Olmesartan medoxomil/Amlodipine besylate/Hydrochlorothiazide

Description

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide are provided as tablets for oral administration, representing a fixed combination of olmesartan medoxomil (an angiotensin II receptor blocker), amlodipine (a calcium channel blocker), and hydrochlorothiazide (a thiazide diuretic). Olmesartan medoxomil, a prodrug, is converted to olmesartan during absorption from the gastrointestinal tract.

The olmesartan medoxomil component is chemically described as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-p-(o-1H-tetrazol-5-ylphenyl)benzylimidazole-5-carboxylate, cyclic 2,3-carbonate, with an empirical formula of C29H30N6O6 and a molecular weight of 558.6 g/mol. Amlodipine besylate is chemically described as 3-ethyl-5-methyl (±)-2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate, with an empirical formula of C20H25ClN2O5 • C6H6O3S and a molecular weight of 567.1 g/mol. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiazidiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.7 g/mol.

The tablets contain olmesartan medoxomil, a white to light yellowish-white powder or crystalline powder; amlodipine besylate, a white to off-white crystalline powder; and hydrochlorothiazide, a white or practically white crystalline powder. Each tablet formulation is available in various strengths: 20/5/12.5 mg, 40/5/12.5 mg, 40/5/25 mg, 40/10/12.5 mg, and 40/10/25 mg, containing respective amounts of olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide.

Inactive ingredients include silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The color coating for the 20/5/12.5 mg and 40/5/25 mg tablets contains titanium dioxide, hypromellose, polyethylene glycol, and polysorbate. The 40/10/25 mg and 40/5/12.5 mg tablets are coated with polyvinyl alcohol (partially dehydrolyzed), titanium dioxide, polyethylene glycol, talc, and iron oxide red, while the 40/10/12.5 mg tablets are coated with polyvinyl alcohol (partially dehydrolyzed), titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and FD&C #6.

Uses and Indications

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are indicated for the treatment of hypertension to effectively lower blood pressure. The reduction of blood pressure is associated with a decreased risk of both fatal and nonfatal cardiovascular events, including strokes and myocardial infarctions.

These tablets are not indicated for initial therapy in the management of hypertension.

Dosage and Administration

The recommended dosage is to administer the medication once daily. Initial dosing should be individualized based on the patient's previous therapy. After a period of 2 weeks, the dosage may be increased, with a maximum allowable dose of 40 mg/10 mg/25 mg once daily. It is essential for healthcare professionals to assess the patient's response to therapy and adjust the dosage accordingly to achieve optimal therapeutic outcomes.

Contraindications

Use of this product is contraindicated in patients with anuria due to the risk of exacerbating renal impairment. Additionally, hypersensitivity to sulfonamide-derived drugs is a contraindication, as it may lead to severe allergic reactions.

Coadministration of aliskiren with Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets is contraindicated in patients with diabetes, as it may increase the risk of adverse effects.

Warnings and Precautions

When pregnancy is detected, olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets should be discontinued as soon as possible due to the risk of fetal toxicity. Medications that act directly on the renin-angiotensin system have the potential to cause injury or death to the developing fetus.

Healthcare professionals should exercise caution regarding hypotension. It is essential to correct any volume or salt depletion prior to the administration of these tablets. Additionally, renal function and potassium levels should be monitored in patients who are susceptible to these changes.

There is a risk of increased angina or myocardial infarction associated with the initiation or increase of dosage of calcium channel blockers. Therefore, careful observation for signs of fluid or electrolyte imbalance is warranted. Furthermore, there is a possibility of exacerbation or activation of systemic lupus erythematosus, as well as the occurrence of acute angle-closure glaucoma.

Sprue-like enteropathy has been reported in patients taking olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. In cases where no other etiology is identified, consideration should be given to discontinuing the medication.

For patients at risk, it is recommended to monitor renal function and potassium levels regularly to ensure safe use of the medication.

Side Effects

Patients receiving olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets may experience a range of adverse reactions. The most common adverse reactions observed in clinical trials include dizziness, peripheral edema, headache, fatigue, nasopharyngitis, muscle spasms, nausea, upper respiratory tract infection, diarrhea, urinary tract infection, and joint swelling.

