Olmesartan medoxomil/Amlodipine besylate/Hydrochlorothiazide

Uses and Indications

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are indicated for the treatment of hypertension, aimed at lowering blood pressure. Lowering blood pressure is associated with a reduced risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

These tablets are not indicated for initial therapy.

Limitations of Use

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are not suitable for initial therapy.

Dosage and Administration

The recommended dosage of Olmesartan Medoxomil, Amlodipine Besylate, and Hydrochlorothiazide is one tablet taken once daily. Dosage may be increased after 2 weeks based on the patient's response, with a maximum allowable dose of 40 mg of Olmesartan, 10 mg of Amlodipine, and 25 mg of Hydrochlorothiazide administered 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's blood pressure and adjust the dosage as necessary to achieve optimal therapeutic outcomes.

Contraindications

Use of this medication is contraindicated in patients with anuria and those with hypersensitivity to sulfonamide-derived drugs. Additionally, coadministration of aliskiren with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets is contraindicated in patients with diabetes.

Warnings and Precautions

WARNING: FETAL TOXICITY When pregnancy is detected, olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets should be discontinued as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

General Precautions

• Hypotension: Correct volume or salt depletion prior to administration.

• Renal Function Monitoring: Monitor renal function and potassium levels in susceptible patients.

• Cardiovascular Risk: Increased angina or myocardial infarction may occur with calcium channel blockers upon dosage initiation or increase.

• Fluid and Electrolyte Imbalance: Observe for signs of fluid or electrolyte imbalance.

• Systemic Lupus Erythematosus: Exacerbation or activation may occur.

• Acute Angle-Closure Glaucoma: Risk of acute angle-closure glaucoma should be considered.

• Sprue-like Enteropathy: This condition has been reported; consider discontinuation of the medication in cases where no other etiology is found.

Laboratory Tests

• Regular monitoring of renal function and potassium levels is recommended for susceptible patients.

Emergency Medical Help

Specific instructions for obtaining emergency medical help are not provided in the available text.

Stop Taking and Call Your Doctor

Specific instructions for when to stop taking the medication and contact a doctor are not provided in the available text.

Side Effects

Most common adverse reactions reported in clinical trials and postmarketing experience include:

• Dizziness

• Peripheral edema

• Headache

• Fatigue

• Nasopharyngitis

• Muscle spasms

• Nausea

• Upper respiratory tract infection

• Diarrhea

• Urinary tract infection

• Joint swelling

Serious warnings include:

Fetal Toxicity: When pregnancy is detected, olmesartan medoxomil, amlodipine, and hydrochlorothiazide should be discontinued as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Additional adverse reactions or important notes include:

• Hypotension: It is advised to correct volume or salt depletion prior to administration.

• Renal Function: Monitoring of renal function and potassium levels is recommended in susceptible patients.

• Increased Angina or Myocardial Infarction: There is a risk of increased angina or myocardial infarction with calcium channel blockers upon dosage initiation or increase.

• Fluid or Electrolyte Imbalance: Patients should be observed for signs of fluid or electrolyte imbalance.

• Exacerbation or Activation of Systemic Lupus Erythematosus: This condition may be exacerbated or activated.

• Acute Angle-Closure Glaucoma: This condition has been reported.

• Sprue-like Enteropathy: Consider discontinuation of olmesartan medoxomil, amlodipine, and hydrochlorothiazide in cases where no other etiology is found.

• Anuria: This may occur in patients with hypersensitivity to sulfonamide-derived drugs.

• Co-administration Warning: Aliskiren should not be co-administered with olmesartan medoxomil, amlodipine, and hydrochlorothiazide in patients with diabetes.

Drug Interactions

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide exhibit several significant drug interactions that can impact their efficacy and safety.

Olmesartan Medoxomil Interactions

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

• Dual Inhibition of the Renin-Angiotensin System: This combination can lead to an increased risk of renal impairment, hypotension, and hyperkalemia.

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

• Lithium: Olmesartan may increase serum lithium concentrations, raising the risk of lithium toxicity.

Amlodipine Interactions

• Simvastatin: When amlodipine is coadministered with simvastatin, the dose should be limited to 20 mg daily to avoid increased risk of adverse effects.

• Cyclosporin and Tacrolimus: Amlodipine can increase the exposure to these immunosuppressants, necessitating careful monitoring.

