Tribenzor

Description

Tribenzor is an oral tablet formulation that combines three active ingredients: olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide. Olmesartan medoxomil, a prodrug, is converted to olmesartan during gastrointestinal absorption. It is chemically characterized 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 described as 3-ethyl-5-methyl (±)-2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate, having 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 olmesartan medoxomil component appears as a white to light yellowish-white powder or crystalline powder, while amlodipine besylate is a white to off-white crystalline powder, and hydrochlorothiazide is a white or practically white crystalline powder. In terms of solubility, olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol; amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol; hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.

Each tablet of Tribenzor also contains inactive ingredients, including silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The color coating of the tablets consists of polyvinyl alcohol, macrogol/polyethylene glycol 3350, titanium dioxide, talc, and various iron oxides (yellow, red, and black) depending on the specific tablet formulation.

Uses and Indications

Tribenzor is 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.

Tribenzor is not indicated for initial therapy.

Dosage and Administration

The recommended dosage is to administer the medication once daily. After an initial period of 2 weeks, the dosage may be increased based on the patient's response and tolerability, with a maximum allowable dose of 40 mg/10 mg/25 mg once daily.

Dose selection should be individualized, taking into account the patient's previous therapy and clinical response. It is essential for healthcare professionals to monitor the patient closely during the titration period to ensure optimal therapeutic outcomes while minimizing potential adverse effects.

Contraindications

Use of this product is contraindicated in patients with anuria due to the risk of exacerbating renal function. Additionally, hypersensitivity to sulfonamide-derived drugs is a contraindication, as it may lead to severe allergic reactions. Co-administration of aliskiren with Tribenzor is contraindicated in patients with diabetes, as this combination may increase the risk of adverse effects.

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of Tribenzor. It is imperative that the medication be discontinued as soon as pregnancy is detected, as drugs 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 the administration of Tribenzor. 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 complications. Additionally, there is a risk of increased angina or myocardial infarction associated with the initiation or increase of dosage in patients taking calcium channel blockers. Vigilance for signs of fluid or electrolyte imbalance is also recommended.

Patients may experience exacerbation or activation of systemic lupus erythematosus, and acute angle-closure glaucoma has been reported. Furthermore, cases of sprue-like enteropathy have been documented; therefore, discontinuation of Tribenzor should be considered if no other etiology is identified.

For patients at risk, regular monitoring of renal function and potassium levels is advised to ensure safe use of the medication.

Side Effects

Patients receiving Tribenzor 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 been noted, 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 in patients using calcium channel blockers. Additionally, signs of fluid or electrolyte imbalance should be observed.

The use of Tribenzor carries a warning for fetal toxicity. It is imperative to discontinue the medication as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Other important adverse reactions include exacerbation or activation of systemic lupus erythematosus, acute angle-closure glaucoma, and sprue-like enteropathy, which has been reported in some cases. In instances where no other etiology is identified, discontinuation of Tribenzor should be considered. Anuria may occur in patients with hypersensitivity to sulfonamide-derived drugs. Furthermore, it is contraindicated to co-administer aliskiren with Tribenzor in patients with diabetes.

Drug Interactions

The following drug interactions have been identified for olmesartan medoxomil and amlodipine, 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.

• Amlodipine and Antidiabetic Drugs: When amlodipine is coadministered with antidiabetic medications, dosage adjustments may be necessary to maintain glycemic control.

• Amlodipine and NSAIDs: The use of NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of diuretics, including those that may be used alongside amlodipine.

Pharmacokinetic Interactions

• Olmesartan medoxomil and Colesevelam Hydrochloride: It is advisable 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 recommended.

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

• Amlodipine and Cyclosporin/Tacrolimus: Amlodipine may increase the exposure to cyclosporin and tacrolimus, necessitating careful monitoring of drug levels and potential dose adjustments.

• Amlodipine and CYP3A Inhibitors: The coadministration of amlodipine with CYP3A inhibitors may result in increased exposure to amlodipine, which could necessitate dose adjustments based on clinical response.

• Amlodipine and Cholestyramine/Colestipol: The absorption of thiazides may be reduced when taken with cholestyramine or colestipol, which could impact the efficacy of thiazide diuretics used in conjunction with amlodipine.

Packaging & NDC

The table below lists all NDC Code configurations of Tribenzor (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 Tribenzor in pediatric patients have not been established. There are currently no available data to support its use in children or adolescents. Healthcare professionals should exercise caution when considering treatment options for this population, as the lack of established pediatric use may impact clinical decision-making.

Geriatric Use

In a controlled clinical trial involving hypertensive patients treated with Tribenzor, 123 patients were aged 65 years and older, with 18 patients aged 75 years and older. While no overall differences in the efficacy or safety of Tribenzor were observed in these populations, it is important to note that greater sensitivity in some elderly patients cannot be ruled out.

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 formulation of Tribenzor. 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 treatment as necessary is advised to ensure optimal safety and efficacy in this population.

Pregnancy

Tribenzor can cause fetal harm when administered to a pregnant woman. 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, Tribenzor 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 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 carefully 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 the week of gestation. It is important to note that oligohydramnios may not be detected 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.

