symptomatic hypotension, particularly during the initial days of therapy. They should be advised to report any lightheadedness to their healthcare provider. Additionally, it is important to inform patients 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.

Healthcare providers should caution patients against using potassium supplements or salt substitutes containing potassium without prior consultation. Patients should also be made aware of the symptoms of acute myopia and secondary angle-closure glaucoma, and advised to discontinue the medication and seek immediate medical attention if they experience these symptoms.

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

Patients should be reminded to inform their healthcare provider about all medical conditions, including any plans for pregnancy, and to disclose all medications they are currently taking, including prescription and non-prescription drugs, vitamins, and herbal supplements. Maintaining an updated list of medications to share with healthcare providers is also recommended.

Patients must take losartan potassium and hydrochlorothiazide tablets exactly as prescribed. If a dose is missed, they should take it as soon as they remember unless it is close to the time of their next dose; in that case, they should skip the missed dose and resume their regular schedule. Patients should be instructed to seek immediate medical attention if they suspect an overdose.

Regular blood tests may be necessary while on this medication, and patients should be encouraged to report any bothersome or persistent side effects to their healthcare provider. For a complete list of side effects, patients should consult their doctor or pharmacist. They may also report side effects to Solco Healthcare US, LLC at 1-866-257-2597 or the FDA at 1-800-FDA-1088.

Finally, patients should be advised on the proper storage of losartan potassium and hydrochlorothiazide tablets, which should be kept at room temperature (59°F to 86°F or 15°C to 30°C) in a tightly closed container, away from light, and out of reach of children.

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 efficacy.

Additional Clinical Information

Postmarketing experience has revealed several rare adverse events associated with losartan treatment. Clinicians should be aware of reports of hepatitis, thrombocytopenia, and angioedema, which may include severe manifestations such as laryngeal and glottic swelling leading to airway obstruction, as well as facial, lip, pharyngeal, and tongue swelling. Additional serious reactions include vasculitis, anaphylactic responses that can manifest as respiratory distress (including pneumonitis and pulmonary edema), rhabdomyolysis, and 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 indicate that the heightened risk is primarily observed in white patients receiving large cumulative doses. Specifically, the overall population faces an approximate risk increase of one additional SCC case per 16,000 patients per year, while white patients with a cumulative dose of ≥50,000 mg may see an increase of one additional SCC case for every 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 Solco Healthcare US, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)