• CYP3A Inhibitors: The coadministration of CYP3A inhibitors can lead to increased exposure to amlodipine, which may enhance its effects and side effects.

Hydrochlorothiazide Interactions

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when hydrochlorothiazide is used, as it can affect glucose metabolism.

• Cholestyramine and Colestipol: These agents can reduce the absorption of hydrochlorothiazide, potentially decreasing its effectiveness.

• NSAIDs: Similar to olmesartan, NSAIDs can reduce the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide.

In summary, careful consideration and monitoring are advised when these medications are used in conjunction with NSAIDs, lithium, simvastatin, cyclosporin, tacrolimus, and certain antidiabetic drugs to mitigate the risk of adverse effects and ensure therapeutic efficacy.

Pediatric Use

The safety and effectiveness of olmesartan medoxomil, amlodipine, and hydrochlorothiazide, as well as the combination product Tribenzor, have not been established in pediatric patients. There are no available data to support the use of these medications in children or adolescents. Therefore, caution is advised when considering treatment options for this population.

Geriatric Use

In controlled clinical trials involving hypertensive patients, 123 individuals aged ≥65 years and 18 individuals aged ≥75 years were treated with olmesartan medoxomil, amlodipine, and hydrochlorothiazide. No overall differences in efficacy or safety were observed in these populations; however, greater sensitivity in some older individuals cannot be ruled out.

For geriatric patients aged ≥75 years, the recommended initial dose of amlodipine is 2.5 mg, which is not available in the combination formulation of olmesartan medoxomil, amlodipine, and hydrochlorothiazide. Therefore, careful consideration should be given to dose selection and monitoring in this age group to ensure safety and efficacy.

Pregnancy

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide 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.

When pregnancy is detected, it is recommended to discontinue the use of olmesartan medoxomil, amlodipine, and hydrochlorothiazide as soon as possible and to consider alternative antihypertensive therapies. The estimated background risk of major birth defects and miscarriage in the U.S. general population is approximately 2% to 4% and 15% to 20%, respectively. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes.

Hypertension during pregnancy poses additional risks, including increased maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and complications during delivery, 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 patients with hypertension should be closely monitored and managed appropriately.

The use of renin-angiotensin system-affecting drugs 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 are recommended 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 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 cases where oliguria or hypotension occurs, measures should be taken to maintain adequate blood pressure and renal perfusion, which may include exchange transfusions or dialysis.

Hydrochlorothiazide, a component of this medication, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. It may cause placental hypoperfusion and accumulate in the amniotic fluid, with concentrations reported to be 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 pre-eclampsia, they should not be used to treat hypertension in pregnant women, and their use for other indications during pregnancy should be avoided.

No reproductive studies have been conducted with the combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide; however, individual studies on the components have been performed. No teratogenic effects were observed in animal studies with olmesartan or hydrochlorothiazide at specified doses, although developmental toxicity was noted at higher doses of olmesartan in rats.

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 observed in rat milk following a single oral administration of 5 mg/kg to lactating rats.

Due to the potential for adverse effects on nursing infants, it is advised that lactating mothers refrain from breastfeeding during treatment with olmesartan medoxomil, amlodipine, and hydrochlorothiazide. The lack of specific data on the effects of these medications on breastfed infants underscores the importance of caution in their use during lactation.

Renal Impairment

Patients with renal impairment should be approached with caution when considering the use of olmesartan medoxomil, amlodipine, and hydrochlorothiazide. There are no specific studies evaluating the safety and efficacy of these medications in this population. It is advised to avoid use in patients with severe renal impairment, defined as a creatinine clearance of less than 30 mL/min.

In patients with renal insufficiency, serum concentrations of olmesartan may be significantly elevated. After repeated dosing, the area under the curve (AUC) for olmesartan was found to be approximately tripled in individuals 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, which may allow for its continued use in this patient population. Conversely, caution is warranted when prescribing thiazides, as they may precipitate azotemia in patients with severe renal disease, and cumulative effects can develop in those with impaired renal function.

Regular monitoring of renal function and potassium levels is essential in patients with renal impairment to mitigate potential risks associated with these medications.

Hepatic Impairment

In patients with hepatic impairment, there are no specific studies conducted on the combination of olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide. However, both amlodipine and olmesartan medoxomil exhibit moderate increases in exposure in individuals with severe hepatic impairment.

