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 receptor blocker), amlodipine (a calcium channel blocker), and hydrochlorothiazide (a thiazide diuretic). Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. The olmesartan medoxomil component is chemically described as 1H-Imadazole-5-carboxylic acid, 4-(1-hydroxy-1-methyl-ethyl)-2-Propyl-1-[[2’-(1H tetrazole-5-yl) 1,1’-biphenyl-4-yl]methyl-, (5-methyl-2-oxo-1, 3-dioxol-4-yl)methyl ester, with an empirical formula of C29H30N6O6 and a molecular weight of 558.6. Amlodipine besylate is chemically described as 3,5-pyridine dicarboxylic acid, 2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-6-methyl,3-ethyl 5-methyl ester, (±)-monobenzene sulfonate, with an empirical formula of C26H31ClN2O8S and a molecular weight of 567.1. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.7.

Olmesartan medoxomil USP is a white to off-white, crystalline powder that is practically insoluble in water and in heptane, slightly soluble in ethanol (96%), and sparingly soluble in methanol. Amlodipine besylate USP is a white or almost white powder that is slightly soluble in water, freely soluble in methanol, sparingly soluble in anhydrous ethanol, and slightly soluble in 2-propanol. Hydrochlorothiazide USP is a white or practically white, practically odourless, crystalline powder that is very slightly soluble in water, freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethyl formamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids.

Each tablet contains inactive ingredients including colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and pregelatinized starch, which is derived from corn starch. The color coating consists of iron oxide black, iron oxide red, iron oxide yellow, macrogol, polyvinyl alcohol, talc, and titanium dioxide.

Uses and Indications

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablet 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.

This combination therapy is not indicated for initial therapy. There are no teratogenic or nonteratogenic effects reported for this medication.

Dosage and Administration

The recommended dosage is to administer the medication once daily. Initial dosing should be individualized based on the patient's previous therapy. After a period of 2 weeks, the dosage may be increased, with a maximum allowable dose of 40 mg/10 mg/25 mg once daily. It is essential 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 is contraindicated in patients with diabetes, as this combination may increase the risk of serious complications.

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.

General precautions should be observed prior to administration. It is essential to correct any volume or salt depletion to mitigate the risk of hypotension. Healthcare professionals are advised to monitor renal function and potassium levels in patients who may be susceptible to these changes.

Increased incidence of angina or myocardial infarction may occur with the initiation or increase of dosage of calcium channel blockers. Therefore, careful observation for signs of fluid or electrolyte imbalance is warranted. Additionally, there is a risk of exacerbation or activation of systemic lupus erythematosus, as well as the potential for acute angle-closure glaucoma.

Reports of sprue-like enteropathy have been noted; thus, consideration should be given to discontinuing olmesartan medoxomil, amlodipine, and hydrochlorothiazide in cases where no other etiology for gastrointestinal symptoms is identified.

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 may experience a range of adverse reactions while using olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. 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 fetal toxicity, which can result in injury or death to the developing fetus. It is crucial to discontinue the medication as soon as pregnancy is detected. Additionally, hypotension may occur; therefore, it is recommended to correct any volume or salt depletion prior to administration. Patients should also have their renal function and potassium levels monitored, particularly those who are susceptible.

There is a risk of increased angina or myocardial infarction, which may arise upon initiation or dosage increase of calcium channel blockers. Patients should be observed for signs of fluid or electrolyte imbalance. Other serious reactions include exacerbation or activation of systemic lupus erythematosus, acute angle-closure glaucoma, and sprue-like enteropathy, for which 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, caution is advised against the co-administration of aliskiren with olmesartan medoxomil, amlodipine, and hydrochlorothiazide in patients with diabetes due to potential adverse effects.

Drug Interactions

Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of renal impairment and diminish the antihypertensive effect of olmesartan medoxomil. Clinicians should monitor renal function and blood pressure in patients receiving this combination.

The dual inhibition of the renin-angiotensin system can lead to an elevated risk of renal impairment, hypotension, and hyperkalemia when olmesartan medoxomil is used. Close monitoring of renal function and serum potassium levels is recommended.

When coadministering colesevelam hydrochloride with olmesartan medoxomil, it is advisable to administer olmesartan at least 4 hours prior to the colesevelam dose to minimize interaction.

Lithium levels may increase, leading to potential toxicity when olmesartan medoxomil is used concurrently. Regular monitoring of serum lithium concentrations is recommended to avoid toxicity.

For patients taking amlodipine, it is recommended to limit simvastatin to a maximum of 20 mg daily to reduce the risk of adverse effects.

