Losartan potassium/Hydrochlorothiazide

Uses and Indications

Losartan potassium and hydrochlorothiazide is indicated for the treatment of hypertension, aimed at lowering blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

This fixed-dose combination is not indicated for initial therapy of hypertension, except in cases where the hypertension is severe enough that the value of achieving prompt blood pressure control exceeds the risk of initiating combination therapy in these patients.

Additionally, this medication is indicated for the reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy. However, there is evidence that this benefit does not apply to Black patients.

Dosage and Administration

The usual starting dose of Losartan Potassium and Hydrochlorothiazide for the treatment of hypertension is 50 mg/12.5 mg administered orally once daily. This dosage may be titrated as needed to a maximum dose of 100 mg/25 mg.

For hypertensive patients with left ventricular hypertrophy who are not adequately controlled on monotherapy, treatment should be initiated with 50 mg/12.5 mg once daily, with titration as necessary to a maximum of 100 mg/25 mg.

In cases where blood pressure remains uncontrolled after approximately three weeks of therapy, the dosage may be increased to 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.

Losartan Potassium and Hydrochlorothiazide tablets may be taken with or without food. For patients with intravascular volume depletion, a recommended starting dose of 25 mg once daily may be considered.

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

Contraindications

Losartan potassium and hydrochlorothiazide tablets are contraindicated in patients with hypersensitivity to any component of the product. The use of this medication is also contraindicated in patients with anuria. Additionally, coadministration with aliskiren is contraindicated in patients with diabetes due to the potential for adverse effects.

Warnings and Precautions

WARNING: FETAL TOXICITY When pregnancy is detected, losartan potassium and hydrochlorothiazide tablets should be discontinued as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. The use of these drugs during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has been reported, presumably resulting from decreased fetal renal function, and has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. In rare cases where no alternative to an angiotensin II receptor antagonist is found, mothers should be informed of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, losartan potassium and hydrochlorothiazide should be discontinued unless it is considered life-saving for the mother. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia.

General Precautions

• Hypotension: Correct volume or salt depletion prior to administration of losartan potassium and hydrochlorothiazide.

• Monitor renal function and potassium in susceptible patients.

• Observe for clinical signs of fluid or electrolyte imbalance.

• Acute angle-closure glaucoma may occur.

• Exacerbation of systemic lupus erythematosus has been reported.

• Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

• Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Laboratory Tests

• Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

• Monitor renal function and potassium in susceptible patients, particularly when the patient is vomiting excessively or receiving parenteral fluids.

Get Emergency Medical Help

• Angioedema may occur, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue. Anaphylactic reactions can present as respiratory distress (including pneumonitis and pulmonary edema).

• If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

Stop Taking and Call Your Doctor

• If you experience symptoms of angioedema or any severe allergic reactions, or if pregnancy is detected, losartan potassium and hydrochlorothiazide should be discontinued as soon as possible.

• Symptoms such as persistent dry cough, signs of kidney problems (such as change in the amount of urine), or any other unusual symptoms should prompt immediate consultation with a healthcare provider.

Side Effects

Most common adverse reactions observed in clinical trials (incidence ≥2% and greater than placebo) include:

• Dizziness

• Upper respiratory infection

• Cough

• Back pain

Warnings: Fetal Toxicity Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, losartan potassium and hydrochlorothiazide tablets should be discontinued as soon as possible.

Additional Adverse Reactions or Important Notes

• Hypotension: It is essential to correct volume or salt depletion prior to administration of losartan potassium and hydrochlorothiazide.

• Renal Function Monitoring: Renal function and potassium levels should be monitored in susceptible patients.

• Fluid or Electrolyte Imbalance: Clinical signs of fluid or electrolyte imbalance should be observed.

• Acute Angle-Closure Glaucoma: This condition may occur.

• Exacerbation of Systemic Lupus Erythematosus: Patients may experience exacerbation of this condition.

• Hypersensitivity: Reactions may occur in patients with hypersensitivity to any component of losartan potassium and hydrochlorothiazide.

• Anuria: This condition may be observed.

• Coadministration with Aliskiren: Coadministration with aliskiren in patients with diabetes is contraindicated.

