Losartan potassium/Hydrochlorothiazide

Description

Losartan potassium and hydrochlorothiazide are combined in three tablet formulations: 50 mg/12.5 mg, 100 mg/12.5 mg, and 100 mg/25 mg. Losartan potassium, a non-peptide angiotensin II receptor (type AT1) antagonist, is chemically defined as 2-butyl-4-chloro-1-p-(o-1H-tetrazol-5-ylphenyl)benzylimidazole-5-methanol monopotassium salt, with an empirical formula of C22H22ClKN6O and a molecular weight of 461.01. It appears as a white to off-white free-flowing crystalline powder, freely soluble in water, soluble in alcohols, and slightly soluble in organic solvents such as acetonitrile and methyl ethyl ketone.

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

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

Inactive ingredients include lactose monohydrate, microcrystalline cellulose, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose, titanium dioxide, quinoline yellow aluminum lake, and carnauba wax.

Uses and Indications

Losartan potassium and hydrochlorothiazide tablets 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 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

Losartan is typically initiated at a starting dose of 50 mg once daily. For patients with intravascular volume depletion, a recommended starting dose of 25 mg once daily should be considered. The medication can be administered either 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 the dose may be warranted.

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

For combination therapy, the usual dose of losartan potassium and hydrochlorothiazide is one tablet of losartan potassium and hydrochlorothiazide 50 mg/12.5 mg once daily. If blood pressure remains uncontrolled after approximately 3 weeks, the dose may be escalated to either two tablets of losartan potassium and hydrochlorothiazide 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide 100 mg/25 mg once daily. It is important to note that the maximum recommended doses should not exceed two tablets of losartan potassium and hydrochlorothiazide 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide 100 mg/25 mg once daily.

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

In patients with renal impairment, usual regimens may be followed if creatinine clearance is greater than 30 mL/min. However, the medication is not recommended for patients with more severe renal impairment. For patients with hepatic impairment, titration is not recommended due to the inability to provide the appropriate starting dose of losartan.

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.

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 these drugs 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 also been reported, likely due to decreased fetal renal function, which 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, losartan potassium and hydrochlorothiazide tablets should be discontinued 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.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients, regardless of their allergy or bronchial asthma history, although such reactions are more common in those with a prior history. Caution is advised when prescribing thiazides to patients with impaired hepatic function or progressive liver disease, as even minor fluid and electrolyte imbalances can precipitate hepatic coma.

To ensure safe use, periodic monitoring of serum electrolytes is recommended to detect potential electrolyte imbalances. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly critical in patients experiencing excessive vomiting or those receiving parenteral fluids.

In the event of oliguria, immediate medical attention is necessary to support blood pressure and renal perfusion. Interventions such as exchange transfusion or dialysis may be required to address hypotension and/or to compensate for impaired renal function.

Healthcare professionals should remain vigilant and proactive in monitoring and managing these risks to ensure patient safety.

Side Effects

Patients may experience a range of adverse reactions while using this medication, categorized by frequency and seriousness.

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

• Nervous/Psychiatric: Dizziness (5.7%), with other notable reactions such as anxiety, depression, and insomnia.

• 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%).

Additional adverse reactions, which may occur less frequently but are clinically significant, include:

• Cardiovascular: Serious events such as myocardial infarction, arrhythmias (including atrial fibrillation and ventricular tachycardia), hypotension, and second-degree AV block.

• Hematologic: Anemia, aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia.

• Hypersensitivity: Reactions such as purpura, urticaria, and respiratory distress, including pneumonitis and pulmonary edema.

• Metabolic: Conditions like hyperglycemia, gout, and hyperuricemia.

• Musculoskeletal: A variety of symptoms including muscle cramps, joint swelling, and fibromyalgia.

• Nervous System/Psychiatric: Symptoms such as confusion, memory impairment, and tremors.

• Respiratory: Dyspnea, nasal congestion, and pharyngeal discomfort.

• Skin: Reactions including alopecia, dermatitis, and photosensitivity.

Post-marketing experience has revealed additional adverse reactions, albeit rarely, such as hepatitis, angioedema, and rhabdomyolysis. Patients may also experience metabolic disturbances like hyperkalemia and hyponatremia.

Warnings associated with this medication include the potential for fetal and neonatal morbidity and mortality when administered to pregnant women, particularly due to effects on the renin-angiotensin system. Adverse effects in this context may include hypotension and renal failure.

Patients with a history of allergy or bronchial asthma may be at increased risk for hypersensitivity reactions, which can occur even in those without such a history. Furthermore, thiazide diuretics have been associated with exacerbation or activation of systemic lupus erythematosus.

Drug Interactions

Coadministration of losartan with various agents has been studied for potential drug interactions, categorized primarily into pharmacokinetic interactions.

Anticoagulants and Cardiac Glycosides Losartan does not significantly affect the pharmacokinetics or pharmacodynamics of warfarin when administered for 12 days. Additionally, there is no observed interaction with either oral or intravenous digoxin.

Diuretics No pharmacokinetic interaction has been identified between losartan and hydrochlorothiazide.

Cimetidine The coadministration of losartan with cimetidine results in an approximate 18% increase in the area under the curve (AUC) of losartan. However, this interaction does not alter the pharmacokinetics of losartan's active metabolite.

Anticonvulsants When losartan is administered alongside phenobarbital, a reduction of about 20% in the AUC of both losartan and its active metabolite is observed.

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.

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. Conversely, ketoconazole, an inhibitor of P450 3A4, does not affect the conversion of losartan to its active metabolite following intravenous administration. Erythromycin, another P450 3A4 inhibitor, does not alter the AUC of the active metabolite but increases the AUC of losartan by 30%.