Coadministration of amlodipine with cyclosporin or tacrolimus may result in increased exposure to these immunosuppressants. Monitoring for signs of toxicity is advised.

Amlodipine exposure may be increased when used with CYP3A inhibitors. Dose adjustments may be necessary based on clinical response and tolerability.

Antidiabetic drugs may require dosage adjustments when used in conjunction with hydrochlorothiazide, as the diuretic can affect glycemic control.

The absorption of thiazides, including hydrochlorothiazide, may be reduced when coadministered with cholestyramine or colestipol. It is advisable to separate the administration of these agents to ensure optimal therapeutic effect.

NSAIDs can diminish the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. Monitoring of blood pressure and renal function is recommended in patients receiving this combination.

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 in pediatric patients have not been established. Therefore, caution is advised when considering the use of these medications in children and adolescents. Further studies are necessary to determine appropriate dosing and 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, including 18 patients aged 75 years and older. The trial did not reveal any overall differences in the efficacy or safety of the combination therapy among these geriatric patients. However, it is important to note that greater sensitivity to the medication may be present in some older individuals, which necessitates careful monitoring.

For elderly patients, particularly those 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 combination formulation of olmesartan medoxomil, amlodipine, and hydrochlorothiazide. Therefore, healthcare providers should consider this dosage adjustment and the potential for increased sensitivity when prescribing this medication to geriatric patients. Regular monitoring of blood pressure and renal function is advised to ensure safety and efficacy in this population.

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. Therefore, when pregnancy is detected, these medications 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% to 4% and 15% to 20%, respectively.

Hypertension during pregnancy poses additional risks, including increased maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications such as the need for cesarean section and postpartum hemorrhage. Fetal risks associated with maternal hypertension include intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be closely monitored and managed appropriately.

The use of drugs affecting the renin-angiotensin system in the second and third trimesters can lead to oligohydramnios, which may result in reduced fetal renal function, anuria, renal failure, fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and death. Serial ultrasound examinations should be performed to assess the intra-amniotic environment, and fetal testing may be warranted based on gestational age. It is important to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury.

Infants with a history of in utero exposure to olmesartan should be closely observed for hypotension, oliguria, and hyperkalemia. In neonates experiencing oliguria or hypotension, measures should be taken to maintain adequate blood pressure and renal perfusion, which may include exchange transfusions or dialysis to reverse hypotension and support renal function.

Hydrochlorothiazide, a thiazide diuretic, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. It may cause placental hypoperfusion and accumulates in the amniotic fluid, with reported concentrations up to 19 times that in umbilical vein plasma. The use of thiazides during pregnancy is associated with risks of fetal or neonatal jaundice and thrombocytopenia. Since thiazides do not prevent or alter the course of preeclampsia, they should not be used to treat hypertension in pregnant women. Additionally, the use of hydrochlorothiazide for other indications, such as heart disease, during pregnancy should be avoided.

Lactation

There is no specific information available regarding the use of this medication in nursing mothers or its effects on lactation. Consequently, healthcare professionals should exercise caution when prescribing this medication to lactating mothers, as the potential risks to breastfed infants are not well characterized. It is advisable to consider the benefits of breastfeeding alongside the potential risks associated with the medication.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored closely. This is particularly important for those with reduced kidney function, as they may be at increased risk for complications. Dosing adjustments may be necessary based on the degree of renal impairment to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In the event of an overdosage involving olmesartan medoxomil, amlodipine, and hydrochlorothiazide, it is important to note that there is currently no documented information regarding human overdosage for these agents. However, potential manifestations of overdosage may include hypotension and tachycardia, with bradycardia possible due to parasympathetic stimulation.

Amlodipine, in particular, has been associated with severe outcomes in animal studies. Single oral doses equivalent to 40 mg amlodipine/kg in mice and 100 mg amlodipine/kg in rats resulted in fatalities. In canine models, doses of 4 mg amlodipine/kg or higher led to significant peripheral vasodilation and hypotension. Consequently, an overdose of amlodipine may result in excessive peripheral vasodilation, marked hypotension, and potentially reflex tachycardia.

In cases of massive overdose, it is critical to initiate active cardiac and respiratory monitoring, including frequent blood pressure measurements. Should hypotension occur, immediate cardiovascular support is necessary. This may involve elevating the extremities and judiciously administering fluids. If hypotension persists despite these measures, the use of vasopressors, such as phenylephrine, should be considered to restore hemodynamic stability. Additionally, intravenous calcium gluconate may be beneficial in reversing the effects of calcium entry blockade associated with amlodipine overdose.