Thiazides, such as hydrochlorothiazide, 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, including fetal or neonatal jaundice and thrombocytopenia, and they do not prevent or alter the course of preeclampsia. Therefore, thiazides should not be used to treat hypertension in pregnant women, and their use for other indications, such as heart disease, should also be avoided.

Lactation

There is limited information regarding the presence of Tribenzor in human milk, as well as its effects on breastfed infants and milk production. Amlodipine and hydrochlorothiazide have been detected in human milk, while olmesartan has been found in the milk of lactating rats. Following a single oral administration of 5 mg/kg 14C 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 Tribenzor.

Renal Impairment

Patients with renal impairment should be approached with caution when considering the use of Tribenzor. There are no studies evaluating the safety and efficacy of Tribenzor in this population. 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 are elevated compared to those with normal renal function. Notably, after repeated dosing, the area under the curve (AUC) for olmesartan was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). However, no initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min). The pharmacokinetics of olmesartan in patients undergoing hemodialysis have not been studied.

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

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

Hepatic Impairment

Patients with hepatic impairment may experience altered pharmacokinetics of the components in Tribenzor. Although there are no specific studies conducted with Tribenzor in this population, 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 dosage is not available in the formulation of Tribenzor. Amlodipine is extensively metabolized by the liver, and in individuals with severely impaired hepatic function, the plasma elimination half-life (t½) is approximately 56 hours.

Additionally, olmesartan has shown increased pharmacokinetic parameters in patients with moderate hepatic impairment, with an approximate 60% increase in the area under the curve (AUC0-∞) and peak plasma concentration (Cmax) compared to matched controls.

It is important to note that in patients with impaired hepatic function or progressive liver disease, even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Therefore, careful monitoring of these patients is recommended to avoid potential complications.

Overdosage

In the event of an overdosage with Tribenzor, it is important to note that there is currently no available information regarding human overdosage. 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.

Amlodipine maleate has been associated with significant toxicity in animal studies, where single oral doses equivalent to 40 mg amlodipine/kg in mice and 100 mg amlodipine/kg in rats resulted in fatalities. In dogs, doses of 4 mg amlodipine/kg or higher—exceeding the maximum recommended human dose on a mg/m² basis—led to marked peripheral vasodilation and hypotension. Consequently, overdosage with amlodipine may result in excessive peripheral vasodilation, pronounced hypotension, and potentially reflex tachycardia. Clinical experience with intentional overdosage in humans is limited.

In cases of 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. Should hypotension persist despite these conservative measures, the use of vasopressors, such as phenylephrine, should be considered, taking into account circulating volume and urine output. Additionally, intravenous calcium gluconate may 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 related to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has also been 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 triple 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 demonstrated that the combined administration of these agents neither exacerbated existing toxicities nor induced new toxicities, with no toxicologically synergistic effects observed.

No studies have been conducted to evaluate the carcinogenicity, mutagenicity, or fertility effects of the combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide. However, individual studies for each compound have been performed.

Olmesartan medoxomil was not found to be carcinogenic in a two-year dietary study in rats at doses up to 2000 mg/kg/day, which is approximately 480 times the maximum recommended human dose (MRHD) of 40 mg/day. 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, no evidence of carcinogenicity was observed at doses up to 1000 mg/kg/day, roughly 120 times the MRHD. In vitro studies indicated that olmesartan medoxomil and olmesartan did not induce genetic toxicity in the Syrian hamster embryo cell transformation assay or the Ames test. However, both compounds induced chromosomal aberrations in cultured cells and tested positive for thymidine kinase mutations in the 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 doses up to 2000 mg/kg. Fertility studies in rats showed no adverse effects at doses as high as 1000 mg/kg/day, which is 240 times the MRHD.

Amlodipine maleate was administered to rats and mice in dietary studies for up to two years, with no evidence of carcinogenicity observed at doses of 0.5, 1.25, and 2.5 mg/kg/day. The highest dose for mice was comparable to the MRHD, while for rats, it was about twice the MRHD. Mutagenicity studies revealed no drug-related effects at the gene or chromosome level. Additionally, no adverse effects on fertility were noted in rats treated with amlodipine maleate at 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 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. These doses are about 117 and 39 times the MRHD, respectively. However, equivocal evidence for hepatocarcinogenicity was noted in male mice. Hydrochlorothiazide was not genotoxic in various in vitro and in vivo assays, although positive results were obtained in specific clastogenicity and mutagenicity assays. Fertility studies indicated no adverse effects in mice and rats exposed to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation, which are approximately 19 and 1.5 times the MRHD.

Postmarketing Experience

No postmarketing experience details were provided in the text.

Patient Counseling

Healthcare providers should inform female patients of childbearing age about the potential consequences of exposure to Tribenzor 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 not to breastfeed while undergoing treatment with Tribenzor. Additionally, 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 Tribenzor and consult their physician before resuming treatment.

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 must be cautioned against using potassium supplements or salt substitutes that contain potassium without prior consultation with their healthcare provider. Finally, patients should be instructed to discontinue Tribenzor 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 25ºC (77ºF), with permissible excursions between 15ºC and 30ºC (59ºF to 86ºF) as outlined by USP guidelines.

Care should be taken to ensure that the product is kept in its original container to maintain stability and integrity. Special handling requirements include avoiding exposure to extreme temperatures and protecting the product from moisture and light.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Tribenzor as submitted by Cosette Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)