Monitoring of losartan levels may be warranted when coadministered with fluconazole, rifampin, or phenobarbital due to the potential for significant alterations in pharmacokinetics. Adjustments in dosage may be necessary based on clinical judgment and patient response.

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

The safety and effectiveness of losartan potassium and hydrochlorothiazide tablets in pediatric patients have not been established. Therefore, caution is advised when considering the use of this medication in children and adolescents. Further studies are necessary 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.

In animal studies, adverse effects on fetal outcomes have been observed, and there is a potential for fetal harm. Therefore, healthcare professionals are advised to weigh the benefits against the risks when considering this medication for pregnant patients, particularly during the later stages of pregnancy.

It is recommended that women of childbearing potential discuss their pregnancy status and any plans for pregnancy with their healthcare provider prior to initiating treatment. Close monitoring and appropriate counseling should be provided to ensure the safety of both the mother and the fetus.

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 medication, weighing the importance of the drug 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 renal function and overall clinical status.

Hepatic Impairment

Patients with hepatic impairment should not be treated with losartan potassium and hydrochlorothiazide tablets if titration with losartan is required. The lower starting dose of losartan that is recommended for patients with compromised liver function cannot be administered using this combination tablet.

Additionally, thiazide diuretics, such as hydrochlorothiazide, should be used with caution in patients who have impaired hepatic function or progressive liver disease. This caution is warranted because even minor alterations in fluid and electrolyte balance may precipitate hepatic coma in these patients. Regular monitoring of liver function and electrolyte levels is advised to mitigate potential risks associated with treatment in this population.

Overdosage

In cases of 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).

Limited clinical data regarding human overdosage is available; however, the most likely symptoms include hypotension and tachycardia. In some instances, bradycardia may occur due to parasympathetic (vagal) stimulation. Should symptomatic hypotension arise, it is imperative that supportive treatment be initiated promptly to manage the 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 planning management strategies for overdosage.

Nonclinical Toxicology

Losartan potassium, when coadministered with hydrochlorothiazide, demonstrated no adverse effects on 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 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 that fertility and reproductive performance were not adversely affected. Conversely, the administration of higher toxic dosage levels in females (300/200 mg/kg/day) was 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 observed. Hydrochlorothiazide did not exhibit adverse effects on the fertility of mice and rats of either sex in studies where these species were exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

No carcinogenicity studies have been conducted with the combination of losartan potassium and hydrochlorothiazide. In mutagenicity assessments, losartan potassium and hydrochlorothiazide, tested at a weight ratio of 4:1, were 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 in 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 was also negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays, as well as in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. The active metabolite of losartan potassium showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.

Two-year feeding studies in mice and rats revealed no evidence of carcinogenic potential for hydrochlorothiazide in female mice at doses of up to approximately 600 mg/kg/day or in male and female rats at doses of up to approximately 100 mg/kg/day. 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 and 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 test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays.

Postmarketing Experience

In postmarketing surveillance, data from double-blind clinical trials involving various doses of losartan potassium and hydrochlorothiazide indicated that 6.7% of hypertensive patients developed hypokalemia (serum potassium <3.5 mEq/L), compared to 3.5% in the placebo group. The incidence of hyperkalemia (serum potassium >5.7 mEq/L) was reported at 0.4%. Notably, no patients discontinued treatment due to fluctuations in serum potassium levels. The mean decrease in serum potassium among patients receiving losartan and hydrochlorothiazide was observed to be 0.123 mEq/L. Additionally, a dose-related decrease in the hypokalemic response to hydrochlorothiazide was noted as the dose of losartan increased, along with a corresponding decrease in serum uric acid levels with higher doses of losartan.

Patient Counseling

Healthcare providers should inform female patients of childbearing age about the potential consequences of exposure to drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy. It is important to clarify that these consequences do not appear to arise from intrauterine drug exposure limited to the first trimester. Patients should be encouraged to report any pregnancies to their physicians as soon as possible.

Patients receiving losartan potassium and hydrochlorothiazide tablets should be cautioned about the possibility of experiencing lightheadedness, particularly during the initial days of therapy. They should be advised to report any instances of lightheadedness to their prescribing physician. In cases where syncope occurs, 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 and potential syncope.

Additionally, patients taking losartan potassium and hydrochlorothiazide tablets should be advised against using potassium supplements or salt substitutes that contain potassium without prior consultation with their prescribing physician.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), adhering to the standards set by the United States Pharmacopeia (USP) for controlled room temperature. It is essential to protect the product from light to maintain its integrity and efficacy. Proper handling and storage conditions must be observed to ensure optimal product quality.

Additional Clinical Information

Periodic determination of serum electrolytes is recommended for patients receiving thiazide therapy to monitor for potential electrolyte imbalances. Clinicians should observe all patients for clinical signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. This monitoring is particularly crucial in cases of excessive vomiting or when patients are receiving parenteral fluids.

Female patients of childbearing age should be informed about the risks associated with exposure to drugs that act on the renin-angiotensin system during the second and third trimesters, while noting that first-trimester exposure does not appear to pose the same risks. Patients should report any pregnancies to their physicians promptly. Additionally, patients taking losartan potassium and hydrochlorothiazide tablets should be advised of the potential for lightheadedness, especially during the initial days of therapy, and to consult their physician if syncope occurs. They should also be cautioned that inadequate fluid intake, excessive sweating, diarrhea, or vomiting may lead to significant drops in blood pressure. Furthermore, patients are advised against using potassium supplements or salt substitutes containing potassium without prior consultation with their physician.