Losartan potassium/Hydrochlorothiazide

Description

Losartan potassium and hydrochlorothiazide tablets USP are formulated in three combinations: 50 mg/12.5 mg, 100 mg/12.5 mg, and 100 mg/25 mg. Each tablet combines losartan potassium, an angiotensin II receptor (type AT₁) antagonist, with hydrochlorothiazide, a diuretic.

Losartan potassium 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, having a molecular weight of 461.01 and a structural formula of C₂₂H₂₂ClKN₆O. It 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 is chemically identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular weight of 297.74 and a structural formula of C₇H₈ClN₃O₄S₂. It is a white or practically white crystalline powder, slightly soluble in water but freely soluble in sodium hydroxide solution.

The tablets are intended for oral administration, with the following active ingredient compositions: the 50 mg/12.5 mg tablets contain 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide; the 100 mg/12.5 mg tablets contain 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide; and the 100 mg/25 mg tablets contain 100 mg of losartan potassium and 25 mg of hydrochlorothiazide.

Each tablet also contains inactive ingredients, including lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol-part hydrolyzed, pregelatinized starch, talc, and titanium dioxide. The 50 mg/12.5 mg tablets additionally contain D&C Yellow #10 (Aluminum Lake) and FD&C Blue #1 (Aluminum Lake), while the 100 mg/25 mg tablets contain D&C Yellow #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 tablets, and 8.48 mg (0.216 mEq) in both the 100 mg/12.5 mg and 100 mg/25 mg tablets.

Uses and Indications

Losartan potassium and hydrochlorothiazide tablets USP are indicated for the treatment of hypertension. This fixed-dose combination is not recommended for initial therapy of hypertension, except in cases where the hypertension is severe enough that the benefits of achieving prompt blood pressure control outweigh the risks associated with initiating combination therapy in these patients.

Additionally, losartan potassium and hydrochlorothiazide tablets USP are indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy. However, it is important to note that evidence suggests this benefit does not extend to Black patients.

Dosage and Administration

The usual starting dose of losartan is 50 mg administered once daily. For patients with intravascular volume depletion, a recommended starting dose of 25 mg once daily is advised. Losartan can be given once or twice daily, with total daily doses ranging from 25 mg to 100 mg. In cases where the antihypertensive effect is insufficient with once-daily dosing, a twice-daily regimen at the same total daily dose or an increase in dose may be considered.

Hydrochlorothiazide is effective at doses of 12.5 mg to 50 mg once daily. It can also be administered in combination with losartan at doses of 12.5 mg to 25 mg as losartan potassium and hydrochlorothiazide tablets.

For patients whose blood pressure is not adequately controlled with losartan monotherapy or hydrochlorothiazide alone, it is recommended to switch to losartan potassium and hydrochlorothiazide tablets at a dose of 50 mg/12.5 mg once daily. If blood pressure remains uncontrolled after approximately 3 weeks, the dose may be increased to two tablets of losartan potassium and hydrochlorothiazide tablets, 50 mg/12.5 mg once daily, or one tablet of losartan potassium and hydrochlorothiazide tablets, 100 mg/25 mg once daily. The usual dose of losartan potassium and hydrochlorothiazide tablets is one tablet of 50 mg/12.5 mg once daily. The maximum recommended dose should not exceed two tablets of losartan potassium and hydrochlorothiazide tablets, 50 mg/12.5 mg once daily, or one tablet of losartan potassium and hydrochlorothiazide tablets, 100 mg/25 mg once daily.

For patients with severe hypertension, the starting dose is one tablet of losartan potassium and hydrochlorothiazide tablets, 50 mg/12.5 mg once daily. If there is an inadequate response after 2 to 4 weeks, the dose may be increased to one tablet of losartan potassium and hydrochlorothiazide tablets, 100 mg/25 mg once daily. The maximum dose for this indication is one tablet of losartan potassium and hydrochlorothiazide tablets, 100 mg/25 mg once daily.

Losartan potassium and hydrochlorothiazide tablets may be administered with or without food.

Contraindications

Losartan potassium and hydrochlorothiazide tablets are contraindicated in patients with a known hypersensitivity to any component of the formulation. Additionally, due to the presence of hydrochlorothiazide, this product should not be used in patients with anuria or those who have a hypersensitivity to other sulfonamide-derived drugs. Furthermore, coadministration of aliskiren with losartan potassium and hydrochlorothiazide tablets is contraindicated in patients with diabetes.

Warnings and Precautions

Drugs that act directly on the renin-angiotensin system, including losartan potassium and hydrochlorothiazide tablets, pose significant risks during pregnancy. Administration of these medications to pregnant women can lead to fetal and neonatal morbidity and mortality. Therefore, upon detection of pregnancy, it is imperative that these tablets be discontinued immediately.

