Olmesartan medoxomil/Amlodipine besylate/Hydrochlorothiazide

Description

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide are provided as a tablet for oral administration, forming a fixed combination of olmesartan medoxomil (an angiotensin II receptor blocker), amlodipine (a calcium channel blocker), and hydrochlorothiazide (a thiazide diuretic). Olmesartan medoxomil is a prodrug that is hydrolyzed 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. It appears as a white to light yellowish-white powder or crystalline powder, is practically insoluble in water, and sparingly soluble in methanol.

The amlodipine besylate component 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. It is a white to off-white crystalline powder, slightly soluble in water, and sparingly soluble in ethanol.

The hydrochlorothiazide component 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. It appears as a white or practically white crystalline powder, slightly soluble in water, and freely soluble in sodium hydroxide solution.

Each tablet is available in several 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. Each tablet contains inactive ingredients including 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 includes titanium dioxide, hypromellose, polyethylene glycol, and polysorbate. The color coating for the 40/10/25 mg and 40/5/12.5 mg tablets contains polyvinyl alcohol (part dehydrolyzed), titanium dioxide, polyethylene glycol, talc, and iron oxide red. The color coating for the 40/10/12.5 mg tablets includes polyvinyl alcohol (part 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.

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

Dosage and Administration

The recommended dosing regimen involves administration of the medication once daily. Initial dosage should be tailored to the individual patient, taking into account their previous therapy. After a period of 2 weeks, the dosage may be increased based on clinical response and tolerability, 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, 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 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 warranting attention include hypotension, which may occur if patients are volume or salt depleted prior to administration. It is essential to monitor renal function and potassium levels in susceptible patients. Additionally, there is a risk of increased angina or myocardial infarction associated with the initiation or increase of calcium channel blocker dosage. Patients should be observed for signs of fluid or electrolyte imbalance, as well as exacerbation or activation of systemic lupus erythematosus. Acute angle-closure glaucoma has also been reported.

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

Other important considerations include the potential for sprue-like enteropathy, which has been reported in some 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. Furthermore, it is contraindicated to coadminister aliskiren with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in patients with diabetes.

Drug Interactions

Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of renal impairment and diminish the antihypertensive effect of certain medications. Clinicians should monitor renal function and blood pressure in patients receiving NSAIDs alongside antihypertensive therapies.

When considering dual inhibition of the renin-angiotensin system, there is an elevated risk of renal impairment, hypotension, and hyperkalemia. Close monitoring of renal function and serum potassium levels is advised in patients receiving this combination.

Colesevelam hydrochloride should be administered at least 4 hours prior to olmesartan to avoid potential interactions that may affect the efficacy of olmesartan.

Lithium coadministration may result in increased serum lithium concentrations, leading to a risk of lithium toxicity. Regular monitoring of lithium levels is recommended to prevent adverse effects.

For patients taking amlodipine, it is recommended to limit simvastatin to a maximum of 20 mg daily to mitigate the risk of adverse effects associated with this combination.

Coadministration of amlodipine with cyclosporin or tacrolimus may lead to increased exposure to these immunosuppressants. Monitoring of drug levels and renal function is warranted to avoid toxicity.

Amlodipine exposure may be increased when administered with CYP3A inhibitors. Clinicians should consider dosage adjustments and monitor for potential adverse effects.

When hydrochlorothiazide is coadministered with antidiabetic drugs, dosage adjustments may be necessary to maintain glycemic control.

Cholestyramine and colestipol can reduce the absorption of thiazide diuretics when taken together. It is advisable to separate the dosing of these medications to ensure therapeutic efficacy.

Lastly, NSAIDs can diminish the diuretic, natriuretic, and antihypertensive effects of diuretics. Monitoring of blood pressure and renal function is recommended in patients receiving this combination to ensure optimal therapeutic outcomes.

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, with 18 of these patients being 75 years of age or 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 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 this age group to ensure optimal safety and efficacy. Regular assessment and monitoring of these patients are advised to mitigate potential risks associated with increased sensitivity to the medication.

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, as well as increased 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.

Hydrochlorothiazide, a component of this combination therapy, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. The use of thiazides during pregnancy is associated with risks such as 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. The use of hydrochlorothiazide for other indications during pregnancy should also be avoided.