For hydrochlorothiazide, the most common signs of overdose include electrolyte depletion, specifically hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, which significantly exceeds the highest recommended human dose, indicating a wide margin of safety in humans. Nonetheless, careful monitoring and management of electrolyte levels and hydration status are essential in cases of suspected overdose.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. The fertility of rats was unaffected by the administration of olmesartan at dose levels as high as 1000 mg/kg/day, which is approximately 240 times the maximum recommended human dose (MRHD) of 40 mg/day on a mg/m² basis. In a separate study, oral treatment with amlodipine maleate did not impact the fertility of rats, with males treated for 64 days and females for 14 days prior to mating at doses up to 10 mg/kg/day, roughly 10 times the MRHD of 10 mg/day on a mg/m² basis. Hydrochlorothiazide also demonstrated no adverse effects on the fertility of mice and rats of either sex when exposed to dietary doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation, corresponding to about 19 and 1.5 times the MRHD of 25 mg/day on a mg/m² basis.

The rationale for the absence of new or limited 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 three-month repeated dose toxicity study in rats indicated that the combined administration of these agents did not exacerbate any existing toxicities nor induce new toxicities, with no toxicologically synergistic effects observed.

No carcinogenicity, mutagenicity, or fertility studies have been conducted on the combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide; however, such studies have been performed on each compound individually. Olmesartan was not found to be carcinogenic when administered via diet to rats for up to two 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 six-month gavage study in p53 knockout mice and a six-month dietary study in Hras2 transgenic mice, doses up to 1000 mg/kg/day (about 120 times the MRHD of 40 mg/day on a mg/m² basis) showed no evidence of carcinogenic effects.

Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and did not exhibit genetic toxicity in the Ames test. However, they were associated with 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 this context.

Rats and mice treated with amlodipine maleate in the diet for up to two years at calculated daily dosages of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenic effects. Mutagenicity studies with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level. Two-year feeding studies conducted under 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 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 obtained in the in vitro CHO Sister Chromatid Exchange assay, the Mouse Lymphoma Cell assay, and the Aspergillus nidulans nondisjunction assay.

Postmarketing Experience

Severe, chronic diarrhea with considerable weight loss has been reported to develop months to years after initiating treatment with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. Patients experiencing these symptoms are advised to consult their healthcare provider.

Eye problems, potentially leading to vision loss, have also been associated with one of the components in olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. Symptoms may manifest within hours to weeks of starting the medication and include decreased vision and eye pain. Immediate medical attention is recommended for individuals experiencing these symptoms.

Changes in body salts, such as sodium and potassium, as well as alterations in body fluids, have been observed during treatment. Signs and symptoms that may indicate these changes include dry mouth, increased thirst, weakness, fatigue or sleepiness, restlessness, confusion, seizures, muscle pains or cramps, muscle fatigue, dizziness or fainting, low or no urine output, rapid heartbeat, and nausea or vomiting. Patients should inform their doctor if they experience any of these symptoms.

Allergic reactions have been reported in association with hydrochlorothiazide, one of the components of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets.

Patient Counseling

Healthcare providers should inform female patients of childbearing age about the potential consequences of exposure to olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets during pregnancy. It is essential to discuss treatment options with women who are planning to become pregnant and to encourage them to report any pregnancies to their physicians as soon as possible.

Patients should be advised that lightheadedness may occur, particularly during the initial days of therapy, and they should report this symptom to their prescribing physician. In the event of syncope, patients must discontinue the use of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets and consult their physician before resuming treatment.

Healthcare providers should educate patients about the risks associated with inadequate fluid intake, excessive perspiration, diarrhea, or vomiting, as these conditions can lead to a significant drop in blood pressure, resulting in lightheadedness or syncope. For 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 be cautioned against using potassium supplements or salt substitutes containing potassium without prior consultation with their healthcare provider. Additionally, they must be informed 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.

Patients are encouraged to read the Patient Information that accompanies olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets before initiating treatment and each time they receive a refill. It is also advisable for patients to discuss alternative methods for lowering blood pressure with their doctor if they plan to become pregnant. If a patient becomes pregnant while on this medication, they should notify their doctor immediately. Nursing women should be advised not to breastfeed during treatment with these tablets.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20° to 25°C (68° to 77°F), as defined by the United States Pharmacopeia (USP) 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 and Hydrochlorothiazide as submitted by Camber Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)