Overdosage The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension occurs, supportive treatment should be instituted. Common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

Fetal/Neonatal Adverse Reactions Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy can result in:

• Oligohydramnios

• Reduced fetal renal function leading to anuria and renal failure

• Fetal lung hypoplasia

• Skeletal deformations, including skull hypoplasia

• Hypotension

• Death

Pediatric Use Neonates with a history of in utero exposure to losartan potassium and hydrochlorothiazide tablets should be monitored for oliguria or hypotension, with direct attention toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

Geriatric Use Adverse events were somewhat more frequent in the elderly compared to non-elderly patients for both the losartan-hydrochlorothiazide and control groups.

Drug Interactions

Agents that increase serum potassium levels may lead to a risk of hyperkalemia when coadministered with Losartan Potassium and Hydrochlorothiazide. Additionally, the use of lithium can increase the risk of lithium toxicity.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) may pose an increased risk of renal impairment and can reduce the diuretic, natriuretic, and antihypertensive effects of this combination. The dual inhibition of the renin-angiotensin system can further elevate the risk of renal impairment, hypotension, syncope, and hyperkalemia.

Patients taking antidiabetic drugs may require dosage adjustments when using this combination. Furthermore, the absorption of hydrochlorothiazide is significantly reduced when administered with cholestyramine or colestipol, with reductions of up to 85% and 43%, respectively. It is recommended to stagger the administration of hydrochlorothiazide and these anionic exchange resins, ensuring that hydrochlorothiazide is given at least 4 hours before or 4 to 6 hours after the resin.

In terms of pharmacokinetic interactions, Losartan has been shown not to affect the pharmacokinetics or pharmacodynamics of warfarin, nor does it impact the pharmacokinetics of oral or intravenous digoxin. There is no pharmacokinetic interaction between losartan and hydrochlorothiazide. However, coadministration with cimetidine can increase the area under the curve (AUC) of losartan by approximately 18%, while phenobarbital can reduce the AUC of losartan and its active metabolite by about 20%. A more significant interaction has been observed with rifampin, which can lead to a reduction of approximately 40% in the AUC of the active metabolite and about 30% in the AUC of losartan.

Fluconazole, an inhibitor of cytochrome P450 2C9, has been reported to decrease the AUC of the active metabolite by approximately 40% while increasing the AUC of losartan by about 70% after multiple doses. The conversion of losartan to its active metabolite following intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. Erythromycin, another P450 3A4 inhibitor, does not affect the AUC of the active metabolite but increases the AUC of losartan by 30%.

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 losartan potassium and hydrochlorothiazide, if oliguria or hypotension occurs, it is essential to direct attention toward the support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

Geriatric Use

In a controlled clinical study involving hypertensive patients with left ventricular hypertrophy, 62% of participants were aged 65 years and older, and 18% were aged 75 years and older. No overall differences in effectiveness were observed between elderly patients and younger patients. However, adverse events were reported somewhat more frequently in elderly patients compared to their younger counterparts for both the losartan-hydrochlorothiazide combination and the control groups.

Healthcare professionals should monitor geriatric patients closely for potential adverse effects and consider appropriate dose adjustments based on individual patient response and tolerability.

Pregnancy

Losartan potassium and hydrochlorothiazide 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, which can lead to oligohydramnios, increased fetal and neonatal morbidity, and death. 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 in the U.S. general population is 2% to 4% and 15% to 20%, respectively. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. Hypertension in pregnancy increases maternal risks for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, while also increasing fetal risks for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be closely monitored and managed accordingly.

In the second and third trimesters, the use of renin-angiotensin system inhibitors can result in serious fetal outcomes, including fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, anuria, renal failure, and death. In cases where there is no appropriate alternative therapy, 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, discontinuation of therapy should be considered unless it is deemed lifesaving for the mother.

Neonates with in utero exposure to losartan potassium and hydrochlorothiazide should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, supportive measures for blood pressure and renal perfusion may be necessary, including exchange transfusions or dialysis.

Thiazides, including hydrochlorothiazide, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. Hydrochlorothiazide may cause placental hypoperfusion and can accumulate in the amniotic fluid, with concentrations reported to be 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.

Pregnancy categories for losartan potassium and hydrochlorothiazide are C for the first trimester and D for the second and third trimesters, indicating potential risks associated with their use during these periods.

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, which are components of the combination therapy, are known to appear in human milk. Due to the potential for adverse effects on breastfed infants, healthcare providers should consider the importance of the medication to the lactating mother when making decisions about continuing nursing or discontinuing the drug.