The use of renin-angiotensin system inhibitors during the second and third trimesters has been linked to serious fetal and neonatal injuries, such as hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and even death. Oligohydramnios has been reported, likely due to decreased fetal renal function, and this condition can result in fetal limb contractures, craniofacial deformation, and hypoplastic lung development. In rare instances where no alternative to an angiotensin II receptor antagonist is available, healthcare providers must inform mothers of the potential risks to their fetuses. In such cases, serial ultrasound examinations should be conducted to monitor the intra-amniotic environment. If oligohydramnios is detected, discontinuation of losartan potassium and hydrochlorothiazide tablets is advised unless their use is deemed life-saving for the mother.

Infants who have been exposed in utero to an angiotensin II receptor antagonist should be closely monitored for signs of hypotension, oliguria, and hyperkalemia.

Angioedema is a potential adverse effect that may occur in patients with or without a history of allergy or bronchial asthma, although it is more prevalent in those with such histories. Caution is warranted when prescribing thiazides to patients with impaired hepatic function or progressive liver disease, as even minor changes in fluid and electrolyte balance can precipitate hepatic coma.

To ensure safe use of losartan potassium and hydrochlorothiazide tablets, periodic monitoring of serum electrolytes is recommended to detect any potential electrolyte imbalances. This is particularly crucial for patients experiencing excessive vomiting or those receiving parenteral fluids, as serum and urine electrolyte determinations are essential in these situations.

In the event of oliguria, immediate attention should be directed toward supporting blood pressure and renal perfusion. Emergency interventions, such as exchange transfusion or dialysis, may be necessary to address hypotension and/or compensate for impaired renal function.

Side Effects

Patients receiving treatment with losartan may experience a range of adverse reactions. The following sections outline common and additional adverse reactions observed in clinical trials and postmarketing experiences.

Common adverse reactions, occurring in 1% or more of patients, include:

• Nervous/Psychiatric: Dizziness (5.7%).

• Respiratory: Upper respiratory infection (6.1%), cough (2.6%), and sinusitis (1.2%).

• Musculoskeletal: Back pain (2.1%).

• Cardiovascular: Palpitations (1.4%).

• Body as a Whole: Edema/swelling (1.3%) and abdominal pain (1.2%).

• Skin: Rash (1.4%).

In addition to these common reactions, other adverse experiences have been reported. These include:

• Body as a Whole: Chest pain, facial edema, fever, orthostatic effects, and syncope.

• Cardiovascular: Angina pectoris, various arrhythmias (including atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia, and ventricular fibrillation), cerebrovascular accident (CVA), hypotension, myocardial infarction, and second-degree AV block.

• Digestive: Anorexia, constipation, dental pain, dry mouth, dyspepsia, flatulence, gastritis, and vomiting.

• General Disorders: Malaise.

• Hematologic: Anemia.

• Metabolic: Gout.

• Musculoskeletal: Arm pain, arthralgia, arthritis, fibromyalgia, hip pain, joint swelling, knee pain, leg pain, muscle cramps, muscle weakness, musculoskeletal pain, myalgia, shoulder pain, and stiffness.

• Nervous System/Psychiatric: Anxiety, anxiety disorder, ataxia, confusion, depression, abnormal dreams, hypesthesia, insomnia, decreased libido, memory impairment, migraine, nervousness, panic disorder, paresthesia, peripheral neuropathy, sleep disorder, somnolence, tremor, and vertigo.

• Respiratory: Dyspnea, epistaxis, nasal congestion, pharyngeal discomfort, respiratory congestion, rhinitis, and sinus disorder.

• Skin: Alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, sweating, and urticaria.

• Special Senses: Blurred vision, burning or stinging in the eye, conjunctivitis, decreased visual acuity, taste perversion, and tinnitus.

• Urogenital: Impotence, nocturia, urinary frequency, and urinary tract infection.

Postmarketing experience has revealed additional serious adverse reactions, including but not limited to:

• Hepatitis (rarely).

• Thrombocytopenia.

• Angioedema, which may involve swelling of the larynx and glottis, potentially leading to airway obstruction.

• Vasculitis, including Henoch-Schönlein purpura.

• Anaphylactic reactions.

• Electrolyte imbalances such as hyperkalemia and hyponatremia.

• Rare cases of rhabdomyolysis.

• Dry cough.

• Erythroderma.

It is important to note specific warnings associated with losartan. Drugs that act directly on the renin-angiotensin system may cause fetal and neonatal morbidity and mortality when administered to pregnant women. Additionally, symptomatic hypotension may occur in patients who are intravascularly volume-depleted after initiation of therapy. Angioedema may occur, particularly in patients with a history of allergy or bronchial asthma.

