Hydrochlorothiazide/Losartan potassium

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: losartan potassium and hydrochlorothiazide tablets 50/12.5 mg contain 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide; losartan potassium and hydrochlorothiazide tablets 100/12.5 mg contain 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide; and losartan potassium and hydrochlorothiazide tablets 100/25 mg contain 100 mg of losartan potassium and 25 mg of hydrochlorothiazide.

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 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 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.

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of losartan potassium and hydrochlorothiazide tablets. It is imperative that these tablets be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system may lead to injury or death of 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 complications. Additionally, vigilance for clinical signs of fluid or electrolyte imbalance is recommended. Patients should also be assessed for the potential exacerbation of conditions such as acute angle-closure glaucoma and systemic lupus erythematosus.

Laboratory tests are crucial for ensuring patient safety. Regular monitoring of renal function and potassium levels is advised for susceptible patients to prevent adverse effects.

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 may also occur, presenting as respiratory distress, including pneumonitis and pulmonary edema.

Patients are advised to discontinue the medication and contact their healthcare provider if they experience symptoms indicative 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.

Patients receiving losartan potassium and hydrochlorothiazide tablets should be made aware of the potential for serious adverse reactions, including fetal toxicity. Drugs that act directly on the renin-angiotensin system, such as losartan, 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 use of this medication may result in several significant drug interactions, categorized primarily into pharmacodynamic and pharmacokinetic interactions.

Pharmacodynamic Interactions:

• Agents Increasing Serum Potassium: Co-administration with agents that elevate serum potassium levels may lead to hyperkalemia. Monitoring of serum potassium levels is advised.

• Lithium: Concurrent use with lithium may increase the risk of lithium toxicity. Regular monitoring of lithium levels is recommended to avoid potential toxicity.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs may enhance the risk of renal impairment and diminish the diuretic, natriuretic, and antihypertensive effects of this medication. Caution is advised when prescribing NSAIDs alongside this treatment.

• Dual Inhibition of the Renin-Angiotensin System: The combination of this medication with other agents that inhibit the renin-angiotensin system may elevate 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 in conjunction with this medication. Regular monitoring of blood glucose levels is advised to ensure appropriate glycemic control.

Pharmacokinetic Interactions:

• Cholestyramine and Colestipol: The absorption of thiazides, including hydrochlorothiazide, is significantly reduced in the presence of anionic exchange resins such as cholestyramine and colestipol. Specifically, single doses of cholestyramine or colestipol can reduce the absorption of hydrochlorothiazide by up to 85% and 43%, respectively. To mitigate this interaction, it is recommended that hydrochlorothiazide be administered at least 4 hours before or 4 to 6 hours after the administration of these resins to optimize therapeutic 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 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

There is no available information regarding the use of this medication during pregnancy, including safety concerns, dosage modifications, or any special precautions that should be taken. 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 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

In cases of overdosage, significant lethality has been observed in animal studies, with mice and rats exhibiting fatal outcomes following oral administration of 1,000 mg/kg and 2,000 mg/kg, respectively. These doses correspond to approximately 44 and 170 times the maximum recommended human dose when adjusted for body surface area (mg/m²).

Limited clinical data regarding human overdosage is available; however, the most likely symptoms 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 removed through hemodialysis, which should be taken into consideration when planning management strategies for overdosage cases.

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 dosage 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 in studies where 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 and 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 the microbial mutagenesis and V-79 mammalian cell mutagenesis assays, as well as in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. The active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.

Two-year feeding studies in mice and rats revealed no evidence of carcinogenic potential for hydrochlorothiazide in female mice at doses of up to approximately 600 mg/kg/day or in male and female rats at doses of 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 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Positive test 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

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 who are planning to become pregnant and encourage them to report any pregnancies to their physicians as soon as possible.

Inform patients 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.

Patients should be cautioned against using potassium supplements or salt substitutes containing potassium without prior consultation with their healthcare provider. It is crucial to instruct patients 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. Encourage patients to discuss with their healthcare provider how to protect their skin from sun exposure and the recommended frequency 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 medications. It is important for patients to communicate all their medical conditions to their healthcare provider, including any current or planned pregnancies. If a patient becomes pregnant while taking losartan potassium and hydrochlorothiazide tablets, they should inform their doctor immediately. Additionally, patients should engage in discussions with their healthcare provider regarding alternative methods for managing blood pressure if they are considering pregnancy.

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, it is essential to protect the product 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 instances of hepatitis have been reported among patients treated with losartan. Hematologic concerns include thrombocytopenia. Clinicians should be aware of hypersensitivity reactions, which may manifest as angioedema, potentially leading to airway obstruction, as well as swelling of the face, lips, pharynx, and tongue. Additional hypersensitivity reactions include vasculitis, such as Henoch-Schönlein purpura, and anaphylactic reactions that can present with 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 indicate that the overall risk for SCC is approximately one additional case per 16,000 patients per year, with a heightened risk for white patients receiving cumulative doses of ≥50,000 mg, where the risk increases to about one 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)