Olmesartan medoxomil/Hydrochlorothiazide

Description

Olmesartan medoxomil and hydrochlorothiazide tablets comprise a combination of olmesartan medoxomil, an angiotensin II receptor antagonist (AT1 subtype), and hydrochlorothiazide (HCTZ), 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 an empirical formula of C29H30N6O6 and a molecular weight of 558.6. It appears as a white to light yellowish-white crystalline powder and is practically insoluble in water, with limited solubility in methanol.

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

The tablets are formulated for oral administration, 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, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, colloidal silicon dioxide, talc, and titanium dioxide. Additionally, red iron oxide, yellow iron oxide, and black iron oxide are incorporated into the 20 mg/12.5 mg and 40 mg/12.5 mg tablet formulations.

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.

There are no teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

In patients not adequately controlled with olmesartan monotherapy, the recommended starting dose is 40 mg of olmesartan combined with 12.5 mg of hydrochlorothiazide. For those 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 therapy. The maximum recommended dose is 40 mg of olmesartan combined with 25 mg of hydrochlorothiazide. It is essential to monitor the patient's blood pressure and adjust the dosage accordingly to achieve optimal control.

Contraindications

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

Patients with hypersensitivity to any component of the formulation should not use this medication due to the risk of severe allergic reactions.

Anuria is a contraindication, as the medication may exacerbate renal function issues in these patients.

Co-administration of aliskiren with olmesartan medoxomil and hydrochlorothiazide tablets is contraindicated in patients with diabetes, due to the potential for increased risk of adverse effects.

Warnings and Precautions

When pregnancy is detected, olmesartan medoxomil 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 the administration of olmesartan medoxomil and hydrochlorothiazide tablets. It is essential to correct any volume 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 imbalances. 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 these tablets. Furthermore, cases of sprue-like enteropathy have been reported; therefore, consideration should be given to discontinuing olmesartan medoxomil and hydrochlorothiazide tablets if no other etiology is identified.

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

Side Effects

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

Serious adverse reactions include fetal toxicity, which necessitates the discontinuation of olmesartan medoxomil and hydrochlorothiazide tablets as soon as pregnancy is detected. Drugs that act directly on the renin-angiotensin system, such as this combination, can cause injury and death to the developing fetus.

Additional adverse reactions of clinical significance include hypotension, which may occur if volume depletion is not corrected prior to administration. It is important to monitor renal function and potassium levels in susceptible patients, as well as to observe for signs of fluid or electrolyte imbalance. Other serious conditions reported include acute angle-closure glaucoma and sprue-like enteropathy, which may warrant discontinuation of the medication if no other etiology is identified.

Patients may also experience hypersensitivity reactions to any component of the tablets, anuria, and it is advised that aliskiren not be co-administered with olmesartan medoxomil and hydrochlorothiazide tablets in patients with diabetes.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacological effects and clinical implications.

Pharmacodynamic Interactions

• Lithium: Concurrent use may increase the risk of lithium toxicity. Monitoring of lithium levels is recommended to avoid adverse effects.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs may lead to reduced diuretic, natriuretic, and antihypotensive effects. Additionally, there is an increased risk of renal toxicity. Patients should be monitored for renal function and blood pressure.

• Dual Inhibition of the Renin-Angiotensin System: This combination may elevate the risk of renal impairment, hypotension, and hyperkalemia. Regular monitoring of renal function and serum potassium levels is advised.

Pharmacokinetic Interactions

• Colesevelam Hydrochloride: It is recommended that olmesartan be administered at least 4 hours prior to the dose of colesevelam hydrochloride to minimize potential interactions.

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used concurrently. Close monitoring of blood glucose levels is suggested to ensure effective glycemic control.

• Cholestyramine and Colestipol: These agents may reduce the absorption of thiazide diuretics. Monitoring of blood pressure and electrolyte levels is recommended to assess the effectiveness of thiazide therapy.

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 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 needed to determine appropriate dosing and outcomes in this population.

Geriatric Use

Clinical studies of olmesartan medoxomil and hydrochlorothiazide tablets did not include a sufficient number of subjects aged 65 and older to determine whether these elderly patients respond differently compared to 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 initiate treatment at the lower 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 that may affect treatment outcomes.

Given that olmesartan and hydrochlorothiazide are substantially excreted by the kidneys, there is an elevated risk of toxic reactions in patients with impaired renal function. Therefore, careful monitoring of renal function is recommended when prescribing these medications to geriatric patients to mitigate potential adverse effects.

Pregnancy

The use of olmesartan medoxomil and hydrochlorothiazide tablets during pregnancy is classified as Pregnancy Category D. Administration of drugs that act on the renin-angiotensin system during the second and third trimesters is associated with significant risks, including reduced fetal renal function, increased morbidity, and potential mortality. These risks can lead to oligohydramnios, which is linked to fetal lung hypoplasia and skeletal deformations.

Neonates exposed to these medications may experience adverse effects such as skull hypoplasia, anuria, hypotension, renal failure, and death. Therefore, it is imperative to discontinue olmesartan medoxomil and hydrochlorothiazide tablets as soon as pregnancy is confirmed. The adverse outcomes are primarily associated with the use of these drugs during the later stages of pregnancy.

