Olmesartan medoxomil/Amlodipine besylate/Hydrochlorothiazide

Description

Olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets USP are formulated as a fixed combination for oral administration, comprising 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.

The chemical structure of 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. 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. 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.

The components of the tablets include olmesartan medoxomil USP, which appears as a white to light yellowish-white powder or crystalline powder; amlodipine besylate USP, a white to off-white crystalline powder; and hydrochlorothiazide USP, a white or practically white crystalline powder. Solubility characteristics indicate that olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol, amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol, while hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.

Each tablet also contains inactive ingredients, including microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The color coating consists of polyvinyl alcohol, macrogol/polyethylene glycol 3350, titanium dioxide, talc, and various iron oxides for color differentiation across different tablet strengths.

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.

This combination therapy is not indicated for initial therapy in the management of hypertension.

There are no teratogenic or nonteratogenic effects associated with the use of this medication.

Dosage and Administration

The recommended dosing regimen involves administering the medication once daily. Initial dose selection should be individualized based on the patient's previous therapy and clinical response. 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 monitor the patient's response to therapy and adjust the dosage accordingly to achieve optimal therapeutic outcomes.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with anuria or hypersensitivity to sulfonamide-derived drugs should not use this product due to the potential for adverse reactions. Additionally, co-administration 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

The use of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets necessitates careful consideration of several warnings and precautions to ensure patient safety.

Fetal Toxicity It is imperative to note that these medications carry a significant risk of fetal toxicity. Healthcare professionals should refer to the complete boxed warning in the full prescribing information. If pregnancy is confirmed, the administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets should be discontinued immediately, as drugs that act directly on the renin-angiotensin system can lead to serious injury or death in the developing fetus.

General Precautions Prior to initiating treatment, it is essential to correct any volume or salt depletion to mitigate the risk of hypotension. Continuous monitoring of renal function and serum potassium levels is recommended, particularly in patients who may be susceptible to these changes.

Healthcare providers should be vigilant for the potential exacerbation of angina or myocardial infarction, which may occur upon the initiation or increase of dosage with calcium channel blockers. Additionally, signs of fluid or electrolyte imbalance should be closely observed throughout the treatment period.

There is a risk of exacerbation or activation of systemic lupus erythematosus in some patients. Acute angle-closure glaucoma has also been reported as a potential adverse effect. Furthermore, sprue-like enteropathy has been documented; therefore, consideration should be given to discontinuing the medication if no other etiology for gastrointestinal symptoms is identified.

Laboratory Tests Regular monitoring of renal function and potassium levels is crucial for patients at risk, ensuring timely identification and management of any abnormalities that may arise during treatment.

In summary, adherence to these warnings and precautions is essential for the safe administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets, thereby optimizing patient outcomes while minimizing potential risks.

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 warrant particular attention. Notably, fetal toxicity has been observed; therefore, when pregnancy is detected, it is crucial to discontinue the medication 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 also have their renal function and potassium levels monitored, especially those who are susceptible.

There is a risk of increased angina or myocardial infarction, particularly upon initiation or dosage increase of calcium channel blockers. Patients should be observed for signs of fluid or electrolyte imbalance. Other serious adverse reactions include exacerbation or activation of systemic lupus erythematosus and acute angle-closure glaucoma.

Sprue-like enteropathy has been reported, and discontinuation of the medication should be considered if no other etiology is found. Anuria may occur in patients with hypersensitivity to sulfonamide-derived drugs. Furthermore, caution is advised against the co-administration of 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:

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

  • Dual Inhibition of the Renin-Angiotensin System: This combination may elevate the risk of renal impairment, hypotension, and hyperkalemia.

• Hydrochlorothiazide:

  • Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used in conjunction with hydrochlorothiazide.

  • NSAIDs: The antihypertensive, diuretic, and natriuretic effects of hydrochlorothiazide may be reduced when NSAIDs are administered concurrently.

Pharmacokinetic Interactions

• Olmesartan medoxomil:

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

  • Lithium: Co-administration may lead to increased serum lithium concentrations, raising the risk of lithium toxicity.

• Amlodipine:

  • Simvastatin: The daily dose of simvastatin should be limited to 20 mg when coadministered with amlodipine to mitigate the risk of adverse effects.

  • Cyclosporin and Tacrolimus: Amlodipine may increase the exposure to these immunosuppressants, necessitating careful monitoring of their levels.

  • CYP3A Inhibitors: Co-administration with CYP3A inhibitors may result in increased exposure to amlodipine, warranting dosage adjustments and monitoring for potential adverse effects.

