Losartan potassium/Hydrochlorothiazide

Description

Losartan potassium is a non-peptide molecule chemically described as 2-butyl-4-chloro-1-p-(o-1H-tetrazol-5-ylphenyl)benzylimidazole-5-methanol monopotassium salt, with an empirical formula of C22H22ClKN6O. It is a white to off-white free-flowing crystalline powder with a molecular weight of 461.01. Losartan potassium 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 an empirical formula of C7H8ClN3O4S2. It appears as a white or practically white crystalline powder with a molecular weight of 297.74. Hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.

Losartan potassium and hydrochlorothiazide tablets are available for oral administration in three combinations: 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide, 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide, and 100 mg of losartan potassium and 25 mg of hydrochlorothiazide. The inactive ingredients include hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and titanium dioxide. The 50 mg/12.5 mg and 100 mg/25 mg tablet formulations also contain D&C yellow No. 10 aluminum lake. The potassium content in the tablets is 4.24 mg (0.108 mEq) for the 50 mg/12.5 mg formulation, and 8.48 mg (0.216 mEq) for both the 100 mg/12.5 mg and 100 mg/25 mg formulations.

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 be initiated 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. Additionally, the presence of anuria contraindicates use, as the medication relies on renal function for efficacy. 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 serious 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, vigilance for clinical signs of fluid or electrolyte imbalance is recommended.

Patients should be aware of 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 safe use of the medication.

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. 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 be monitored for renal function and potassium levels, 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. Caution is advised when coadministering losartan potassium and hydrochlorothiazide with aliskiren in patients with diabetes, as this may lead to further complications.

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: 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 with this medication. Regular monitoring of lithium levels is recommended to avoid toxicity.

• Dual Inhibition of the Renin-Angiotensin System: The combination of this medication with agents that inhibit the renin-angiotensin system may lead to an increased risk of renal impairment, hypotension, syncope, and hyperkalemia. Close monitoring of renal function and blood pressure is warranted.

• 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 this medication. Caution is advised, and renal function should be monitored.

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

Pharmacokinetic Interactions

• Cholestyramine and Colestipol: These agents may reduce the absorption of thiazides, potentially diminishing their effectiveness. It is advisable to separate the administration of these medications to optimize therapeutic outcomes.

No additional drug interactions or laboratory test interactions have been identified. Regular monitoring and appropriate dosage adjustments are recommended where applicable to mitigate the risks associated with these interactions.

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 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 across both the losartan-hydrochlorothiazide and control groups.

Given these observations, 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 tolerance and response.

Pregnancy

Losartan potassium and hydrochlorothiazide tablets can cause fetal harm when administered to pregnant patients. 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, leading to increased fetal and neonatal morbidity and mortality. Most epidemiologic studies examining fetal abnormalities following antihypertensive use in the first trimester have not differentiated between drugs affecting the renin-angiotensin system and other antihypertensive agents.

When pregnancy is detected, losartan potassium and hydrochlorothiazide tablets should be discontinued as soon as possible. The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2% to 4% and 15% to 20%, respectively. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. Hypertension during pregnancy increases maternal risks for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, while also increasing fetal risks for intrauterine growth restriction and intrauterine death.

Pregnant women with hypertension should be closely monitored and managed appropriately. The use of drugs that act on the renin-angiotensin system in the second and third trimesters can lead to oligohydramnios, reduced fetal renal function resulting in 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, healthcare providers should inform the mother of the potential risks to the fetus and perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, losartan potassium and hydrochlorothiazide tablets should be discontinued unless deemed lifesaving for the mother.

Fetal testing may be warranted based on gestational age, and it is important to note 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 tablets should be closely observed for hypotension, oliguria, and hyperkalemia. In cases of oliguria or hypotension, supportive measures for blood pressure and renal perfusion may be necessary, including potential exchange transfusions or dialysis.

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 risks of fetal or neonatal jaundice and thrombocytopenia, and since thiazides do not alter the course of pre-eclampsia, they should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications during pregnancy should also be avoided.

Lactation

It is not known whether losartan is excreted in human milk; however, significant levels of losartan and its active metabolite have been detected in rat milk. Thiazides are known to appear in human milk.

