Losartan potassium/Hydrochlorothiazide

Description

Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-p-(o-1H-tetrazol-5-ylphenyl)benzylimidazole-5-methanol monopotassium salt. Its molecular formula is C22H22ClKN6O, and it has a molecular weight of 461.01. Losartan potassium USP appears as a white to off-white powder and is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents such as acetonitrile and methyl ethyl ketone.

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

Losartan potassium and hydrochlorothiazide are available for oral administration in three tablet combinations. The formulations include losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg, which contain 50 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP; losartan potassium and hydrochlorothiazide tablets USP, 100 mg/12.5 mg, containing 100 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP; and losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25 mg, which contain 100 mg of losartan potassium USP and 25 mg of hydrochlorothiazide USP.

Inactive ingredients in these formulations include colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinised starch (maize), and titanium dioxide. The 50 mg/12.5 mg and 100 mg/25 mg formulations also contain D&C yellow No. 10 aluminum lake. The potassium content in the tablets is as follows: 4.24 mg (0.108 mEq) in the 50 mg/12.5 mg formulation, and 8.48 mg (0.217 mEq) in both the 100 mg/12.5 mg and 100 mg/25 mg formulations. These tablets meet USP Dissolution Test 2.

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 mg/12.5 mg administered once daily. Healthcare professionals may titrate the dosage as needed, with a maximum allowable dose of 100 mg/25 mg.

In hypertensive patients with left ventricular hypertrophy who are not adequately controlled on monotherapy, treatment should also begin with 50 mg/12.5 mg once daily. Similar to the general hypertension protocol, titration may be performed as necessary, up to a maximum dose of 100 mg/25 mg.

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 another contraindication, as the presence of this condition indicates a lack of urine production, which may lead to complications when using this medication.

Additionally, 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. This is critical as drugs that act directly on the renin-angiotensin system have the potential to cause injury or death to the developing fetus.

Prior to initiating treatment with losartan potassium and hydrochlorothiazide, it is essential to correct any 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 complications.

Clinicians should remain vigilant for clinical signs indicative of fluid or electrolyte imbalance during the course of treatment. Additionally, there is a risk of acute angle-closure glaucoma associated with the use of this medication, necessitating careful patient assessment.

Patients with a history of systemic lupus erythematosus may experience exacerbation of their condition while on this therapy. Therefore, ongoing evaluation and monitoring are recommended to ensure patient safety and effective management of any potential adverse effects.

Side Effects

Patients receiving losartan potassium and hydrochlorothiazide 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. Drugs that act directly on the renin-angiotensin system, such as losartan potassium and hydrochlorothiazide, 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 that may occur include hypotension, which necessitates the correction of volume or salt depletion prior to administration. Patients should also have their renal function and potassium levels monitored, particularly those who are susceptible. Clinical signs of fluid or electrolyte imbalance should be observed, as these may arise during treatment. Other notable adverse reactions include acute angle-closure glaucoma, exacerbation of systemic lupus erythematosus, and hypersensitivity reactions to any component of the medication. Anuria has also been reported in some cases.

Coadministration with aliskiren is contraindicated in patients with diabetes, highlighting the need for careful consideration of patient history and concurrent medications.

Drug Interactions

The use of certain agents may lead to significant drug interactions that require careful consideration and monitoring.

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. Regular monitoring of lithium levels is recommended to avoid toxicity.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The combination with NSAIDs may result in an increased risk of renal impairment and a reduction in the diuretic, natriuretic, and antihypertensive effects. Caution is advised, and renal function should be monitored.

• Dual Inhibition of the Renin-Angiotensin System: This combination may lead to an increased risk of renal impairment, hypotension, syncope, and hyperkalemia. Close monitoring of blood pressure and renal function is recommended.

Pharmacokinetic Interactions

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used concurrently. Blood glucose levels should be closely monitored to ensure effective management.