The recommended initial dose of amlodipine for patients with severe hepatic impairment is 2.5 mg; however, this dosage is not available in the combination tablet form. Amlodipine is extensively metabolized by the liver, and its plasma elimination half-life (t½) can extend to 56 hours in patients with severely impaired hepatic function.

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.

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 parameters is advised in this patient population.

Overdosage

In cases of overdosage with olmesartan medoxomil, amlodipine, and hydrochlorothiazide, the most likely manifestations include hypotension and tachycardia, with the potential for bradycardia if parasympathetic (vagal) stimulation occurs. Limited data are available regarding human overdosage; however, the experience with intentional overdosage of amlodipine is also limited.

Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg in mice and 100 mg amlodipine/kg in rats have resulted in fatalities. In dogs, doses of 4 mg amlodipine/kg or higher have caused significant peripheral vasodilation and hypotension. Overdosage may lead to excessive peripheral vasodilation, marked hypotension, and possibly reflex tachycardia.

If a massive overdose occurs, active cardiac and respiratory monitoring should be instituted, with frequent blood pressure measurements being essential. Should hypotension arise, cardiovascular support should be initiated, which includes elevating the extremities and judiciously administering fluids. If hypotension remains unresponsive to these conservative measures, the administration of vasopressors, such as phenylephrine, should be considered, with careful attention to circulating volume and urine output. Additionally, intravenous calcium gluconate may assist in reversing the effects of calcium entry blockade. It is important to note that, due to the high protein binding of amlodipine, hemodialysis is unlikely to be beneficial.

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 administered concurrently, hypokalemia may exacerbate cardiac arrhythmias. The extent to which hydrochlorothiazide is removed by hemodialysis has not been established, but the oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, significantly exceeding the highest recommended human dose.

Nonclinical Toxicology

Teratogenic Effects

No teratogenic effects have been reported for the combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide.

Non-Teratogenic Effects

Fertility studies indicate that the administration of olmesartan at doses as high as 1000 mg/kg/day (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 (females) or 9 weeks (males) prior to mating. Similarly, amlodipine maleate did not impact the fertility of rats treated orally at doses up to 10 mg/kg/day (approximately 10 times the MRHD of 10 mg/day on a mg/m² basis) when males were dosed 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 (mice) and 4 mg/kg (rats) 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.

Nonclinical Toxicology

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 demonstrated that the combined administration of these agents neither augmented existing toxicities nor induced new toxicities, with no toxicologically synergistic effects observed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted specifically on the combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide; however, such studies have been performed on each component individually.

Olmesartan Medoxomil

Olmesartan was not found to be carcinogenic in dietary studies conducted in rats for up to 2 years, with the highest tested dose being 2000 mg/kg/day (approximately 480 times the MRHD of 40 mg/day on a mg/m² basis). 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, at doses up to 1000 mg/kg/day (about 120 times the MRHD), also revealed no evidence of carcinogenicity. In vitro assays, including the Syrian hamster embryo cell transformation assay and the Ames test, indicated no genetic toxicity. However, olmesartan was associated with chromosomal aberrations in cultured cells (Chinese hamster lung) and positive results 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.

Amlodipine

Rats and mice treated with amlodipine maleate in the diet 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 indicated no drug-related effects at either the gene or chromosome level. Fertility studies demonstrated no impact on the fertility of rats treated orally with amlodipine maleate at doses up to 10 mg/kg/day.

Hydrochlorothiazide

Two-year feeding studies conducted under the National Toxicology Program (NTP) found no evidence of carcinogenic potential in female mice (up to approximately 600 mg/kg/day) or in male and female rats (up to approximately 100 mg/kg/day). Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay or the Chinese Hamster Ovary (CHO) 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 the fertility of mice and rats at doses of up to 100 mg/kg (mice) and 4 mg/kg (rats) prior to mating and throughout gestation.

Storage and Handling

Olmesartan Medoxomil / Amlodipine Besylate / Hydrochlorothiazide is supplied in film-coated tablet form. The product should be stored at a temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines.

The product is packaged in a plastic bottle containing 30 tablets. For optimal preservation, it should be dispensed in a tight container as defined by the USP, equipped with a child-resistant closure as required.

Additionally, Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide should be stored at temperatures ranging from 20° to 25°C (68° to 77°F), with similar excursion allowances of 15° to 30°C (59° to 86°F).

All handling and storage practices should adhere to these specified conditions to ensure the integrity and efficacy of the product.