Losartan potassium/Hydrochlorothiazide

Description

Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-p-(o-1H-tetrazol-5-ylphenyl)benzylimidazole-5-methanol monopotassium salt. Its empirical formula is C22H22ClKN6O, and it has a molecular weight of 461.01. Losartan potassium, USP appears as a white to off-white free-flowing crystalline powder that 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 and a molecular weight of 297.74. Hydrochlorothiazide, USP is a white or practically white crystalline powder that 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: Losartan potassium and hydrochlorothiazide tablet USP 50 mg/12.5 mg contains 50 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP; Losartan potassium and hydrochlorothiazide tablet USP 100 mg/12.5 mg contains 100 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP; and Losartan potassium and hydrochlorothiazide tablet USP 100 mg/25 mg contains 100 mg of losartan potassium USP and 25 mg of hydrochlorothiazide USP.

Inactive ingredients in these tablets include microcrystalline cellulose, lactose monohydrate, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose, and titanium dioxide. Additionally, the Losartan potassium and hydrochlorothiazide tablet USP 50 mg/12.5 mg and 100 mg/25 mg formulations also contain D&C yellow No. 10 aluminum lake. The potassium content in the formulations 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 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

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 hypersensitivity to any component of the formulation should not use this medication due to the risk of severe allergic reactions.

Anuria is a contraindication, as the medication may exacerbate renal function impairment.

Coadministration with aliskiren is contraindicated in patients with diabetes, as this combination may increase the risk of adverse effects related to renal function and blood pressure regulation.

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 fetal toxicity, leading to injury or death of 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 assessed for the risk of acute angle-closure glaucoma, as well as the potential exacerbation of systemic lupus erythematosus. Regular laboratory tests to monitor renal function and potassium levels are advised for those at risk.

Side Effects

Patients receiving losartan potassium and hydrochlorothiazide tablets may experience a range of adverse reactions. The most common adverse reactions, occurring in 2% or more of participants and at a higher incidence than placebo, include dizziness, upper respiratory infection, cough, and back pain.

Serious warnings associated with the use of this medication include the potential for fetal toxicity. Drugs that act directly on the renin-angiotensin system, such as losartan potassium, 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 of clinical significance include hypotension, which necessitates the correction of volume or salt depletion prior to administration. Patients should be monitored for renal function and potassium levels, particularly those who are susceptible. Clinical signs of fluid or electrolyte imbalance should also be observed.

Other notable adverse reactions include acute angle-closure glaucoma, exacerbation of systemic lupus erythematosus, hypersensitivity to any component of the medication, and anuria. Caution is advised when coadministering losartan potassium and hydrochlorothiazide tablets with aliskiren in patients with diabetes, as this may lead to further complications.

Drug Interactions

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

Pharmacodynamic Interactions

• Agents Increasing Serum Potassium: The use of agents that elevate serum potassium levels may result in hyperkalemia. Monitoring of serum potassium is advised to mitigate this risk.

• Lithium: Co-administration with lithium may increase the risk of lithium toxicity. Regular monitoring of lithium levels is recommended to ensure safe therapeutic ranges.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs can lead to an increased risk of renal impairment and may diminish the diuretic, natriuretic, and antihypertensive effects. Caution is advised when prescribing NSAIDs to patients on this medication.

• Dual Inhibition of the Renin-Angiotensin System: The combination of agents that inhibit the renin-angiotensin system may heighten the risk of renal impairment, hypotension, syncope, and hyperkalemia. Close monitoring of renal function and blood pressure is recommended.

Pharmacokinetic Interactions

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used concurrently. Regular monitoring of blood glucose levels is advised to maintain optimal control.

• Cholestyramine and Colestipol: The presence of cholestyramine or colestipol may reduce the absorption of thiazide diuretics. It is recommended to separate the administration of these agents to minimize the impact on thiazide efficacy.

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 the support of blood pressure and renal perfusion. In such cases, exchange transfusion or dialysis may be required to reverse hypotension and/or substitute for disordered renal function.

Geriatric Use

In a controlled clinical study aimed at reducing the combined risk of cardiovascular death, stroke, and myocardial infarction in hypertensive patients with left ventricular hypertrophy, a significant proportion of participants were elderly, with 62% (n=2857) aged 65 years and older and 18% (n=808) aged 75 years and older.

The findings indicated that there were no overall differences in effectiveness between elderly patients and their younger counterparts. However, it is important to note that adverse events occurred somewhat more frequently in the elderly population compared to non-elderly patients, observed in both the losartan-hydrochlorothiazide and control groups.

Given these considerations, healthcare providers should exercise caution when prescribing this medication to geriatric patients. Monitoring for adverse events is recommended, and dose adjustments may be necessary based on individual patient response and tolerability.

Pregnancy

The use of losartan potassium and hydrochlorothiazide tablets during pregnancy is classified as Pregnancy Category D. Administration of drugs that act on the renin-angiotensin system during the second and third trimesters is associated with significant risks, including reduced fetal renal function, increased fetal and neonatal morbidity, and mortality. Oligohydramnios resulting from such use can lead to fetal lung hypoplasia and skeletal deformations. Potential adverse effects in neonates may include skull hypoplasia, anuria, hypotension, renal failure, and death. Therefore, when pregnancy is detected, discontinuation of losartan is recommended as soon as possible.

