Losartan potassium/Hydrochlorothiazide

Uses and Indications

Losartan potassium and hydrochlorothiazide is indicated for the treatment of hypertension, aimed at lowering blood pressure. Effective blood pressure reduction is associated with a decreased risk of both fatal and nonfatal cardiovascular events, including strokes and myocardial infarctions.

This combination therapy is also indicated for the reduction of stroke risk in patients with hypertension and left ventricular hypertrophy. However, it is important to note that the evidence supporting this benefit does not extend to Black patients.

There are no teratogenic or nonteratogenic effects reported in the available data.

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 patients with hypertension who also present with left ventricular hypertrophy and are not adequately controlled on monotherapy, treatment should be initiated with a dose of 50/12.5 mg once daily. Similar to the general hypertension population, titration may be performed as necessary, with 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 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 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, necessitating prompt cessation of therapy.

General precautions must be observed prior to the administration of losartan potassium and hydrochlorothiazide. It is essential to correct any volume or salt depletion to mitigate the risk of hypotension. Healthcare professionals should monitor renal function and potassium levels in patients who are susceptible to these complications. Additionally, vigilance for clinical signs of fluid or electrolyte imbalance is advised.

Patients should be aware of the risk of acute angle-closure glaucoma and the potential exacerbation of systemic lupus erythematosus. Regular laboratory tests to monitor renal function and potassium levels are recommended for those at risk.

In the event of any concerning symptoms or adverse effects, patients should seek emergency medical assistance or contact their healthcare provider for further guidance.

Side Effects

Patients receiving losartan potassium and hydrochlorothiazide 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 this medication include the potential for fetal toxicity. It is imperative that losartan potassium and hydrochlorothiazide be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can lead to injury or death of 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 notable adverse reactions include acute angle-closure glaucoma, exacerbation of systemic lupus erythematosus, and hypersensitivity to any component of the medication. Anuria has also been reported. Caution is advised when coadministering losartan potassium and hydrochlorothiazide with aliskiren in patients with diabetes, as this may increase the risk of adverse effects.

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 absorption of thiazides may be reduced when administered with cholestyramine or colestipol. It is advisable to separate the dosing of these agents to minimize the impact on thiazide absorption.

Packaging & NDC

The table below lists all NDC Code configurations of Losartan Potassium and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of losartan potassium and hydrochlorothiazide in pediatric patients have not been established. In neonates with a history of in utero exposure to these medications, if oliguria or hypotension occurs, it is essential to direct attention toward supporting blood pressure and renal perfusion. In such cases, exchange transfusion or dialysis may be required to reverse hypotension and/or substitute for disordered renal function.

Geriatric Use

In a controlled clinical study aimed at reducing the combined risk of cardiovascular death, stroke, and myocardial infarction in hypertensive patients with left ventricular hypertrophy, a significant proportion of participants were elderly, 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 treatment group and the control group.

Given these considerations, healthcare providers should exercise caution when prescribing this medication to geriatric patients. Monitoring for adverse events is recommended, and while no specific dosage adjustments are indicated based on age alone, clinicians should remain vigilant in assessing the individual needs and responses of elderly patients during treatment.

Pregnancy

Losartan potassium and hydrochlorothiazide can cause fetal harm when administered to pregnant women. 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 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 closely 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 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 should be closely observed 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 could 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 their use for other indications during pregnancy should be avoided.

Lactation

It is not known whether losartan is excreted in human milk; however, significant levels of losartan and its active metabolite have been detected in rat milk. Thiazides are known to appear in human milk.

Due to the potential for adverse effects on the nursing infant, healthcare professionals should consider the importance of the drug to the lactating mother when making a decision to either discontinue nursing or discontinue the medication.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored closely, as they may be at increased risk for complications. Dosing adjustments may be necessary based on the degree of reduced kidney function 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 clinical manifestations of an overdose 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.

It is important to note that neither losartan nor its active metabolite can be effectively removed through hemodialysis, which may complicate management in cases of overdose.

Regarding hydrochlorothiazide, the oral LD50 is greater than 10 g/kg in both mice and rats. The predominant signs and symptoms associated with hydrochlorothiazide overdosage are typically related to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has been co-administered, hypokalemia may exacerbate the risk of cardiac arrhythmias. The extent to which hydrochlorothiazide is removed by hemodialysis remains undetermined, necessitating careful monitoring and management of electrolyte levels in cases of overdose.

