Olmesartan medoxomil/Hydrochlorothiazide

Description

Olmesartan medoxomil and hydrochlorothiazide tablets comprise a combination of olmesartan medoxomil, an angiotensin II receptor antagonist (AT1 subtype), and hydrochlorothiazide, a thiazide diuretic. Olmesartan medoxomil is chemically defined 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 a molecular formula of C29H30N6O6 and a molecular weight of 558.6. It appears as a white to off-white, crystalline powder that is practically insoluble in water and sparingly soluble in methanol.

Hydrochlorothiazide is identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular formula of C7H8ClN3O4S2 and a molecular weight of 297.7. This compound is presented as a white or practically white, practically odorless, crystalline powder that is slightly soluble in water and freely soluble in sodium hydroxide solution.

The tablets are formulated for oral administration and are available in two strengths: 20 mg or 40 mg of olmesartan medoxomil combined with 12.5 mg of hydrochlorothiazide, or 40 mg of olmesartan medoxomil combined with 25 mg of hydrochlorothiazide. Inactive ingredients include hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, talc, and titanium dioxide.

Uses and Indications

Olmesartan medoxomil and hydrochlorothiazide tablets are indicated for the treatment of hypertension, aimed at lowering blood pressure. Effective management of hypertension is associated with a reduction in the risk of both fatal and nonfatal cardiovascular events, including strokes and myocardial infarctions.

Limitations of use specify that olmesartan medoxomil and hydrochlorothiazide tablets are not indicated for initial therapy.

Dosage and Administration

The recommended starting dose for patients not adequately controlled with olmesartan monotherapy is 40 mg of olmesartan combined with 12.5 mg of hydrochlorothiazide. For patients not adequately controlled with hydrochlorothiazide monotherapy, the recommended starting dose is 20 mg of olmesartan combined with 12.5 mg of hydrochlorothiazide.

Dosing adjustments may be made after 2 to 4 weeks based on the patient's response to treatment. The maximum allowable dose is 40 mg of olmesartan and 25 mg of hydrochlorothiazide. It is essential to monitor the patient's blood pressure and overall response to therapy during this adjustment period to ensure optimal management of their condition.

Contraindications

Use of olmesartan medoxomil and hydrochlorothiazide is contraindicated in the following situations:

Patients with hypersensitivity to any component of the formulation may experience severe allergic reactions. Anuria is another contraindication, as the medication relies on renal function for efficacy. Additionally, co-administration of aliskiren with olmesartan medoxomil and hydrochlorothiazide is contraindicated in patients with diabetes due to the potential for adverse effects.

Warnings and Precautions

When pregnancy is detected, olmesartan medoxomil and hydrochlorothiazide should be discontinued immediately. Medications that act directly on the renin-angiotensin system have been associated with fetal toxicity, potentially leading to injury or death of the developing fetus.

General precautions must be observed prior to the administration of olmesartan medoxomil and hydrochlorothiazide. It is essential to correct any volume 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, vigilance for signs of fluid or electrolyte imbalance is recommended.

There is a risk of acute angle-closure glaucoma associated with the use of this medication. Furthermore, cases of sprue-like enteropathy have been reported; therefore, consideration should be given to discontinuing olmesartan medoxomil and hydrochlorothiazide if no other etiology for gastrointestinal symptoms is identified.

Laboratory tests should include regular monitoring of renal function and potassium levels in patients deemed susceptible to these adverse effects.

Side Effects

Patients receiving olmesartan medoxomil and hydrochlorothiazide may experience a range of adverse reactions. The most common adverse reactions, occurring in at least 2% of participants, include nausea, hyperuricemia, dizziness, and upper respiratory infections.

Serious warnings associated with this medication include Fetal Toxicity. It is imperative that olmesartan medoxomil and hydrochlorothiazide be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can lead to injury or death of the developing fetus.

Additional adverse reactions that may occur include hypotension, which necessitates correction of volume depletion prior to administration. Patients should be monitored for renal function and potassium levels, particularly those who are susceptible. Signs of fluid or electrolyte imbalance should also be observed.

Other reported adverse reactions include acute angle-closure glaucoma and sprue-like enteropathy. In cases of sprue-like enteropathy, discontinuation of the medication should be considered if no other etiology is identified. Hypersensitivity reactions to any component of olmesartan medoxomil and hydrochlorothiazide have been noted, as well as anuria.

