Olmesartan medoxomil/Amlodipine besylate/Hydrochlorothiazide

Description

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are formulated for oral administration as 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 gastrointestinal absorption.

Chemically, olmesartan medoxomil is 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 characterized 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 defined 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 active ingredients exhibit varying solubility profiles: olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol; amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol; and hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.

Each tablet contains inactive ingredients including colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and talc. The color coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Specific tablet formulations include color additives: the 20 mg/5 mg/12.5 mg tablets contain black iron oxide, red iron oxide, and yellow iron oxide; the 40 mg/10 mg/25 mg tablets and 40 mg/10 mg/12.5 mg tablets contain red iron oxide and yellow iron oxide; while the 40 mg/5 mg/12.5 mg tablets and 40 mg/5 mg/25 mg tablets contain yellow iron oxide.

Uses and Indications

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are indicated for the treatment of hypertension, aimed at lowering blood pressure. Effective management of hypertension is associated with a reduction in the 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. There are no teratogenic or nonteratogenic effects associated with the use of this combination therapy.

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.

Co-administration 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.

General precautions should be observed prior to administration. It is essential to correct any volume or salt depletion to mitigate the risk of hypotension. Healthcare professionals are advised to monitor renal function and potassium levels in patients who may be susceptible to imbalances. Increased incidence of angina or myocardial infarction may occur with the initiation or increase of dosage of calcium channel blockers. Therefore, careful observation for signs of fluid or electrolyte imbalance is warranted.

Additionally, there is a risk of exacerbation or activation of systemic lupus erythematosus, as well as the potential for acute angle-closure glaucoma. Reports of sprue-like enteropathy have also been noted; in cases where no other etiology is identified, consideration should be given to discontinuing olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets.

For patients at risk, it is imperative 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, occurring in 2% or more of participants, include dizziness, peripheral edema, headache, fatigue, nasopharyngitis, muscle spasms, nausea, upper respiratory tract infection, diarrhea, urinary tract infection, and joint swelling.

Serious adverse reactions have also been reported. Notably, fetal toxicity is a significant concern; when pregnancy is detected, it is imperative to discontinue the use of these tablets as soon as possible, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. Additionally, hypotension may occur, necessitating 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. There is a risk of increased angina or myocardial infarction associated with the initiation or increase of dosage of calcium channel blockers. Clinicians should observe for signs of fluid or electrolyte imbalance, as well as the exacerbation or activation of systemic lupus erythematosus.

Other important adverse reactions include 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 also occur, particularly in patients with hypersensitivity to sulfonamide-derived drugs.

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 blood pressure and renal function is recommended.

• Hydrochlorothiazide and Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary to maintain glycemic control.

• Hydrochlorothiazide and NSAIDs: The antihypertensive, diuretic, and natriuretic effects of hydrochlorothiazide may be reduced when used with NSAIDs. Monitoring of blood pressure and renal function is suggested.

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. Regular monitoring of lithium levels is advised.

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

• Amlodipine and Cyclosporin/Tacrolimus: Co-administration may result in increased exposure to cyclosporin and tacrolimus. Monitoring of drug levels and renal function is recommended.

• Amlodipine and CYP3A Inhibitors: The exposure to amlodipine may be increased when coadministered with CYP3A inhibitors. Dose adjustments of amlodipine may be necessary based on clinical response.

• 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.

Packaging & NDC

The table below lists all NDC Code configurations of Olmesartan Medoxomil and Amlodipine Besylate and 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 should be exercised when considering the use of this medication in children and adolescents. Further studies are necessary to determine appropriate dosing and safety profiles 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 tablets, 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 among these geriatric patients. However, it is important to note that greater sensitivity to the medication may be present in some older individuals, 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 dosage 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 elderly patients in this age group to ensure safety and efficacy.

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, these tablets should be discontinued as soon as possible, and alternative antihypertensive therapy should be considered.

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 approximately 2%–4% and 15%–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. It also 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 appropriate 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 component of the combination therapy, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. This diuretic 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, and their use for other indications, such as heart disease, should be avoided during pregnancy.

Lactation

There is limited information regarding the presence of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets 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 have their renal function and potassium levels monitored closely. This is particularly important for those with reduced kidney function, as they may be at increased risk for complications. Dosing adjustments may be necessary based on the degree of renal impairment to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

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 may result in excessive peripheral vasodilation, pronounced hypotension, and potentially reflex tachycardia. Clinical 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, including elevation of the extremities and careful administration of fluids, should be initiated. Should hypotension persist despite these conservative measures, 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 exceeds 10 g/kg in both mice and rats, which is more than 1000-fold the highest recommended human dose.

Nonclinical Toxicology

The rationale for the absence of new toxicity associated with 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 did not exacerbate any existing toxicities nor induce new toxicities, with no toxicologically synergistic effects observed.

No carcinogenicity, mutagenicity, or fertility studies have been conducted specifically on the combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide. However, individual studies have been performed for each compound. Olmesartan was not found to be carcinogenic when administered via diet to rats for up to two years at a maximum dose of 2000 mg/kg/day, which is approximately 480 times the maximum recommended human dose (MRHD) of 40 mg/day. In two carcinogenicity studies involving mice, including a six-month gavage study in p53 knockout mice and a six-month dietary study in Hras2 transgenic mice, doses up to 1000 mg/kg/day (about 120 times the MRHD) showed no evidence of carcinogenic effects.

In terms of mutagenicity, both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and did not exhibit genetic toxicity in the Ames test. However, both compounds induced chromosomal aberrations in cultured Chinese hamster lung cells and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil was negative for mutations in vivo 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 these assays.

Fertility studies in rats indicated that administration of olmesartan at doses as high as 1000 mg/kg/day (240 times the MRHD) did not affect fertility, with dosing initiated two weeks prior to mating for females and nine weeks for males. Amlodipine maleate, when administered in the diet to rats and mice for up to two years at doses 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, and fertility was unaffected in rats treated orally with doses up to 10 mg/kg/day (approximately 10 times the MRHD).

Hydrochlorothiazide was evaluated in two-year feeding studies in mice and rats, revealing no evidence of carcinogenic potential 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. It 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 involving mouse germinal cell chromosomes or Chinese Hamster bone marrow chromosomes. However, positive results were obtained in the in vitro CHO Sister Chromatid Exchange assay, the Mouse Lymphoma Cell assay, and the Aspergillus nidulans nondisjunction assay. Hydrochlorothiazide did not adversely affect fertility in mice and rats exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

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 essential to discuss treatment options with women who are planning to become pregnant and to encourage them to report any pregnancies to their physicians as soon as possible.

Patients should be advised 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 must discontinue the use of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets and consult their physician before resuming treatment.

Healthcare providers should also educate patients about the risks associated with inadequate fluid intake, excessive perspiration, diarrhea, or vomiting, as these conditions can lead to a significant drop in blood pressure, resulting in lightheadedness or syncope.

For patients taking hydrochlorothiazide, it is important to instruct them to protect their skin from sun exposure and to undergo regular skin cancer screenings. Additionally, patients should be cautioned against using potassium supplements or salt substitutes that contain potassium without prior consultation with their healthcare provider.

Finally, patients must be advised 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 upon request. 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 and Amlodipine Besylate and Hydrochlorothiazide as submitted by Slate Run Pharmaceuticals, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)