• Cholestyramine and Colestipol: These agents may reduce the absorption of thiazides. It is advisable to separate the administration of thiazides from these medications to minimize interaction effects.

No additional drug interactions or laboratory test interactions have been identified.

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 in pediatric patients have not been established. In neonates with a history of in utero exposure to these medications, if oliguria or hypotension occurs, it is essential to direct attention toward supporting 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 is recommended, and dose adjustments may be necessary based on individual patient response and tolerability.

Pregnancy

Losartan potassium and hydrochlorothiazide 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 increased fetal and neonatal morbidity and mortality. Therefore, when pregnancy is detected, it is recommended to discontinue losartan potassium and hydrochlorothiazide 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 approximately 2% to 4% and 15% to 20%, respectively. Hypertension in pregnancy poses additional maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and delivery complications such as the need for cesarean section and post-partum hemorrhage. Furthermore, hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Pregnant women with hypertension should be closely monitored and managed accordingly. The use of drugs that affect the renin-angiotensin system in the second and third trimesters can result in oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and death. In cases where there is no appropriate alternative to therapy with these drugs, it is essential to 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 should be discontinued unless deemed lifesaving for the mother.

Fetal testing may be appropriate based on gestational age, and both patients and physicians should be aware that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. Neonates with a history of in utero exposure to losartan potassium and hydrochlorothiazide should be closely observed for hypotension, oliguria, and hyperkalemia. In cases of oliguria or hypotension, it may be necessary to support blood pressure and renal perfusion, with exchange transfusions or dialysis potentially required to reverse hypotension and restore renal function.

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 a risk 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. Additionally, the use of hydrochlorothiazide for other indications during pregnancy should be avoided.

Lactation

There is no specific information available regarding the use of this drug in nursing mothers or its effects on lactation. Consequently, healthcare professionals should exercise caution when considering this medication for lactating mothers, as the potential risks to breastfed infants are not well characterized. It is advisable to weigh the benefits of treatment against any unknown risks when prescribing this medication to lactating individuals.

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

There is no available information regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise caution and consider the overall clinical context when prescribing this medication to patients with liver problems, as the absence of specific guidance necessitates careful evaluation of potential risks and benefits.

Overdosage

Significant lethality has been observed in animal studies following oral administration of high doses of the compound, 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 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 overdosage, 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, including 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 the studies conducted with losartan potassium-hydrochlorothiazide. In terms of non-teratogenic effects, the combination 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 when 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 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 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 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, although positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays.

The relationship of findings related to drug treatment in females remains uncertain, as there was no effect at these dosage levels on implants in pregnant females, percent post-implantation loss, or live animals per litter at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) 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.

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 patients to understand that this leaflet does not replace discussions with their healthcare provider regarding their condition and treatment.

Inform female patients of childbearing age about the potential consequences of exposure to losartan potassium and hydrochlorothiazide during pregnancy. Encourage discussions about treatment options for women who are planning to become pregnant, and instruct patients to report any pregnancies to their healthcare provider as soon as possible. Additionally, if a patient becomes pregnant while taking these medications, they should notify their doctor immediately.

Advise patients that lightheadedness may occur, particularly during the initial days of therapy, and they should report this symptom to their healthcare provider. It is also essential to inform patients 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 should contact their healthcare provider promptly.

Patients should be cautioned against using potassium supplements or salt substitutes containing potassium without prior consultation with their healthcare provider. Furthermore, 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. It is also crucial for patients to communicate all medical conditions to their healthcare provider, including any plans for pregnancy or breastfeeding. Losartan potassium and hydrochlorothiazide can pass into breast milk and may pose risks to a nursing infant; therefore, a decision regarding the use of these medications versus breastfeeding should be made collaboratively with their healthcare provider.

Encourage patients to maintain an updated list of all medications they are taking, including prescription and non-prescription drugs, vitamins, and herbal supplements, and to share this list with their healthcare provider and pharmacist when obtaining new medications.

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° to 25°C (68° to 77°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

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

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)