Drug Interactions

Coadministration of losartan with various medications has been studied for potential drug interactions, primarily focusing on pharmacokinetic effects.

Antihypertensives and Diuretics Losartan does not exhibit significant pharmacokinetic interactions with hydrochlorothiazide, nor does it affect the pharmacokinetics or pharmacodynamics of warfarin. Additionally, there is no impact on the pharmacokinetics of oral or intravenous digoxin when losartan is administered.

Cimetidine The coadministration of losartan with cimetidine results in an approximate 18% increase in the area under the curve (AUC) of losartan; however, this does not affect the pharmacokinetics of its active metabolite. Monitoring may be warranted due to this increase.

Anticonvulsants When losartan is administered alongside phenobarbital, a reduction of about 20% in the AUC of both losartan and its active metabolite is observed. This interaction suggests that dosage adjustments may be necessary when these drugs are used concurrently.

Antimycobacterial Agents Rifampin has been shown to cause a more pronounced interaction, leading to approximately a 40% reduction in the AUC of the active metabolite and about a 30% reduction in the AUC of losartan. Clinicians should consider this interaction when prescribing rifampin with losartan.

Antifungals Fluconazole, a known inhibitor of cytochrome P450 2C9, decreases the AUC of the active metabolite by approximately 40% while increasing the AUC of losartan by about 70% after multiple doses. This significant alteration in pharmacokinetics may necessitate careful monitoring and potential dosage adjustments.

Other Inhibitors The conversion of losartan to its active metabolite following intravenous administration is unaffected by ketoconazole, an inhibitor of P450 3A4. In contrast, erythromycin, another P450 3A4 inhibitor, does not alter the AUC of the active metabolite but increases the AUC of losartan by 30%. Monitoring is advised due to the increased exposure to losartan.

In summary, while losartan generally exhibits a favorable interaction profile, specific combinations with cimetidine, phenobarbital, rifampin, fluconazole, and erythromycin warrant careful consideration regarding monitoring and potential dosage adjustments.

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. Therefore, caution should be exercised when considering the use of this medication in children and adolescents. Further studies are needed to determine appropriate dosing and outcomes in this population.

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 somewhat more frequently in the elderly population compared to non-elderly patients across both the losartan and hydrochlorothiazide treatment groups as well as the control groups.

Given these observations, healthcare providers should exercise caution when prescribing this medication to geriatric patients. Monitoring for adverse events may be warranted, and consideration should be given to potential dose adjustments based on individual patient factors, including age and overall health status.

Pregnancy

Pregnant patients should be aware that this medication is classified as Category C during the first trimester and Category D during the second and third trimesters. This indicates that there may be potential risks associated with its use in pregnancy, particularly as gestation progresses.

Clinical and animal studies have shown that the use of this medication may lead to adverse fetal outcomes. Healthcare professionals are advised to consult the WARNINGS section regarding fetal and neonatal morbidity and mortality associated with this medication. It is recommended that the benefits of treatment be carefully weighed against the potential risks to the fetus, especially in the later stages of pregnancy. Women of childbearing potential should be counseled on the importance of effective contraception while using this medication and should be informed of the potential risks should they become pregnant during treatment.

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, lactating mothers should consider whether to discontinue breastfeeding or to discontinue the drug, weighing the importance of the medication to the mother against the potential risks to the breastfed infant.

Renal Impairment

Patients with renal impairment should be closely monitored when considering the use of losartan potassium and hydrochlorothiazide tablets. These tablets are not recommended for patients with hepatic impairment who require titration with losartan, as the lower starting dose of losartan suitable for these patients cannot be administered in this combination formulation.

Additionally, thiazides, including hydrochlorothiazide, should be used with caution in patients with impaired hepatic function or progressive liver disease. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma, necessitating careful assessment and monitoring of their condition.

Hepatic Impairment

Patients with hepatic impairment who require titration with losartan should not use losartan potassium and hydrochlorothiazide tablets, as the lower starting dose of losartan recommended for this population cannot be administered in this combination formulation.

Additionally, thiazides, including hydrochlorothiazide, should be used with caution in patients with impaired hepatic function or progressive liver disease. This caution is warranted due to the potential for minor alterations in fluid and electrolyte balance, which may precipitate hepatic coma. Regular monitoring of liver function and electrolyte levels is advised in these patients to mitigate risks associated with treatment.

Overdosage

Significant lethality has been observed in animal studies, with mice and rats exhibiting fatal outcomes following oral administration of 1000 mg/kg and 2000 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).

In humans, data regarding overdosage are limited. The most likely clinical manifestations of an overdose 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 eliminated from the body through hemodialysis, which should be taken into consideration when managing cases of overdosage.