Nonclinical Toxicology

No specific teratogenic effects have been identified for losartan potassium-hydrochlorothiazide. In studies involving male rats, the combination did not affect fertility or mating behavior 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. Fertility and reproductive performance were unaffected in studies with male rats receiving oral doses of losartan potassium up to approximately 150 mg/kg/day. Conversely, the administration of higher toxic dosage levels in females (300/200 mg/kg/day) led to a significant decrease in the number of corpora lutea, implants, and live fetuses at C-section (p<0.05). At a dose of 100 mg/kg/day, only a decrease in the number of corpora lutea was observed. Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex when 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 losartan potassium-hydrochlorothiazide combination. The combination was 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 or 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. However, female rats given the highest dose of 270 mg/kg/day exhibited a slightly higher incidence of pancreatic acinar adenoma. Losartan potassium was consistently negative in various mutagenesis assays, including the microbial mutagenesis and V-79 mammalian cell mutagenesis assays, as well as in vitro alkaline elution and chromosomal aberration assays. The active metabolite also showed no evidence of genotoxicity in these 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. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay or in the Chinese Hamster Ovary test for chromosomal aberrations, although positive results were obtained in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays.

The relationship of findings related to drug treatment in females remains uncertain, as there was no effect at these dosage levels on implants, 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

Adverse reactions have been identified during post-approval use of losartan potassium and hydrochlorothiazide. These reactions are reported voluntarily from a population of uncertain size, making it challenging to estimate their frequency reliably or to establish a causal relationship to drug exposure.

Digestive: Hepatitis has been reported rarely in patients treated with losartan.

Hematologic: Thrombocytopenia has been observed.

Hypersensitivity: 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 reported in patients treated with losartan. Some of these patients had a history of angioedema with other medications, including ACE inhibitors. Additionally, vasculitis, including Henoch-Schönlein purpura, and anaphylactic reactions have been reported.

Musculoskeletal: Rhabdomyolysis has been documented.

Skin: Erythroderma has been reported.

Non-melanoma Skin Cancer: Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. A study conducted in the Sentinel System indicated that the increased risk was predominantly for squamous cell carcinoma (SCC) and was particularly noted in white patients receiving large cumulative doses. The overall increased risk for SCC was approximately 1 additional case per 16,000 patients per year, while for white patients taking a cumulative dose of ≥50,000 mg, the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

Patient Counseling

Healthcare providers should advise patients that if pregnancy is detected, losartan potassium and hydrochlorothiazide should be discontinued as soon as possible. It is important to communicate that these medications can cause injury and death to the developing fetus, particularly when used during the second and third trimesters of pregnancy. The use of drugs that act on the renin-angiotensin system during this period can lead to reduced fetal renal function, increased morbidity, and mortality. Patients should be informed that oligohydramnios, which may result from such use, can be associated with serious complications including fetal lung hypoplasia and skeletal deformations.

Healthcare providers should also discuss the potential neonatal adverse effects, which may include skull hypoplasia, anuria, hypotension, renal failure, and death. It is essential to explain that thiazides, including hydrochlorothiazide, cross the placental barrier and can appear in cord blood, potentially leading to fetal or neonatal jaundice and thrombocytopenia.

In cases where there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, healthcare providers should inform the mother of the potential risks to the fetus. They should recommend performing serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, losartan potassium and hydrochlorothiazide should be discontinued unless deemed lifesaving for the mother.

Healthcare providers should closely monitor neonates with a history of in utero exposure to losartan potassium and hydrochlorothiazide for signs of hypotension, oliguria, and hyperkalemia. In instances where oliguria or hypotension occurs, it is crucial to support blood pressure and renal perfusion, and be prepared for interventions such as exchange transfusions or dialysis to address hypotension and restore renal function.

Finally, it should be emphasized that hydrochlorothiazide can cause placental hypoperfusion and accumulates in the amniotic fluid, with concentrations significantly higher than in umbilical vein plasma. Given that thiazides do not alter the course of pre-eclampsia, they should not be used to treat hypertension in pregnant women.

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, the product must be protected from light to ensure its efficacy. It is essential to keep this and all medications out of the reach of children.

Additional Clinical Information

No additional information is available regarding laboratory tests, abuse information, route, method, and frequency of administration, or patient counseling information.

In postmarketing experience, cases of cough, including instances of positive re-challenges, have been reported in patients using losartan.

FDA Insert (PDF)

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

View full prescribing information (PDF)