It is important to note that co-administration of aliskiren with olmesartan medoxomil and hydrochlorothiazide is contraindicated in patients with diabetes. Overdosage of this medication may lead to hypotension and tachycardia, with bradycardia potentially occurring due to parasympathetic (vagal) stimulation. Symptoms of hydrochlorothiazide overdose can include electrolyte depletion (such as hypokalemia, hypochloremia, and hyponatremia) and dehydration resulting from excessive diuresis.

Drug Interactions

Agents that increase potassium levels may result in elevated serum potassium concentrations when co-administered. This interaction necessitates monitoring of serum potassium levels to prevent hyperkalemia.

The concomitant use of lithium poses a risk of lithium toxicity. It is advisable to monitor lithium levels closely and adjust the dosage as necessary to mitigate this risk.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) can diminish the diuretic, natriuretic, and antihypertensive effects of certain medications, while also increasing the risk of renal toxicity. Patients should be monitored for renal function and blood pressure when NSAIDs are used concurrently.

The dual inhibition of the renin-angiotensin system may lead to an increased risk of renal impairment, hypotension, and hyperkalemia. Close monitoring of renal function and blood pressure is recommended in patients receiving such combinations.

When administering olmesartan in conjunction with colesevelam hydrochloride, it is recommended to give olmesartan at least 4 hours prior to the colesevelam hydrochloride dose to ensure optimal absorption.

Antidiabetic drugs may require dosage adjustments when used concurrently, necessitating careful monitoring of blood glucose levels to maintain glycemic control.

Cholestyramine and colestipol can reduce the absorption of thiazide diuretics. It is advisable to monitor the therapeutic effects of thiazides and consider adjusting the dosing regimen accordingly.

Packaging & NDC

The table below lists all NDC Code configurations of Olmesartan Medoxomil and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of olmesartan medoxomil and hydrochlorothiazide 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 needed to determine appropriate dosing and outcomes in this population.

Geriatric Use

Clinical studies of olmesartan medoxomil and hydrochlorothiazide did not include a sufficient number of subjects aged 65 and older to determine whether these elderly patients respond differently from younger individuals. However, other reported clinical experiences have not identified significant differences in responses between geriatric patients and their younger counterparts.

In general, dose selection for elderly patients should be approached with caution. It is advisable to start at the low end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

Both olmesartan and hydrochlorothiazide are substantially excreted by the kidneys, which raises concerns regarding the risk of toxic reactions in patients with impaired renal function. Therefore, careful monitoring of renal function is recommended in geriatric patients receiving these medications to mitigate potential adverse effects.

Pregnancy

Olmesartan medoxomil 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, olmesartan medoxomil and hydrochlorothiazide 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 approximately 2% to 4% and 15% to 20%, respectively. Hypertension during pregnancy poses additional maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and delivery complications such as the need for cesarean section and postpartum hemorrhage. Furthermore, hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death, necessitating careful monitoring and management of pregnant women with hypertension.

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, as oligohydramnios may not manifest until after the fetus has sustained irreversible injury.

Infants with a history of in utero exposure to olmesartan medoxomil and hydrochlorothiazide should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, 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.

It is important to note that thiazides, including hydrochlorothiazide, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. Hydrochlorothiazide may cause placental hypoperfusion and can accumulate 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 a risk of fetal or neonatal jaundice or thrombocytopenia. Since thiazides do not prevent or alter the course of preeclampsia, they should not be used to treat hypertension in pregnant women. Additionally, the use of hydrochlorothiazide for other indications, such as heart disease, during pregnancy should be avoided.

Lactation

There are no specific statements regarding nursing mothers or lactation in the provided drug insert text. Therefore, the effects of this medication on breastfed infants or its excretion in breast milk remain undetermined. Healthcare professionals should consider the absence of data when advising lactating mothers on the use of this medication.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored closely, particularly in those who are susceptible. It is essential to correct any volume-depletion prior to administration of the medication. Additionally, healthcare professionals should observe these patients for signs of fluid or electrolyte imbalance throughout the treatment process.

Hepatic Impairment

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

Overdosage

Limited data are available regarding the overdosage of olmesartan medoxomil in humans. The most likely clinical manifestations associated with an overdose include hypotension and tachycardia. In some cases, bradycardia may occur, particularly if there is parasympathetic (vagal) stimulation.

In the event of symptomatic hypotension, it is essential to initiate supportive treatment promptly. The specific management of overdosage should focus on stabilizing the patient and addressing any symptoms that arise.

