Losartan potassium/Hydrochlorothiazide

Description

Losartan potassium and hydrochlorothiazide tablets are available in three formulations: USP 50/12.5, USP 100/12.5, and USP 100/25. Each formulation combines losartan potassium, an angiotensin II receptor blocker, with hydrochlorothiazide, a diuretic.

Losartan potassium USP 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. Its molecular formula is C22H22ClKN6O, and it has a molecular weight of 461.01. The compound 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. The active metabolite of losartan is formed through the oxidation of the 5-hydroxymethyl group on the imidazole ring.

Hydrochlorothiazide USP is chemically identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular formula of C7H8ClN3O4S and a molecular weight of 297.74. It is presented as a white or practically white crystalline powder, which is slightly soluble in water but freely soluble in sodium hydroxide solution.

The tablets are formulated for oral administration, with the following active ingredient concentrations: USP 50/12.5 contains 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide; USP 100/12.5 contains 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide; and USP 100/25 contains 100 mg of losartan potassium and 25 mg of hydrochlorothiazide. Each tablet formulation contains potassium, with USP 50/12.5 providing 4.24 mg (0.108 mEq), and both USP 100/12.5 and USP 100/25 providing 8.48 mg (0.216 mEq) of potassium.

Inactive ingredients include microcrystalline cellulose, lactose monohydrate, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, hydroxypropyl cellulose, hypromellose, and titanium dioxide. Additionally, losartan potassium and hydrochlorothiazide tablets, USP 50/12.5 and USP 100/25 contain yellow ferric oxide.

Uses and Indications

This drug is indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of 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 apply 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.

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 injury or death to the developing fetus (5.1).

Hypotension may occur; therefore, it is essential to correct any volume or salt depletion prior to the administration of losartan potassium and hydrochlorothiazide tablets (5.2). Healthcare professionals should monitor renal function and potassium levels in patients who are susceptible to these changes (5.3). Additionally, clinicians should remain vigilant for clinical signs of fluid or electrolyte imbalance (5.5).

There is a risk of acute angle-closure glaucoma associated with the use of this medication (5.6). Furthermore, patients with a history of systemic lupus erythematosus may experience exacerbation of their condition while on this therapy (5.7).

Regular laboratory tests to monitor renal function and potassium levels are recommended for patients at risk (5.3).

Side Effects

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

Serious warnings associated with the use of this medication include the potential for fetal toxicity. It is imperative that losartan potassium and hydrochlorothiazide tablets be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can cause injury or death to the developing fetus.

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 serious adverse reactions may include acute angle-closure glaucoma, exacerbation of systemic lupus erythematosus, and hypersensitivity reactions to any component of the medication. Anuria has also been reported.

Coadministration with aliskiren in patients with diabetes is contraindicated. In cases of overdosage, the most likely manifestations include hypotension and tachycardia, with bradycardia potentially occurring due to parasympathetic (vagal) stimulation. If symptomatic hypotension occurs, supportive treatment should be initiated. The most common signs and symptoms observed in overdosage cases are those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, hyponatremia, and dehydration due to excessive diuresis.

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 of the drug. Renal function should be monitored, and alternative analgesics may be considered.

• 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 blood pressure and renal function is recommended.

Pharmacokinetic Interactions

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

• Cholestyramine and Colestipol: The use of cholestyramine or colestipol may reduce the absorption of thiazide diuretics. It is advisable to separate the administration of these agents to optimize therapeutic 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 may be warranted, and dose adjustments should be considered based on the individual patient's health status and response to treatment.

Pregnancy

Losartan potassium and hydrochlorothiazide tablets can cause fetal harm when administered to pregnant patients. The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy is associated with reduced fetal renal function, leading to increased fetal and neonatal morbidity and mortality. Most epidemiologic studies examining fetal abnormalities following antihypertensive use in the first trimester have not differentiated between drugs affecting the renin-angiotensin system and other antihypertensive agents.

When pregnancy is detected, losartan potassium and hydrochlorothiazide tablets should be discontinued as soon as possible. The estimated background risk of major birth defects and miscarriage 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 2% to 4% and 15% to 20%, respectively.

Hypertension in pregnancy poses increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and delivery complications such as the need for cesarean section and post-partum hemorrhage. Additionally, 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, healthcare providers should 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 potassium and hydrochlorothiazide tablets should be discontinued unless deemed lifesaving for the mother.

