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 light yellowish-white powder or crystalline powder, being 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 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: one containing 20 mg of olmesartan medoxomil combined with 12.5 mg of hydrochlorothiazide, and another containing 40 mg of olmesartan medoxomil combined with 25 mg of hydrochlorothiazide. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, hypromellose, talc, titanium dioxide, iron oxide yellow, and iron oxide red.

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, particularly strokes and myocardial infarctions.

There are no teratogenic effects associated with this medication. Additionally, no nonteratogenic effects have been reported.

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 should be made after 2 to 4 weeks, based on the patient's response to therapy. The maximum allowable dose is 40 mg of olmesartan combined with 25 mg of hydrochlorothiazide.

Healthcare professionals should ensure that the dosing regimen is tailored to the individual patient's needs, taking into consideration their response and tolerability to the medication.

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 impairment.

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 potential for injury and death to the developing fetus associated with drugs that act directly on the renin-angiotensin system.

General Precautions Prior to administration, it is essential to correct any volume-depletion to mitigate the risk of hypotension. Healthcare professionals should closely monitor renal function and potassium levels in patients who are susceptible to these changes. 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.

Laboratory Tests Regular monitoring of renal function and potassium levels is advised for patients who may be at risk, ensuring timely identification and management of any abnormalities.

Side Effects

Patients receiving olmesartan medoxomil and hydrochlorothiazide tablets 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 adverse reactions associated with the use of olmesartan medoxomil and hydrochlorothiazide tablets include hypotension, which necessitates correction of volume depletion prior to administration. Patients should be monitored for renal function and potassium levels, particularly in those who are susceptible. Additionally, signs of fluid or electrolyte imbalance should be observed.

There are significant warnings regarding the use of this medication during pregnancy. If pregnancy is detected, olmesartan medoxomil and hydrochlorothiazide tablets should be discontinued as soon as possible, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Other notable adverse reactions include 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 the medication should be considered. Hypersensitivity reactions to any component of the tablets have also been documented.

Additional serious conditions that may arise include anuria and oliguria or hypotension in neonates with a history of in utero exposure to olmesartan medoxomil and hydrochlorothiazide tablets. In such cases, immediate attention should be directed toward supporting blood pressure and renal perfusion, with exchange transfusions or dialysis potentially required to reverse hypotension and address disordered renal function.

It is important to note that co-administration of aliskiren with olmesartan medoxomil and hydrochlorothiazide tablets is contraindicated in patients with diabetes.

Drug Interactions

Concomitant use of certain medications may lead to significant drug interactions that require careful consideration and management.

Lithium: The use of this medication may increase the risk of lithium toxicity. Monitoring of lithium levels is recommended to avoid potential adverse effects.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Co-administration with NSAIDs may result in reduced diuretic, natriuretic, and antihypotensive effects. Additionally, there is an increased risk of renal toxicity. It is advisable to monitor renal function and adjust dosages as necessary.

Dual Inhibition of the Renin-Angiotensin System: The combination of agents that inhibit the renin-angiotensin system may elevate the risk of renal impairment, hypotension, and hyperkalemia. Close monitoring of blood pressure and renal function is recommended.

Colesevelam Hydrochloride: It is advised to administer olmesartan at least 4 hours prior to the dose of colesevelam hydrochloride to minimize potential interactions.

Antidiabetic Drugs: When used concurrently, dosage adjustments of antidiabetic medications may be necessary to maintain glycemic control.

Cholestyramine and Colestipol: The use of these agents may lead to reduced absorption of thiazide diuretics. Monitoring of blood pressure and renal function is recommended, and dosage adjustments may be required based on clinical response.

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

Pediatric patients, particularly neonates with a history of in utero exposure to olmesartan medoxomil and hydrochlorothiazide tablets, may experience complications such as oliguria or hypotension. In such cases, it is crucial to provide support for blood pressure and renal perfusion, which may necessitate interventions such as exchange transfusions or dialysis to address hypotension and restore renal function.

The 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.

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 and younger patients.

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 and potential dose adjustments may be necessary for geriatric patients to mitigate these risks.

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. Adverse fetal outcomes may include oligohydramnios, which can lead to fetal lung hypoplasia and skeletal deformations, as well as neonatal complications such as skull hypoplasia, anuria, hypotension, renal failure, and death.

Upon detection of pregnancy, olmesartan medoxomil and hydrochlorothiazide tablets should be discontinued as soon as possible. The adverse effects noted are primarily linked to the use of these medications 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, caution is warranted.