Recommendations for Monitoring and Dosage Adjustments

Healthcare professionals should consider monitoring renal function and serum potassium levels when using olmesartan in conjunction with NSAIDs or dual renin-angiotensin system inhibitors. For patients receiving hydrochlorothiazide with antidiabetic medications, regular blood glucose monitoring is recommended to adjust dosages as needed. When prescribing amlodipine with simvastatin, cyclosporin, or tacrolimus, appropriate dose adjustments and monitoring of drug levels are advised to ensure patient safety.

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 were treated with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets, including 18 patients aged 75 years and older. While no overall differences in efficacy or safety were observed between these age groups and younger patients, it is important to note that greater sensitivity to the medication may be present in some elderly patients.

For geriatric patients aged 75 years and older, the recommended initial dose of amlodipine is 2.5 mg. However, this specific dosage is not available in the combination formulation of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. Therefore, healthcare providers should exercise caution and consider individual patient factors when prescribing this medication to elderly patients, particularly those who may be more sensitive to its effects. Monitoring for potential adverse reactions and adjusting dosages as necessary is advised to ensure optimal safety and efficacy in this population.

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, olmesartan medoxomil, amlodipine, and hydrochlorothiazide 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 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%-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. Furthermore, hypertension increases the fetal risk for 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 are no specific statements regarding the use of olmesartan medoxomil, amlodipine, and hydrochlorothiazide in lactating mothers. The available information does not address the potential for excretion of these medications in breast milk, the associated risks to breastfed infants, or any special considerations for breastfeeding women. Therefore, healthcare professionals should exercise caution and consider the lack of data when advising lactating mothers on the use of these medications.

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 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 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 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, it is crucial to implement active cardiac and respiratory monitoring. 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, taking into account 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. 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

No information is available regarding teratogenic effects associated with the compounds.

Fertility studies conducted in rats demonstrated that the administration of olmesartan at doses up to 1000 mg/kg/day, which is approximately 240 times the maximum recommended human dose (MRHD) of 40 mg/day on a mg/m² basis, did not adversely affect fertility. Dosing commenced 2 weeks prior to mating in females and 9 weeks prior in males. Similarly, oral treatment with amlodipine maleate at doses up to 10 mg/kg/day, roughly 10 times the MRHD, did not impact fertility in rats, with males treated for 64 days and females for 14 days prior to mating. Hydrochlorothiazide also showed no adverse effects on fertility in both mice and rats, with dietary exposure to doses of up to 100 mg/kg in mice and 4 mg/kg in rats prior to mating and throughout gestation, corresponding to approximately 19 and 1.5 times the MRHD, respectively.

The rationale for the absence of new or enhanced 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 3-month repeated dose toxicity study in rats indicated that the combined administration of these agents did not exacerbate existing toxicities or introduce new toxicities, with no toxicologically synergistic effects observed.

No carcinogenicity, mutagenicity, or fertility studies have been performed on the combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide; however, such studies have been conducted on each compound individually. Olmesartan was not found to be carcinogenic in rats when administered via diet for up to 2 years at the highest tested dose of 2000 mg/kg/day, approximately 480 times the MRHD. In two carcinogenicity studies involving 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 carcinogenicity.

In vitro studies indicated that olmesartan and olmesartan medoxomil did not induce genetic toxicity in the Syrian hamster embryo cell transformation assay or the Ames test. However, both compounds were associated with chromosomal aberrations in cultured Chinese hamster lung cells 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.

Amlodipine maleate, when administered in the diet to rats and mice for up to 2 years at doses of 0.5, 1.25, and 2.5 mg/kg/day, showed no evidence of carcinogenicity. Mutagenicity studies with amlodipine maleate indicated no drug-related effects at either the gene or chromosome level. Hydrochlorothiazide was also evaluated in two-year feeding studies under 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. Hydrochlorothiazide did not exhibit genotoxicity in vitro in the Ames assay or the Chinese Hamster Ovary test for chromosomal aberrations, although 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, cases of non-melanoma skin cancer have been reported. Patients taking hydrochlorothiazide are advised to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Additionally, reports of acute myopia and secondary angle-closure glaucoma have been noted. Patients prescribed olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets should be instructed to discontinue use and seek immediate medical attention if they experience symptoms indicative of these conditions.

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. Patients should be advised to report any pregnancies to their physicians as soon as possible.

Nursing women should be counseled against breastfeeding while undergoing treatment with these medications. 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 must discontinue the use of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets and consult their physician.

Patients should be educated on 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 and potential syncope. For those taking hydrochlorothiazide, it is important to advise them to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Patients should also be cautioned against using potassium supplements or salt substitutes that contain potassium without prior consultation with their healthcare provider. Finally, they should be instructed to discontinue the medication 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 temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permitted between 15° to 30°C (59° to 86°F), in accordance with USP Controlled Room Temperature guidelines. Proper container requirements must be adhered to, and special handling needs should be followed to ensure product integrity.

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 Macleods Pharmaceuticals Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)