No reproductive studies have been conducted with the combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide; however, studies have been performed with olmesartan medoxomil, amlodipine, and hydrochlorothiazide individually, as well as with olmesartan medoxomil and hydrochlorothiazide together. No teratogenic effects were observed in pregnant rats administered olmesartan medoxomil at oral doses up to 1000 mg/kg/day or in pregnant rabbits at doses up to 1 mg/kg/day. However, significant decreases in pup birth weight and weight gain were noted in rats at doses ≥1.6 mg/kg/day, along with delays in developmental milestones and increased incidence of renal pelvis dilation at doses ≥8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day. Similarly, no teratogenic effects were observed with hydrochlorothiazide in mice and rats at doses up to 3000 mg/kg/day and 1000 mg/kg/day, respectively.

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 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 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, specifically those with 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 necessary for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min).

The pharmacokinetics of amlodipine are not significantly affected by renal impairment, while the pharmacokinetics of olmesartan in patients undergoing hemodialysis have not been studied. Caution is warranted when using thiazides in patients with severe renal disease, as they may precipitate azotemia and lead to cumulative effects in those with impaired renal function.

Regular monitoring of renal function and potassium levels is recommended for susceptible patients to ensure safety and efficacy.

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.

Due to the potential for minor alterations in fluid and electrolyte balance to precipitate hepatic coma in patients with impaired liver function or progressive liver disease, careful monitoring of these patients is recommended. Adjustments to therapy should be made with caution, and ongoing assessment of liver function is advised to ensure patient safety.

Overdosage

In the event of an overdosage of olmesartan medoxomil, the primary manifestations are likely to include hypotension and tachycardia. It is important to note that bradycardia may occur as a result of parasympathetic stimulation.

For amlodipine, doses of 4 mg/kg or higher in canine subjects have been associated with significant peripheral vasodilation and hypotension. Overdosage of amlodipine can lead to excessive peripheral vasodilation, resulting in marked hypotension and potentially reflex tachycardia. In cases of massive overdose, it is critical to implement active cardiac and respiratory monitoring, which should include frequent blood pressure measurements.

Should hypotension arise due to amlodipine overdose, immediate cardiovascular support is essential. This may involve elevating the extremities and the judicious administration of fluids. If hypotension persists despite these conservative measures, the consideration of vasopressor administration is warranted. Additionally, intravenous calcium gluconate may be beneficial in reversing the effects of calcium entry blockade associated with amlodipine overdose.

Hydrochlorothiazide overdose typically presents with electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. It is noteworthy that the oral LD50 of hydrochlorothiazide exceeds 10 g/kg in rodent models, which is significantly higher than the maximum recommended dose for humans.

Healthcare professionals are advised to monitor patients closely and provide supportive care as necessary in cases of suspected overdosage.

Nonclinical Toxicology

No information is available regarding teratogenic effects.

Fertility studies 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 affect the fertility of rats when dosing commenced 2 weeks prior to mating for females and 9 weeks prior for males. Similarly, oral treatment 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, did not impact the fertility of rats, with males treated for 64 days and females for 14 days prior to mating. Hydrochlorothiazide also showed no adverse effects on the fertility of mice and rats of either sex when administered via diet at 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 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 nor induce new toxicities, with no toxicologically synergistic effects observed.

No carcinogenicity, mutagenicity, or fertility studies have been conducted on the combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide; however, individual studies have been performed on each compound. 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 of 40 mg/day on a mg/m² basis. 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 of 40 mg/day on a mg/m² basis) revealed no evidence of carcinogenicity.

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 cells in vitro (Chinese hamster lung) 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 these assays.

Rats and mice treated with amlodipine maleate in the diet for up to 2 years at daily dosage levels 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. Two-year feeding studies conducted by 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 also 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 observed in the in vitro CHO Sister Chromatid Exchange assay, the Mouse Lymphoma Cell assay, and the Aspergillus nidulans nondisjunction assay.

Postmarketing Experience

No specific postmarketing experience details are available in the provided text. As such, there are no reported adverse events or case reports to summarize.

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 advise 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 instructed 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 plastic bottle containing 30 units. It should be stored at a temperature of 25°C (77°F), with permissible excursions between 15°C and 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature 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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)