It is crucial to manage maternal hypertension effectively during pregnancy to optimize outcomes for both the mother and fetus. In cases where there is no suitable alternative to therapy with renin-angiotensin system-affecting drugs, healthcare providers should inform the patient of the potential risks to the fetus. Serial ultrasound examinations should be conducted to monitor the intraamniotic environment, and if oligohydramnios is detected, olmesartan medoxomil and hydrochlorothiazide tablets should be discontinued unless deemed lifesaving for the mother.

Fetal testing may be indicated based on gestational age, and it is important for both patients and healthcare providers to recognize that 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 tablets should be closely monitored for signs of hypotension, oliguria, and hyperkalemia.

Lactation

It is not known whether olmesartan is excreted in human milk; however, olmesartan is secreted 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 the medication to the lactating mother when making a decision to either discontinue breastfeeding or discontinue the use of olmesartan medoxomil and hydrochlorothiazide tablets.

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 for signs of fluid or electrolyte imbalance in these patients to ensure their safety and optimize therapeutic outcomes.

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; however, bradycardia may occur if there is parasympathetic (vagal) stimulation. In the event of symptomatic hypotension, it is essential to initiate supportive treatment promptly.

The dialyzability of olmesartan medoxomil remains unknown, which may complicate management strategies in cases of overdose. Notably, acute toxicity studies in mice and rats have shown no lethality with single oral doses up to 2000 mg/kg. In dogs, the minimum lethal oral dose of olmesartan medoxomil was determined to be greater than 1500 mg/kg.

In cases where hydrochlorothiazide is involved, the most common signs and symptoms of overdose in humans are primarily due 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, necessitating careful monitoring and management.

The extent to which hydrochlorothiazide is removed by hemodialysis has not been established, which may influence treatment decisions. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, indicating a relatively high threshold for acute toxicity in these animal models.

Nonclinical Toxicology

No teratogenic effects were observed in pregnant mice and rats administered combinations of olmesartan medoxomil and hydrochlorothiazide at oral doses up to 1625 mg/kg/day, which corresponds to 122 times and 280 times the maximum recommended human dose (MRHD) on a mg/m² basis, respectively. However, in rats, fetal body weights at this dose 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, 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 when dosing commenced 2 weeks prior to mating for females and 9 weeks for males. 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 with olmesartan medoxomil and hydrochlorothiazide. In vitro testing revealed that olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio were negative in the Salmonella-Escherichia coli/mammalian microsome reverse mutation test at the maximum recommended plate concentration. Clastogenic activity was assessed in the in vitro Chinese hamster lung chromosomal aberration assay, where positive responses were observed for each component and combination ratio tested; however, no synergistic clastogenic activity was detected between the two compounds. In vivo, olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio were negative in the mouse bone marrow erythrocyte micronucleus assay at doses up to 3144 mg/kg.

Olmesartan medoxomil was not found to be carcinogenic in a two-year dietary study in rats at the highest tested dose of 2000 mg/kg/day, approximately 480 times the MRHD. 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 showed no evidence of carcinogenic effects. Both olmesartan medoxomil and hydrochlorothiazide tested negative in the in vitro Syrian hamster embryo cell transformation assay and did not exhibit 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 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 reported 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, nor was it genotoxic in vivo in assays using 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 mutagenicity assay, and the Aspergillus nidulans non-disjunction assay. No studies of impairment of fertility with olmesartan medoxomil and hydrochlorothiazide have been conducted.

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. Patients should be instructed to report any pregnancies to their physicians as soon as possible.

Providers should inform patients that lightheadedness may occur, particularly during the initial days of therapy, and encourage them to report this symptom to a 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. Furthermore, healthcare providers should instruct patients 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, it is essential to advise patients to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permitted between 15° to 30°C (59° to 86°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Clinicians should periodically monitor renal function in patients whose renal status may be influenced by the renin-angiotensin system, as well as assess serum electrolytes and calcium levels. In the event of hypotension, patients should be positioned supine and may require intravenous normal saline. For acute angle-closure glaucoma, it is critical to discontinue hydrochlorothiazide promptly, and further medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled.

Postmarketing reports indicate that severe, chronic diarrhea with significant weight loss has occurred in patients taking olmesartan, sometimes months to years after initiation. Intestinal biopsies in these cases often reveal villous atrophy. If such symptoms arise during treatment, it is essential to rule out other causes and consider discontinuing olmesartan medoxomil and hydrochlorothiazide tablets if no alternative etiology is identified.

FDA Insert (PDF)

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

View full prescribing information (PDF)