The dialyzability of olmesartan medoxomil remains unknown, which may influence the approach to treatment in cases of significant overdose. However, it is noteworthy that no lethality was observed in acute toxicity studies conducted in mice and rats, where single oral doses of up to 2000 mg/kg were administered. Additionally, the minimum lethal oral dose in dogs was determined to be greater than 1500 mg/kg, indicating a relatively high threshold for toxicity in these animal models.

Healthcare professionals should remain vigilant for the signs of overdosage and manage the situation according to established clinical guidelines.

Nonclinical Toxicology

No information is available regarding teratogenic effects.

In terms of non-teratogenic effects, no carcinogenicity studies have been conducted with olmesartan medoxomil and hydrochlorothiazide. In a ratio of 20:12.5, these compounds were negative in the Salmonella-Escherichia coli/mammalian microsome reverse mutation test at the maximum recommended plate concentration for standard assays. A positive response was observed for each component and combination ratio in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay; however, no synergistic clastogenic activity was detected between olmesartan medoxomil and hydrochlorothiazide at any combination ratio.

When administered orally in a ratio of 20:12.5, olmesartan medoxomil and hydrochlorothiazide tested negative in the in vivo mouse bone marrow erythrocyte micronucleus assay at doses up to 3144 mg/kg. No studies have been conducted to assess the impairment of fertility with these compounds.

Olmesartan medoxomil was not found to be carcinogenic when administered via diet to rats for up to two years, with the highest tested dose (2000 mg/kg/day) being approximately 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies in mice, including a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of carcinogenic effects.

Both olmesartan medoxomil and hydrochlorothiazide tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) 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.

Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney, as well as for clastogenicity in mouse bone marrow (micronucleus test) at oral doses up to 2000 mg/kg, while olmesartan was not tested. Fertility in rats was unaffected by olmesartan medoxomil at doses as high as 1000 mg/kg/day (240 times the MRHD) when dosing began 2 weeks (female) or 9 weeks (male) prior to mating.

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). However, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay using various Salmonella typhimurium strains or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations.

In vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also indicated that hydrochlorothiazide was not genotoxic. Positive results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) assay, the Mouse Lymphoma Cell (mutagenicity) assay, and the Aspergillus nidulans non-disjunction assay. Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex in studies where these species were exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

Postmarketing Experience

In postmarketing experience, non-melanoma skin cancer has been reported in patients taking hydrochlorothiazide. It is advised that patients receiving this medication take precautions to protect their skin from sun exposure and participate in regular skin cancer screenings.

Patient Counseling

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

Patients should be informed that lightheadedness may occur, particularly during the initial days of therapy. They should be instructed to report this symptom to their healthcare provider. Additionally, patients should be made aware that dehydration resulting from inadequate fluid intake, excessive perspiration, vomiting, or diarrhea can lead to a significant drop in blood pressure. In the event of syncope, patients should be advised to contact their healthcare provider immediately.

Patients must be cautioned against using potassium supplements or salt substitutes that contain potassium without prior consultation with their healthcare provider.

Healthcare providers should instruct patients to discontinue olmesartan medoxomil and hydrochlorothiazide and seek immediate medical attention if they experience symptoms indicative of acute myopia or secondary angle-closure glaucoma.

For patients taking hydrochlorothiazide, it is essential to advise them to protect their skin from sun exposure and to undergo regular skin cancer screenings.

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

Clinicians are advised to monitor renal function periodically in patients whose renal function may be influenced by the renin-angiotensin system. Additionally, it is important to regularly assess serum electrolytes and calcium levels in these patients.

Patient counseling should include instructions for managing hypotension; patients should be placed in a supine position and may require an intravenous infusion of normal saline if hypotension occurs. Patients should also be informed about the symptoms of acute myopia and acute angle-closure glaucoma, which include a sudden decrease in visual acuity or ocular pain, and should discontinue hydrochlorothiazide promptly if these symptoms arise. Furthermore, there have been reports of severe, chronic diarrhea with significant weight loss in patients taking olmesartan, sometimes accompanied by intestinal biopsies showing villous atrophy. In such cases, clinicians should consider discontinuing olmesartan medoxomil and hydrochlorothiazide if no other cause is identified.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Olmesartan Medoxomil and Hydrochlorothiazide as submitted by Aurobindo Pharma Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)