Hydrochlorothiazide/Losartan potassium

Description

Losartan potassium is 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 appears as a white to off-white amorphous powder and has 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 identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2. This compound is 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 USP are formulated for oral administration and are available in three combinations. The 50 mg/12.5 mg tablet contains 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide. The 100 mg/12.5 mg tablet contains 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide. The 100 mg/25 mg tablet contains 100 mg of losartan potassium and 25 mg of hydrochlorothiazide.

Inactive ingredients in these tablets include colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and titanium dioxide. The potassium content in the tablets is as follows: the 50 mg/12.5 mg tablet contains 4.24 mg (0.108 mEq) of potassium, the 100 mg/12.5 mg tablet contains 8.48 mg (0.216 mEq) of potassium, and the 100 mg/25 mg tablet also contains 8.48 mg (0.216 mEq) of potassium.

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

The usual starting dose 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, with subsequent 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 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. Medications that act directly on the renin-angiotensin system have been associated with fetal toxicity, potentially leading to injury or death of the developing fetus.

General precautions must be observed prior to the administration of losartan and hydrochlorothiazide. 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 be aware of the potential for acute angle-closure glaucoma and the possibility of exacerbation of systemic lupus erythematosus. Regular laboratory tests to monitor renal function and potassium levels are advised for those at risk.

Side Effects

Patients may experience a range of adverse reactions while using the combination of losartan potassium and hydrochlorothiazide. The most common adverse reactions reported include dizziness, upper respiratory infection, cough, and back pain.

Serious warnings associated with this medication include 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 crucial to avoid use during pregnancy.

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 can lead to complications. 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, and caution is advised when coadministering with aliskiren in patients with diabetes.

In cases of overdosage, the most likely manifestation from losartan potassium would be hypotension and tachycardia, although bradycardia may occur due to parasympathetic (vagal) stimulation. For hydrochlorothiazide, the most common signs and symptoms observed are those resulting from electrolyte depletion, including hypokalemia, hypochloremia, hyponatremia, and dehydration due to excessive diuresis.

Fetal and neonatal adverse reactions associated with losartan include oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations such as skull hypoplasia, hypotension, and even death. Hydrochlorothiazide has been linked to a risk of fetal or neonatal jaundice or thrombocytopenia.

Drug Interactions

There are currently no documented drug interactions associated with the use of this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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 losartan and hydrochlorothiazide, 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. Specifically, 62% of the 2857 patients enrolled were aged 65 years and older, and 18% were 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 with somewhat greater frequency 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 may be warranted, and dose adjustments should be considered based on the individual patient's response and tolerance, particularly in those aged 65 years and older.

Pregnancy

Losartan 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 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. Furthermore, hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Pregnant women with hypertension should be carefully monitored and managed accordingly. The use of drugs that act on the renin-angiotensin system during 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 and hydrochlorothiazide should be discontinued unless deemed lifesaving for the mother.

Neonates with a history of in utero exposure to losartan and hydrochlorothiazide should be closely observed for hypotension, oliguria, and hyperkalemia. In instances 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 accumulate in the amniotic fluid, and its use during pregnancy is associated with risks of fetal or neonatal jaundice or thrombocytopenia. Thiazides do not alter the course of pre-eclampsia and should not be used to treat hypertension in pregnant women. Additionally, the use of hydrochlorothiazide for other indications during pregnancy should 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 lactating 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. 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 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, 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

Losartan potassium-hydrochlorothiazide has been evaluated for teratogenic effects, and no teratogenic effects were identified in the studies conducted.

In terms of non-teratogenic effects, losartan potassium-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 observed in the in vitro alkaline elution assay using rat hepatocytes, nor in the in vitro chromosomal aberration assay conducted with Chinese hamster ovary cells at noncytotoxic concentrations.

Fertility assessments indicated that the coadministration of losartan potassium and 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, the administration of doses as low as 10 mg/kg/day of losartan and 2.5 mg/kg/day of hydrochlorothiazide was associated with slight but statistically significant decreases in fecundity and fertility indices.

Carcinogenicity studies revealed that losartan potassium was not 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 mutagenesis assays, including the microbial mutagenesis and V-79 mammalian cell mutagenesis assays, as well as in the in vitro alkaline elution and chromosomal aberration assays.

Fertility and reproductive performance were unaffected in studies involving male rats given 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) resulted in a significant decrease in the number of corpora lutea, implants, and live fetuses at C-section, with a decrease in the number of corpora lutea observed at 100 mg/kg/day. 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 also shown to be non-genotoxic in vitro in the Ames mutagenicity assay across various Salmonella typhimurium strains and in the Chinese Hamster Ovary test for chromosomal aberrations. In vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene did not indicate genotoxicity. 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.

Patients with pre-existing kidney issues may experience a deterioration in renal function. Symptoms such as swelling in the feet, ankles, or hands, or unexplained weight gain should prompt immediate consultation with a healthcare professional.

A new or worsening condition known as systemic lupus erythematosus (Lupus; 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 report these symptoms to their doctor without delay.

Increased sensitivity of the skin to sunlight and the associated risk of skin cancer have been observed in some individuals.

Patient Counseling

Advise patients to read the FDA-approved patient labeling (Patient Information) prior to initiating therapy with losartan potassium and hydrochlorothiazide and each time they receive a refill, as there may be new information. It is important for female patients of childbearing age to understand the potential consequences of exposure to losartan and hydrochlorothiazide during pregnancy. Healthcare providers should discuss alternative treatment options with women who are planning to become pregnant and instruct patients 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, 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 be instructed 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. Instruct patients to discontinue losartan and hydrochlorothiazide 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 essential 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 discussion with the healthcare provider is necessary to determine the best course of action regarding breastfeeding.

Patients should be encouraged to inform their healthcare provider about all medications they are taking, including prescription and non-prescription drugs, vitamins, and herbal supplements. Maintaining an updated list of medications to share with healthcare providers and pharmacists is advisable.

Instruct patients to take losartan potassium and hydrochlorothiazide exactly as prescribed, noting that their doctor may adjust the dosage as needed. If a dose is missed, patients should take it as soon as they remember, but if it is close to the time for the next dose, they should skip the missed dose and resume their regular dosing schedule. In cases of overdose, patients should seek immediate medical assistance by contacting their doctor, Poison Control Center, or going to the nearest hospital emergency room.

Finally, patients should be advised 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 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 effectiveness.

Additional Clinical Information

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

Patients should be counseled to discontinue losartan and hydrochlorothiazide as soon as pregnancy is detected. They should also be informed about the potential risk of acute transient myopia and acute angle-closure glaucoma, including the associated symptoms and the necessity for prompt medical attention.

FDA Insert (PDF)

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

View full prescribing information (PDF)