Renal Impairment

Patients with renal impairment should be closely monitored for renal function and potassium levels when using losartan potassium and hydrochlorothiazide. It is essential to assess these parameters regularly, particularly in those who may be susceptible to changes in renal status.

Before initiating treatment, any volume or salt depletion should be corrected to minimize the risk of adverse effects. The combination of losartan and hydrochlorothiazide is not recommended for patients with hepatic impairment who require titration with losartan, as the lower starting dose cannot be administered in this formulation. Additionally, thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease due to the potential for minor alterations in fluid and electrolyte balance, which could precipitate hepatic coma.

Overall, careful consideration and monitoring are crucial for patients with renal impairment to ensure safe and effective use of this medication.

Hepatic Impairment

Patients with hepatic impairment are not recommended to use losartan potassium and hydrochlorothiazide tablets, particularly if they require titration with losartan. The lower starting dose of losartan that is advised for patients with hepatic impairment cannot be administered through losartan potassium and hydrochlorothiazide tablets.

Additionally, thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. There are no specific dosage adjustments, special monitoring requirements, or additional precautions provided for patients with liver problems in the available data.

Overdosage

Significant lethality has been observed in animal studies following oral administration of losartan potassium and hydrochlorothiazide, with LD50 values of 1,000 mg/kg and 2,000 mg/kg in mice and rats, respectively, which corresponds to approximately 44 and 170 times the maximum recommended human dose on a mg/m² basis.

In humans, limited data are available regarding overdosage; however, the most likely manifestations include hypotension and tachycardia. Bradycardia may occur due to parasympathetic (vagal) stimulation. Should symptomatic hypotension arise, supportive treatment should be initiated promptly.

Neither losartan nor its active metabolite can be removed by hemodialysis. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats. Common signs and symptoms associated with hydrochlorothiazide overdosage are primarily due to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may exacerbate cardiac arrhythmias. The extent to which hydrochlorothiazide is removed by hemodialysis has not been established.

Monitoring of electrolyte levels and supportive care are essential in managing potential overdosage cases.

Nonclinical Toxicology

Teratogenic Effects

No teratogenic effects were mentioned in the provided text. The drug is classified as Pregnancy Category C during the first trimester and Category D during the second and third trimesters.

Non-Teratogenic Effects

Losartan potassium and hydrochlorothiazide, when tested at a weight ratio of 4:1, had no effect 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. In female rats, coadministration of doses as low as 10 mg/kg/day of losartan and 2.5 mg/kg/day of hydrochlorothiazide was associated with slight but statistically significant decreases in fecundity and fertility indices. Fertility and reproductive performance were not affected in studies with male rats given oral doses of losartan potassium up to approximately 150 mg/kg/day. However, the administration of toxic dosage levels in females (300/200 mg/kg/day) was associated with a significant (p<0.05) decrease in the number of corpora lutea per female, implants per female, and live fetuses per female at C-section. At 100 mg/kg/day, only a decrease in the number of corpora lutea per female was observed. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.

Nonclinical Toxicology

No carcinogenicity studies have been conducted with the losartan potassium-hydrochlorothiazide combination. Losartan potassium-hydrochlorothiazide was negative in 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 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. Female rats given the highest dose (270 mg/kg/day) had a slightly higher incidence of pancreatic acinar adenoma.

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of 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). The 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, or 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.

Animal Pharmacology and Toxicology

The relationship of findings related to drug treatment in females is uncertain since there was no effect at these dosage levels on implants/pregnant females, percent post-implantation loss, or live animals per litter at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were approximately 66 and 26 times the exposure achieved in humans at the maximum recommended human daily dosage (100 mg). The maximally tolerated dosages (270 mg/kg/day in rats, 200 mg/kg/day in mice) provided systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160 and 90 times (rats) and 30 and 15 times (mice) the exposure of a 50 kg human given 100 mg per day.

Storage and Handling

Losartan Potassium and Hydrochlorothiazide is supplied in the form of film-coated tablets.

It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as defined by USP Controlled Room Temperature. The container must be kept tightly closed and protected from light to maintain the integrity of the product.

Additionally, it is recommended to dispense the medication in a tight, light-resistant container that includes a child-resistant closure, as required. Care should be taken to keep this and all medications out of the reach of children.