Due to the potential for adverse effects on the nursing infant, healthcare professionals should consider the importance of the drug to the mother when making a decision to either discontinue nursing or discontinue the medication.

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

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 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 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 is 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 managing severe cases of overdosage.

In the case 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. Monitoring and correcting these electrolyte imbalances, along with rehydration, are critical components of the management strategy for patients experiencing hydrochlorothiazide overdosage.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted.

Losartan potassium and hydrochlorothiazide, when 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 using rat hepatocytes or in the in vitro chromosomal aberration assay with Chinese hamster ovary cells at noncytotoxic concentrations. In male rats, coadministration of losartan potassium and hydrochlorothiazide at dosages up to 135 mg/kg/day and 33.75 mg/kg/day, respectively, did not affect fertility or mating behavior. 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.

Losartan potassium was not found to be carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Notably, female rats receiving the highest dose of 270 mg/kg/day exhibited a slightly higher incidence of pancreatic acinar adenoma. Furthermore, losartan potassium was consistently negative in various mutagenicity assays, including the microbial mutagenesis and V-79 mammalian cell mutagenesis assays, as well as in vitro alkaline elution and chromosomal aberration assays.

Fertility and reproductive performance in male rats were unaffected by oral doses of losartan potassium up to approximately 150 mg/kg/day. However, the administration of toxic dosage levels in female rats (300/200 mg/kg/day) was associated with 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 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 specifically on the losartan potassium-hydrochlorothiazide combination. However, two-year feeding studies conducted by the National Toxicology Program (NTP) found 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 report equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay across various Salmonella typhimurium strains or in the Chinese Hamster Ovary 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 observed in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays, as well as in the Aspergillus nidulans non-disjunction assay, under specific conditions.

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 discuss protective measures against sun exposure and the frequency of skin cancer screenings with their healthcare provider.

Reports have indicated potential injury or death of unborn babies associated with the use of losartan potassium and hydrochlorothiazide tablets.

Allergic reactions have been documented, with symptoms including swelling of the face, lips, throat, or tongue, and may also involve severe shortness of breath and/or difficulty breathing. Immediate medical attention is recommended in such cases, and discontinuation of the medication is advised.

Instances of low blood pressure (hypotension) have been reported, which may result in feelings of faintness or dizziness. Patients experiencing these symptoms should lie down and contact their healthcare provider promptly.

Worsening kidney function has been observed in patients with pre-existing kidney issues. Symptoms such as swelling in the feet, ankles, or hands, or unexplained weight gain should prompt a consultation with a healthcare professional.

A new or exacerbated condition known as systemic lupus erythematosus (SLE) has been reported in some patients.

Eye problems have also been noted, with one of the components in losartan potassium and hydrochlorothiazide tablets potentially leading to vision loss if untreated. Symptoms may arise within hours to weeks of initiating treatment and include decreased vision and eye pain. Patients are encouraged to inform their doctor immediately if they experience these symptoms.

Increased sensitivity of the skin to sunlight and the associated risk of skin cancer have been highlighted as concerns for patients undergoing treatment with these medications.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) that accompanies losartan potassium and hydrochlorothiazide tablets before initiating therapy and with each 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 possibility of symptomatic hypotension, particularly during the initial days of therapy. They should be advised to report any episodes of lightheadedness to their healthcare provider. Additionally, it is important to inform 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 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 risk of acute myopia and secondary angle-closure glaucoma. If they experience symptoms indicative of these conditions, they should discontinue the medication and seek immediate medical attention.

For those taking hydrochlorothiazide, it is crucial to instruct patients on the importance of protecting their skin from sun exposure and to discuss the frequency of skin cancer screenings, as there is an increased risk of non-melanoma skin cancer associated with this medication.

Patients should be encouraged to maintain an updated list of all medications they are taking and to share this list with their healthcare provider and pharmacist whenever they receive a new prescription. This practice will help ensure safe and effective management of their health conditions.

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 of 25°C (77°F), with permissible excursions between 15° to 30°C (59° 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

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 to ensure patient safety and effective management.

FDA Insert (PDF)

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

View full prescribing information (PDF)