Olmesartan medoxomil/Amlodipine besylate/Hydrochlorothiazide

Description

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are a fixed combination formulation intended for oral administration, comprising olmesartan medoxomil (an angiotensin II receptor blocker), amlodipine (a calcium channel blocker), and hydrochlorothiazide (a thiazide diuretic).

Olmesartan medoxomil, USP, a prodrug, is converted to olmesartan during gastrointestinal absorption. It is chemically defined as 4-(1-hydroxy-1-methylethyl)-2-propyl-1-2'-(1-H-tetrazole-5-yl) biphenyl-4-ylmethyl imidazole-5-carboxylic acid 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl ester, with a structural formula of C29H30N6O6 and a molecular weight of 558.59.

Amlodipine besylate, USP, is described as 2-(2-Amino-ethoxy)methyl-4-(2-chloro-phenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid –3-ethyl ester 5-methyl ester, compound with benzonesulfonic acid, having a structural formula of C20H25ClN2O5 • C6H6O3S and a molecular weight of 567.1.

Hydrochlorothiazide, USP, is characterized as 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a structural formula of C7H8ClN3O4S2 and a molecular weight of 297.74.

The tablets contain olmesartan medoxomil, a white to off-white crystalline powder; amlodipine besylate, a white or almost white powder; and hydrochlorothiazide, a white or practically white, practically odorless crystalline powder. Olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol. Amlodipine besylate is sparingly soluble in ethanol, slightly soluble in water and 2-propanol, and freely soluble in methanol. Hydrochlorothiazide is slightly soluble in water, freely soluble in hydroxide solution, n-butylamine, and dimethylformamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids.

Each tablet also contains inactive ingredients including crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol (partially hydrolyzed), povidone, silicon dioxide, sodium starch glycolate, talc, and titanium dioxide. Specific strengths of the tablets, such as 20 mg/5 mg/12.5 mg, 40 mg/10 mg/12.5 mg, and 40 mg/10 mg/25 mg, may include color additives such as FD&C red #40 aluminum lake, iron oxide black, FD&C yellow #6 aluminum lake, and D&C yellow #10 aluminum lake, as well as iron oxide yellow in certain formulations.

Uses and Indications

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are indicated for the treatment of hypertension to lower blood pressure. Effective blood pressure reduction 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. 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, coadministration of aliskiren with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets is contraindicated in patients with diabetes, as this combination 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. It is important to note that drugs acting directly on the renin-angiotensin system can cause injury and 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 should monitor renal function and potassium levels in patients who are susceptible to these changes. Additionally, there is a risk of increased angina or myocardial infarction associated with the initiation or increase of dosage of calcium channel blockers. Clinicians should remain vigilant for signs of fluid or electrolyte imbalance, as well as the potential exacerbation or activation of systemic lupus erythematosus.

Acute angle-closure glaucoma has been reported as a possible adverse effect. Furthermore, sprue-like enteropathy has been documented; therefore, consideration should be given to discontinuing olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in cases where no other etiology for gastrointestinal symptoms is identified.

Laboratory tests are recommended to monitor renal function and potassium levels in susceptible patients 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.

Other significant adverse reactions include the exacerbation or activation of systemic lupus erythematosus and acute angle-closure glaucoma. Sprue-like enteropathy has also been reported; in such cases, discontinuation of the medication should be considered if no other etiology is identified. Anuria may occur in patients with hypersensitivity to sulfonamide-derived drugs.

It is critical to note the warning regarding fetal toxicity. When pregnancy is detected, olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets should be discontinued as soon as possible, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. Furthermore, coadministration of aliskiren with these tablets is contraindicated 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 Non-Steroidal 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 to maintain glycemic control.

• Hydrochlorothiazide and NSAIDs: The effectiveness of hydrochlorothiazide may be reduced, leading to diminished diuretic, natriuretic, and antihypertensive effects. 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 colesevelam hydrochloride to avoid reduced absorption.

• Olmesartan medoxomil and Lithium: Co-administration may result in increased serum lithium concentrations, raising the risk of lithium toxicity. Regular monitoring of lithium levels is advised.

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

• Amlodipine and Cyclosporin/Tacrolimus: Co-administration may lead to increased exposure to cyclosporin and tacrolimus, necessitating careful monitoring of drug levels and potential dose adjustments.

• Amlodipine and CYP3A Inhibitors: Increased exposure to amlodipine may occur when coadministered with CYP3A inhibitors. Dose adjustments of amlodipine may be required 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 to ensure adequate therapeutic effect.

Packaging & NDC

The table below lists all NDC Code configurations of Olmesartan Medoxomil, Amlodipine 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 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, including 18 patients aged 75 years and older, were treated with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. 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 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 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% 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. Fetal risks associated with maternal hypertension include intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be closely monitored and managed appropriately.

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 their effects on breastfed infants and 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 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 breastfeeding is not recommended 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 if there is parasympathetic (vagal) stimulation. Should symptomatic hypotension arise, it is imperative to initiate supportive treatment. 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 be expected to 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 essential. If hypotension occurs, cardiovascular support should be initiated, which may include elevating the extremities and judicious administration of fluids. If hypotension persists despite these conservative measures, the use of vasopressors, such as phenylephrine, should be considered, with careful attention to circulating volume and urine output. The administration of intravenous calcium gluconate may also be beneficial 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 typically associated with 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. Notably, 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, they did induce 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 this context.

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 conducted by the National Toxicology Program (NTP), which found 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, Chinese Hamster bone marrow chromosomes, or Drosophila. 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

Postmarketing experience has identified a potential association between hydrochlorothiazide and non-melanoma skin cancer. It is recommended that patients receiving hydrochlorothiazide be advised to take protective measures against sun exposure and to 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 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 containing 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 a tight container that meets the specifications outlined in the United States Pharmacopeia (USP), featuring a child-resistant closure as required. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper handling and storage conditions are essential to maintain the integrity 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 and Hydrochlorothiazide as submitted by Teva Pharmaceuticals USA, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)