In cases where there is no appropriate alternative to therapy with renin-angiotensin system agents, healthcare providers should inform the mother of the potential risks to the fetus. Serial ultrasound examinations should be performed to monitor the intra-amniotic environment. If oligohydramnios is detected, losartan potassium and hydrochlorothiazide tablets should be discontinued unless deemed lifesaving for the mother. It is important to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. Infants with a history of in utero exposure to these medications should be closely monitored for hypotension, oliguria, and hyperkalemia.

Animal studies have shown no evidence of teratogenicity in rats or rabbits treated with losartan potassium at a maximum dose of 10 mg/kg/day in combination with 2.5 mg/kg/day of hydrochlorothiazide. At these dosages, the respective exposures (AUCs) in rabbits were approximately 5, 1.5, and 1 times those achieved in humans with 100 mg of losartan and 25 mg of hydrochlorothiazide. However, fetal toxicity was observed in rats treated with higher doses during late gestation and/or lactation, resulting in decreased body weight, renal toxicity, and increased mortality. The AUC values for losartan and its active metabolite at these higher dosages were approximately 35, 10, and 10 times greater than those achieved in humans.

Additionally, thiazides cross the placental barrier and can be detected in cord blood, posing a risk of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions that have been observed in adults. Appropriate management of maternal hypertension during pregnancy is crucial to optimize outcomes for 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, 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 observed in animal studies following oral administration of high doses of the compound, with mice exhibiting a lethal dose (LD50) of 1000 mg/kg and rats showing an LD50 of 2000 mg/kg. These doses correspond to approximately 44 and 170 times the maximum recommended human dose on a mg/m² basis, indicating a substantial risk associated with overdosage.

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 removed through hemodialysis, which limits the options for decontamination in cases of overdose.

In the context 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.

Healthcare professionals should remain vigilant for these symptoms and manage them accordingly to mitigate the effects of overdosage.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. The combination of losartan potassium and hydrochlorothiazide, 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 using rat hepatocytes or in the in vitro chromosomal aberration assay with Chinese hamster ovary cells at noncytotoxic concentrations.

In terms of fertility, losartan potassium, when coadministered with 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, 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. Furthermore, fertility and reproductive performance were unaffected in studies involving male rats given oral doses of losartan potassium up to approximately 150 mg/kg/day. Hydrochlorothiazide also demonstrated no adverse effects on the fertility of mice and rats of either sex when exposed to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.

No carcinogenicity studies have been conducted specifically on the losartan potassium-hydrochlorothiazide combination. In studies involving toxic dosage levels in female rats (300/200 mg/kg/day), there was 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. The relationship of these findings to drug treatment remains uncertain, as there were no effects observed at these dosage levels on implants in pregnant females, percent post-implantation loss, or live animals per litter at parturition.

The maximally tolerated dosages for losartan were determined to be 270 mg/kg/day in rats and 200 mg/kg/day in mice, resulting in systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160 and 90 times (in rats) and 30 and 15 times (in mice) the exposure of a 50 kg human receiving 100 mg per day. Hydrochlorothiazide was not found to be 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 test results were observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Postmarketing Experience

Postmarketing experience has identified several adverse events reported voluntarily or through surveillance programs.

There have been reports of injury or death of unborn babies associated with the use of losartan potassium and hydrochlorothiazide tablets. Additionally, cases of allergic reactions have been documented, characterized by symptoms such as swelling of the face, lips, throat, or tongue, necessitating immediate medical attention and discontinuation of the medication.

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

In individuals with pre-existing kidney conditions, there have been observations of worsening renal function. Patients are encouraged to seek medical advice if they experience swelling in the feet, ankles, or hands, or if they notice unexplained weight gain.

Furthermore, a new or exacerbated condition known as systemic lupus erythematosus (SLE) has been reported in some cases.

Eye problems have also been associated with one of the components of losartan potassium and hydrochlorothiazide tablets. Symptoms may manifest within hours to weeks of initiating treatment and can include a decrease in vision and eye pain. Patients are advised to inform their healthcare provider immediately if they experience these symptoms, as untreated eye issues may lead to vision loss.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) that accompanies losartan potassium and hydrochlorothiazide tablets. It is important for female patients of childbearing age to understand the potential consequences of exposure to these medications during pregnancy. Healthcare providers should discuss treatment options with women who are planning to become pregnant and encourage them to report any pregnancies to their physicians as soon as possible.

Patients should be informed about the possibility of experiencing symptomatic hypotension, particularly during the initial days of therapy. They should be advised to report any feelings of lightheadedness to their healthcare provider. Additionally, patients must be made aware that dehydration resulting from inadequate fluid intake, excessive perspiration, vomiting, or diarrhea can lead to a significant drop in blood pressure. In the event of syncope, patients should be instructed to contact their healthcare provider immediately.

It is crucial to advise patients against using potassium supplements or salt substitutes that contain potassium without prior consultation with their healthcare provider. Patients should also be informed about the risks of acute myopia and secondary angle-closure glaucoma. If they experience symptoms related to these conditions, they should discontinue the medication and seek immediate medical attention.

Patients must be reminded to read the Patient Information leaflet that comes with losartan potassium and hydrochlorothiazide tablets before starting the medication and each time they receive a refill, as there may be new information. This leaflet is not a substitute for discussions with their doctor regarding their condition and treatment.

Finally, patients should be made aware that losartan potassium and hydrochlorothiazide tablets can cause harm or even death to an unborn baby. They should discuss alternative methods for lowering blood pressure with their doctor if they plan to become pregnant. If a patient becomes pregnant while taking these tablets, they should inform their doctor immediately.

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 in these patients to ensure safety and efficacy.

FDA Insert (PDF)

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

View full prescribing information (PDF)