Fetal testing may be appropriate based on gestational age, and both patients and physicians should be aware that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. Neonates with a history of in utero exposure to losartan potassium and hydrochlorothiazide tablets should be closely monitored for hypotension, oliguria, and hyperkalemia. In cases of oliguria or hypotension, support for blood pressure and renal perfusion may be necessary, and exchange transfusions or dialysis may be 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 can also cause placental hypoperfusion and accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. The use of thiazides during pregnancy is associated with risks of fetal or neonatal jaundice and thrombocytopenia. Since thiazides do not alter the course of pre-eclampsia, they should not be used to treat hypertension in pregnant women, and 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 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 for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Significant lethality has been observed in animal studies following oral administration of high doses of the drug, with mice exhibiting a lethal dose (LD50) of 1000 mg/kg and rats showing an LD50 of 2000 mg/kg. These doses correspond to approximately 44 and 170 times the maximum recommended human dose on a mg/m² basis, respectively.

In humans, data regarding overdosage are limited. The most likely manifestations of overdosage include hypotension and tachycardia; however, bradycardia may also occur due to parasympathetic (vagal) stimulation. In the event of symptomatic hypotension, it is recommended that supportive treatment be initiated to manage the condition effectively.

It is important to note that neither losartan nor its active metabolite can be removed through hemodialysis, which limits the options for managing severe cases of overdosage. Additionally, the oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, indicating a high threshold for toxicity in these species.

The most common signs and symptoms associated with overdosage are primarily due to electrolyte depletion, which may include hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. In cases where digitalis has also been administered, hypokalemia may exacerbate the risk of cardiac arrhythmias, necessitating careful monitoring and management of electrolyte levels.

The extent to which hydrochlorothiazide is removed by hemodialysis remains undetermined, further complicating the management of overdose situations involving this diuretic. Healthcare professionals should remain vigilant for these potential complications and provide appropriate supportive care as needed.

Nonclinical Toxicology

No teratogenic effects were observed in studies involving losartan potassium-hydrochlorothiazide. The combination, tested at a weight ratio of 4:1, demonstrated negative results in both the Ames microbial mutagenesis assay and the V-79 Chinese hamster lung cell mutagenesis assay. Additionally, there was no evidence of direct genotoxicity in the in vitro alkaline elution assay conducted in rat hepatocytes or in the in vitro chromosomal aberration assay in Chinese hamster ovary cells at noncytotoxic concentrations.

In terms of fertility, losartan potassium, when coadministered with hydrochlorothiazide, did not affect the mating behavior or fertility 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. 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, while at 100 mg/kg/day, only a decrease in the number of corpora lutea was noted. Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex when administered doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

Carcinogenicity studies have not been conducted with the losartan potassium-hydrochlorothiazide combination. However, two-year feeding studies conducted by the National Toxicology Program (NTP) revealed 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 find equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay across various Salmonella typhimurium strains or in the Chinese Hamster Ovary test for chromosomal aberrations. In vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also showed no genotoxicity. Positive results were only observed in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay.

Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. The maximally tolerated dosages (270 mg/kg/day in rats and 200 mg/kg/day in mice) resulted 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. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure levels 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

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 with their healthcare provider strategies for protecting their skin from sun exposure and the recommended frequency of skin cancer screenings.

Additionally, eye problems have been reported in patients taking losartan potassium and hydrochlorothiazide tablets. These issues may manifest within hours to weeks of initiating treatment and, if left untreated, could potentially lead to vision loss. Symptoms to monitor include a decrease in vision and eye pain, and patients are encouraged to inform their healthcare provider immediately if these symptoms occur.

Furthermore, there have been reports of increased sensitivity of the skin to sunlight, which may further elevate the risk of skin cancer.

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 should be made aware 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.

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

For those taking hydrochlorothiazide, it is important to instruct patients to protect their skin from sun exposure and to undergo regular skin cancer screenings due to the increased risk of non-melanoma skin cancer associated with the medication.

Patients should 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 healthcare provider regarding their condition and treatment. Furthermore, patients planning to become pregnant should discuss alternative methods for lowering blood pressure with their doctor. If a patient becomes pregnant while taking losartan potassium and hydrochlorothiazide 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 range of 20° to 25° C (68° to 77° F), with permissible excursions between 15° to 30° C (59° to 86° F) as defined by USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from light to ensure its stability and efficacy.

Additional Clinical Information

Clinicians should periodically monitor renal function in patients whose renal status may be influenced by the renin-angiotensin system, as well as assess serum electrolytes and calcium levels.

Patients are advised to discontinue losartan potassium and hydrochlorothiazide tablets upon detection of pregnancy. 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. Additionally, it is noted that thiazide diuretics may exacerbate or activate systemic lupus erythematosus based on postmarketing experience.

FDA Insert (PDF)

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

View full prescribing information (PDF)