Serious adverse reactions may occur, including hypotension, which necessitates correction of volume or salt depletion prior to administration. Patients should be monitored for renal function and potassium levels, particularly those who are susceptible. There is a risk of increased angina or myocardial infarction associated with the initiation or increase of dosage of calcium channel blockers. Additionally, patients should be observed for signs of fluid or electrolyte imbalance.

Warnings regarding fetal toxicity are critical; olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets should be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Other notable adverse reactions include exacerbation or activation of systemic lupus erythematosus, acute angle-closure glaucoma, and sprue-like enteropathy, which has been reported in some cases. In instances where no other etiology is identified, discontinuation of the medication should be considered. Anuria may occur in patients with hypersensitivity to sulfonamide-derived drugs. Furthermore, it is advised not to coadminister aliskiren with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in patients with diabetes.

Drug Interactions

The following drug interactions have been identified for olmesartan medoxomil, amlodipine, and hydrochlorothiazide, categorized by interaction type.

Pharmacodynamic Interactions

• Olmesartan medoxomil and Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Concurrent use may increase the risk of renal impairment and diminish the antihypertensive effect of olmesartan. Monitoring of renal function is advised.

• Olmesartan medoxomil and Dual Inhibition of the Renin-Angiotensin System: The combination may elevate the risk of renal impairment, hypotension, and hyperkalemia. Close monitoring of renal function and potassium levels is recommended.

• Hydrochlorothiazide and Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used in conjunction with hydrochlorothiazide due to potential alterations in glycemic control.

• Hydrochlorothiazide and NSAIDs: The antihypertensive, diuretic, and natriuretic effects of hydrochlorothiazide may be reduced when NSAIDs are coadministered. Blood pressure and fluid status should be monitored.

Pharmacokinetic Interactions

• Olmesartan medoxomil and Colesevelam Hydrochloride: It is recommended to administer olmesartan at least 4 hours prior to the dose of colesevelam hydrochloride to avoid reduced absorption.

• Olmesartan medoxomil and Lithium: Co-administration may lead to increased serum lithium concentrations, raising the risk of lithium toxicity. Serum lithium levels should be monitored closely.

• Amlodipine and Simvastatin: When amlodipine is used with simvastatin, the dose of simvastatin should be limited to 20 mg daily to mitigate the risk of adverse effects.

• Amlodipine and Cyclosporin/Tacrolimus: Amlodipine may increase the exposure to cyclosporin and tacrolimus. Monitoring of drug levels and renal function is recommended.

• Amlodipine and CYP3A Inhibitors: Co-administration with CYP3A inhibitors may lead to increased exposure to amlodipine. Dose adjustments may be necessary based on clinical response and tolerability.

• Hydrochlorothiazide and Cholestyramine/Colestipol: The absorption of hydrochlorothiazide may be reduced when taken with cholestyramine or colestipol. It is advisable to separate the dosing of these medications to ensure adequate therapeutic effect.

Packaging & NDC

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

Pediatric Use

The safety and effectiveness of olmesartan medoxomil, amlodipine, 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 potential outcomes in this population.

Geriatric Use

In a controlled clinical trial involving hypertensive patients, 123 individuals aged 65 years and older were treated with olmesartan medoxomil, amlodipine, and hydrochlorothiazide, including 18 patients aged 75 years and older. The trial did not reveal any overall differences in the efficacy or safety of the combination therapy in these geriatric populations. However, it is important to note that greater sensitivity to the medication may be present in some elderly patients, necessitating careful monitoring.

For geriatric patients aged 75 years and older, the recommended initial dose of amlodipine is 2.5 mg. It is important to highlight that this specific dose is not available in the formulation of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. Therefore, healthcare providers should consider alternative dosing strategies or formulations when treating this age group to ensure optimal safety and efficacy. Regular assessment of the patient's response to therapy and potential side effects is advised to mitigate risks associated with increased sensitivity in older adults.

Pregnancy

Olmesartan medoxomil, amlodipine, 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, which can lead to increased fetal and neonatal morbidity and mortality. Therefore, when pregnancy is detected, it is recommended to discontinue olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets as soon as possible and consider alternative antihypertensive therapy.

The estimated background risk of major birth defects and miscarriage in the general 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 approximately 2% to 4% and 15% to 20%, respectively.