While most epidemiologic studies investigating fetal abnormalities following antihypertensive exposure in the first trimester have not specifically differentiated between drugs affecting the renin-angiotensin system and other antihypertensive agents, appropriate management of maternal hypertension is crucial to optimize outcomes for both the mother and fetus. In cases where no suitable alternative therapy exists, healthcare providers should inform the patient of the potential risks to the fetus.

Serial ultrasound examinations are recommended to monitor the intraamniotic environment. If oligohydramnios is detected, olmesartan medoxomil and hydrochlorothiazide tablets should be discontinued unless their use is deemed lifesaving for the mother. 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 these medications should be closely monitored for hypotension, oliguria, and hyperkalemia. Fetal testing may also be warranted, depending on the gestational age.

Lactation

It is not known whether olmesartan is excreted in human milk; however, olmesartan has been detected at low concentrations in the milk of lactating rats. Thiazides, which are components of olmesartan medoxomil and hydrochlorothiazide tablets, are known to appear in human milk.

Due to the potential for adverse effects on the nursing infant, healthcare professionals should consider the importance of olmesartan medoxomil and hydrochlorothiazide to the mother when making a decision to either discontinue nursing or discontinue the medication.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored closely, as they may be at increased risk for complications. Dosing adjustments may be necessary based on the degree of reduced kidney function 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

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

In the event of symptomatic hypotension, it is essential to initiate supportive treatment promptly. The specific dialyzability of olmesartan medoxomil remains unknown, which may influence management strategies in cases of significant overdose.

Acute toxicity studies conducted in mice and rats have shown no lethality with single oral doses of olmesartan medoxomil up to 2000 mg/kg. Furthermore, the minimum lethal oral dose in dogs was determined to be greater than 1500 mg/kg. These findings suggest a relatively high threshold for acute toxicity, although clinical vigilance is warranted in cases of suspected overdose.

Nonclinical Toxicology

No teratogenic effects were observed in pregnant mice or rats administered combinations of olmesartan medoxomil and hydrochlorothiazide at oral doses up to 1625 mg/kg/day. This dosage corresponds to 122 times the maximum recommended human dose (MRHD) on a mg/m² basis for mice and 280 times the MRHD for rats. However, in rats, fetal body weights at this dosage were significantly lower than those of the control group. The no observed effect dose for developmental toxicity in rats was determined to be 162.5 mg/kg/day, which is approximately 28 times the MRHD of olmesartan medoxomil and hydrochlorothiazide tablets.

Fertility assessments in rats indicated that administration of olmesartan medoxomil at doses as high as 1000 mg/kg/day, which is 240 times the MRHD, did not adversely affect reproductive capabilities. Similarly, hydrochlorothiazide did not demonstrate any negative impact 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.

No carcinogenicity studies have been conducted for olmesartan medoxomil and hydrochlorothiazide. However, olmesartan medoxomil and hydrochlorothiazide, when tested in a ratio of 20:12.5, were negative in the Salmonella-Escherichia coli/mammalian microsome reverse mutation test at the maximum recommended plate concentration. In the in vitro Chinese hamster lung chromosomal aberration assay, both olmesartan medoxomil and hydrochlorothiazide were tested individually and in combination ratios of 40:12.5, 20:12.5, and 10:12.5, yielding positive responses for clastogenic activity, although no synergistic effects were observed between the two compounds.

In vivo testing in the mouse bone marrow erythrocyte micronucleus assay with olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio showed negative results at doses up to 3144 mg/kg. No studies have been conducted to assess the impairment of fertility with these compounds. Long-term dietary administration of olmesartan medoxomil to rats for up to 2 years at the highest tested dose of 2000 mg/kg/day, approximately 480 times the MRHD, did not indicate carcinogenicity. Additionally, 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, 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 test. However, both compounds induced chromosomal aberrations in cultured cells in vitro and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. In vivo, olmesartan medoxomil was negative for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow at oral doses up to 2000 mg/kg.

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. However, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay or in the Chinese Hamster Ovary test for chromosomal aberrations. It also showed no genotoxicity in vivo in assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, or the 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 non-disjunction assay.

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 tablets during pregnancy. It is important to discuss treatment options with women who are planning to become pregnant, ensuring they are informed of the risks involved. Patients should be instructed to report any pregnancies to their physicians as soon as possible.

Patients should be made aware that lightheadedness may occur, particularly during the initial days of therapy. They should be encouraged to report this symptom to their healthcare provider. Additionally, it is crucial to inform patients 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. Furthermore, they should be instructed to discontinue olmesartan medoxomil and hydrochlorothiazide tablets and seek immediate medical attention if they experience symptoms indicative of acute myopia or secondary angle-closure glaucoma.

For those taking hydrochlorothiazide, healthcare providers should emphasize the importance of protecting their skin from sun exposure and undergoing regular skin cancer screenings to monitor for any potential issues.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20-25°C (68-77°F), with permissible excursions between 15-30°C (59-86°F) as outlined by 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 and Hydrochlorothiazide as submitted by Solco Healthcare US, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)