Nonclinical Toxicology

Pregnancy Categories C and D have been assigned to losartan potassium and hydrochlorothiazide, indicating potential teratogenic effects during the first and second/third trimesters, respectively.

In terms of non-teratogenic effects, studies demonstrated that losartan potassium and hydrochlorothiazide did not adversely 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, 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. Conversely, fertility and reproductive performance remained unaffected in studies involving male rats administered oral doses of losartan potassium up to approximately 150 mg/kg/day. Toxic dosage levels in females (300/200 mg/kg/day) were associated with 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 exhibit adverse effects on 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 combination of losartan potassium and hydrochlorothiazide. In mutagenicity assessments, the combination tested at a weight ratio of 4:1 yielded 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 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. It also tested 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. The active metabolite of losartan potassium showed no evidence of genotoxicity in the same assays.

Two-year feeding studies in mice and rats revealed no evidence of carcinogenic potential for hydrochlorothiazide in female mice or in male and female rats. However, 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 in 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 observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays.

The relationship of findings related to losartan potassium treatment in females to drug treatment 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

Hepatitis has been reported rarely in patients treated with losartan. Thrombocytopenia has also been noted in postmarketing reports. Rare cases of angioedema, including swelling of the larynx and glottis leading to airway obstruction, as well as swelling of the face, lips, pharynx, and/or tongue, have been documented; some affected patients had a history of angioedema with other medications, including ACE inhibitors. Additionally, vasculitis, such as Henoch-Schönlein purpura, and anaphylactic reactions have been reported in patients receiving losartan.

Metabolic disturbances, including hyperkalemia and hyponatremia, have been observed. Rare instances of rhabdomyolysis have been reported among patients treated with angiotensin II receptor blockers. A dry cough has been associated with losartan use. Furthermore, erythroderma has been reported in patients receiving this medication.

Patient Counseling

Healthcare providers should advise patients that losartan potassium and hydrochlorothiazide tablets should be discontinued as soon as pregnancy is detected. It is important to inform female patients of childbearing age about the potential consequences of exposure to medications that act on the renin-angiotensin system during the second and third trimesters of pregnancy.

Patients should be cautioned that lightheadedness may occur, particularly during the initial days of therapy, and they should report this symptom to their prescribing physician. In the event of syncope, patients must discontinue the use of losartan potassium and hydrochlorothiazide tablets and consult their physician before resuming treatment.

All patients should be made aware that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, which may result in lightheadedness or syncope. Additionally, patients should be instructed not to use potassium supplements or salt substitutes containing potassium without prior consultation with their prescribing physician.

Patients must be informed about the potential for serious side effects, which may include injury or death of unborn babies, allergic reactions, low blood pressure, and worsening kidney or liver function. They should also be advised to report any symptoms related to eye problems, such as a decrease in vision or eye pain, to their doctor immediately.

It is essential for patients to take losartan potassium and hydrochlorothiazide tablets exactly as prescribed and to inform their doctor if they miss a dose. Furthermore, patients should be encouraged to maintain a comprehensive list of all medications they are taking, including over-the-counter drugs and supplements, and to communicate this information to their healthcare provider to prevent potential drug interactions.

Storage and Handling

The product is supplied in a tightly sealed, light-resistant container that complies with USP standards and includes a child-resistant closure as required. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines.

To ensure the integrity of the product, the container must be kept tightly closed and protected from light exposure. Additionally, it is crucial to keep this and all medications out of the reach of children.

Additional Clinical Information

Minor increases in blood urea nitrogen (BUN) and serum creatinine were observed in 0.6% and 0.8% of patients, respectively, treated with losartan potassium and hydrochlorothiazide tablets for essential hypertension. No patients discontinued treatment due to increased BUN, while one patient did so due to a minor increase in serum creatinine. Small decreases in hemoglobin and hematocrit were noted, but these were rarely clinically significant, and no patients discontinued treatment due to anemia. Occasional elevations in liver enzymes and/or serum bilirubin were reported, yet no patients discontinued therapy for these reasons.

Losartan potassium and hydrochlorothiazide tablets can be taken with or without food. Patients should be advised about the potential for lightheadedness, particularly during the initial days of therapy, and to report such symptoms to their physician. They should also be informed that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting may lead to significant drops in blood pressure. Additionally, patients are cautioned against using potassium supplements or salt substitutes containing potassium without consulting their physician. Postmarketing experience has revealed rare adverse reactions, including hepatitis, thrombocytopenia, angioedema, vasculitis, hyperkalemia, hyponatremia, rhabdomyolysis, dry cough, and erythroderma.

FDA Insert (PDF)

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

View full prescribing information (PDF)