Hypertension during pregnancy poses additional risks, including increased maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications such as the need for cesarean section and postpartum hemorrhage. Furthermore, 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 affecting the renin-angiotensin system in the second and third trimesters can lead to oligohydramnios, which may result in reduced fetal renal function, anuria, renal failure, fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and death. Serial ultrasound examinations should be performed to assess the intra-amniotic environment, and fetal testing may be warranted based on gestational age. 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 olmesartan should be closely observed for hypotension, oliguria, and hyperkalemia. In neonates experiencing oliguria or hypotension, measures should be taken to maintain adequate blood pressure and renal perfusion, which may include exchange transfusions or dialysis to reverse hypotension and support renal function.

Hydrochlorothiazide, a thiazide diuretic, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. It can cause placental hypoperfusion and accumulates in the amniotic fluid, with reported concentrations up to 19 times that 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 prevent or alter the course of preeclampsia, they should not be used to treat hypertension in pregnant women. Additionally, the use of hydrochlorothiazide for other indications, such as heart disease, during pregnancy should be avoided.

Lactation

There is limited information regarding the presence of Olmesartan medoxomil, amlodipine, and hydrochlorothiazide in human milk, as well as the effects on breastfed infants or milk production. Amlodipine and hydrochlorothiazide have been detected in human milk, while olmesartan has been found in rat milk. Following a single oral administration of 5 mg/kg of olmesartan medoxomil to lactating rats, the presence of olmesartan in milk was observed.

Due to the potential for adverse effects on the nursing infant, it is advised that lactating mothers refrain from breastfeeding during treatment with Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets.

Renal Impairment

Patients with renal impairment should be approached with caution when considering the use of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. There are no studies specifically evaluating the safety and efficacy of this combination in individuals with renal impairment. It is advised to avoid use in patients with severe renal impairment, defined as a creatinine clearance of less than 30 mL/min.

In patients with renal insufficiency, serum concentrations of olmesartan may be elevated compared to those with normal renal function. Notably, after repeated dosing, the area under the curve (AUC) for olmesartan was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). However, no initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min). The pharmacokinetics of olmesartan in patients undergoing hemodialysis have not been studied.

The pharmacokinetics of amlodipine are not significantly affected by renal impairment, allowing for its use without specific dosage adjustments in this population. Conversely, thiazide diuretics should be used with caution in patients with severe renal disease, as they may precipitate azotemia and lead to cumulative effects in those with impaired renal function.

It is essential to monitor renal function and potassium levels in susceptible patients to mitigate potential risks associated with these medications.

Hepatic Impairment

Patients with hepatic impairment may experience altered pharmacokinetics of the components in olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. Although there are no specific studies conducted on this combination in individuals with hepatic insufficiency, both amlodipine and olmesartan medoxomil demonstrate moderate increases in exposure in patients with severe hepatic impairment.

For patients with severe hepatic impairment, the recommended initial dose of amlodipine is 2.5 mg. However, this specific dosage is not available in the formulation of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. It is important to note that amlodipine is extensively metabolized by the liver, and in patients with severely impaired hepatic function, the plasma elimination half-life (t1/2) can extend to approximately 56 hours.

Additionally, increases in the area under the curve (AUC0-∞) and peak plasma concentration (Cmax) for olmesartan have been observed in patients with moderate hepatic impairment, with an approximate 60% increase in AUC compared to matched controls.

Patients with impaired hepatic function or progressive liver disease should be closely monitored, as even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Therefore, careful consideration and monitoring are advised when prescribing this medication to patients with compromised liver function.

Overdosage

There is currently no available information regarding overdosage with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in humans. However, limited data suggest that the most likely manifestations of overdosage may include hypotension and tachycardia. In some cases, bradycardia could occur due to parasympathetic (vagal) stimulation. Should symptomatic hypotension arise, it is recommended that supportive treatment be initiated. The dialyzability of olmesartan remains unknown.

In animal studies, single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg in mice and 100 mg amlodipine/kg in rats resulted in fatalities. Additionally, doses of 4 mg amlodipine/kg or higher in dogs, which is significantly above the maximum recommended human dose on a mg/m² basis, led to marked peripheral vasodilation and hypotension. Consequently, overdosage in humans may result in excessive peripheral vasodilation, pronounced hypotension, and potentially reflex tachycardia. Experience with intentional overdosage of amlodipine in humans is limited.

In the event of a massive overdose, active cardiac and respiratory monitoring should be implemented. Frequent blood pressure measurements are crucial. If hypotension occurs, cardiovascular support measures should include elevating the extremities and judicious administration of fluids. Should hypotension persist despite these conservative interventions, the use of vasopressors, such as phenylephrine, may be warranted, with careful attention to circulating volume and urine output. The administration of intravenous calcium gluconate may also assist in reversing the effects of calcium entry blockade. Given that amlodipine is highly protein-bound, hemodialysis is unlikely to provide significant benefit.

The most common signs and symptoms of overdose observed in humans are 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 cardiac arrhythmias. The extent to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, which is more than 1000-fold the highest recommended human dose.

Nonclinical Toxicology

No teratogenic effects have been reported in the studies conducted. The fertility of rats was unaffected by the administration of olmesartan at dose levels as high as 1000 mg/kg/day, which is approximately 240 times the maximum recommended human dose (MRHD) of 40 mg/day on a mg/m² basis. In a separate study, no effects on fertility were observed in rats treated orally with amlodipine maleate at doses up to 10 mg/kg/day, about 10 times the MRHD of 10 mg/day on a mg/m² basis. Hydrochlorothiazide also demonstrated no adverse effects on 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, corresponding to approximately 19 and 1.5 times the MRHD of 25 mg/day on a mg/m² basis.

The rationale for the absence of new toxicity from the combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide is supported by the established safety profiles of the individual compounds and their dual combinations. A three-month repeated dose toxicity study in rats indicated that the combined administration of these agents neither augmented existing toxicities nor induced new toxicities, with no toxicologically synergistic effects observed.

No carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide; however, such studies have been performed for each compound individually. Olmesartan was not found to be carcinogenic when administered via diet to rats for up to two years at the highest tested dose of 2000 mg/kg/day, approximately 480 times the MRHD. In two carcinogenicity studies in mice, including a 6-month gavage study in p53 knockout mice and a 6-month dietary study in Hras2 transgenic mice, doses up to 1000 mg/kg/day (about 120 times the MRHD) revealed no evidence of carcinogenic effects.

Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames test. However, both compounds induced chromosomal aberrations in cultured cells in vitro and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. In vivo, olmesartan medoxomil tested negative for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow at oral doses up to 2000 mg/kg, while olmesartan was not tested in this context.

Rats and mice treated with amlodipine maleate in the diet for up to two years at calculated daily dosages of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenic effects. Mutagenicity studies with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level. Two-year feeding studies conducted under the National Toxicology Program (NTP) found 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. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay or in the Chinese Hamster Ovary test for chromosomal aberrations, nor was it genotoxic in vivo in assays using mouse germinal cell chromosomes, Chinese Hamster bone marrow chromosomes, or in Drosophila sex-linked recessive lethal trait gene. Positive results were obtained in the in vitro CHO Sister Chromatid Exchange assay, the Mouse Lymphoma Cell assay, and the Aspergillus nidulans nondisjunction assay.

Postmarketing Experience

In postmarketing experience, non-melanoma skin cancer has been reported in patients taking hydrochlorothiazide. It is advised that patients receiving this medication take precautions to protect their skin from sun exposure and participate in regular skin cancer screenings.

Patient Counseling

Healthcare providers should inform female patients of childbearing age about the potential consequences of exposure to Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets during pregnancy. It is important to discuss treatment options with women who are planning to become pregnant and to encourage patients to report any pregnancies to their physicians as soon as possible.

Nursing women should be advised against breastfeeding while undergoing treatment with Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets.

Patients should be made aware that lightheadedness may occur, particularly during the initial days of therapy, and they should report this symptom to their prescribing physician. In the event of syncope, patients should discontinue the medication and consult their physician before resuming treatment. Additionally, patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, resulting in lightheadedness and potential syncope.

For those taking hydrochlorothiazide, it is essential to instruct patients to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Patients should be advised not to use potassium supplements or salt substitutes containing potassium without prior consultation with their healthcare provider.

Finally, patients must be informed to discontinue Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets and seek immediate medical attention if they experience symptoms indicative of acute myopia or secondary angle-closure glaucoma.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as outlined by USP guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Olmesartan Medoxomil / Amlodipine Besylate / Hydrochlorothiazide as submitted by Endo USA, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)