Olmesartan medoxomil/Hydrochlorothiazide

Description

Olmesartan medoxomil and hydrochlorothiazide tablet is a combination formulation consisting 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 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 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 tablet formulation is available for oral administration 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 hydroxypropylcellulose, hypromellose, lactose monohydrate, low-substituted hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, red iron oxide, talc, titanium dioxide, yellow iron oxide, stearic acid, and polyethylene glycol.

Uses and Indications

Olmesartan medoxomil and hydrochlorothiazide tablet is 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 specific teratogenic or nonteratogenic effects noted in the available data.

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.

Healthcare professionals should consider adjusting the dose after 2 to 4 weeks, based on the patient's response to treatment. The maximum allowable dose is 40 mg of olmesartan combined with 25 mg of hydrochlorothiazide.

Administration should be performed orally, and the medication can be taken with or without food. It is important to monitor the patient's blood pressure and renal function regularly during treatment to ensure optimal therapeutic outcomes.

Contraindications

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

Patients with hypersensitivity to any component of the formulation. Due to the potential for severe allergic reactions, use is strictly prohibited in these individuals.

Patients with anuria, as the medication requires renal function for efficacy and safety.

Co-administration with aliskiren is contraindicated in patients with diabetes, due to the increased risk of adverse effects associated with this combination.

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of olmesartan medoxomil and hydrochlorothiazide tablets. It is imperative that the medication be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system may cause injury or even death to the developing fetus.

General precautions should be observed when administering this medication. Prior to initiation, 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 also a risk of acute angle-closure glaucoma associated with this medication. In rare cases, sprue-like enteropathy has been reported; therefore, consideration should be given to discontinuing olmesartan medoxomil and hydrochlorothiazide tablets if no other etiology for gastrointestinal symptoms is identified.

Laboratory tests should include regular monitoring of renal function and potassium levels, particularly in patients identified as susceptible. This proactive approach is crucial for ensuring patient safety and optimizing therapeutic outcomes.

Side Effects

Patients receiving olmesartan medoxomil and hydrochlorothiazide may experience a range of adverse reactions. The most common adverse reactions reported include nausea, hyperuricemia, dizziness, and upper respiratory infection.

Serious warnings associated with the use of 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 cause injury and death to the developing fetus.

Additional adverse reactions of clinical significance 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 serious 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 olmesartan medoxomil and hydrochlorothiazide have been noted, as well as anuria. Furthermore, it is advised that aliskiren not be co-administered with olmesartan medoxomil and hydrochlorothiazide in patients with diabetes due to potential adverse effects.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacodynamic and pharmacokinetic effects, along with recommendations for monitoring and dosage adjustments where applicable.

Pharmacodynamic Interactions

• Lithium: Co-administration with olmesartan may increase the risk of lithium toxicity. Monitoring of lithium levels is advised to prevent potential adverse effects.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs may lead to reduced diuretic, natriuretic, and antihypotensive effects of olmesartan. 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: Concurrent use of agents that inhibit the renin-angiotensin system may elevate the risk of renal impairment, hypotension, and hyperkalemia. Regular monitoring of renal function and serum potassium levels is recommended.

Pharmacokinetic Interactions

• Colesevelam Hydrochloride: It is advisable to administer olmesartan 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 in conjunction with olmesartan. Close monitoring of blood glucose levels is recommended to ensure effective glycemic control.

• Cholestyramine and Colestipol: The absorption of thiazide diuretics may be reduced when taken with cholestyramine or colestipol. Monitoring of blood pressure and electrolyte levels is suggested to assess the therapeutic efficacy of thiazides.

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 tablet, may experience complications such as oliguria or hypotension. In such cases, it is crucial to provide support for blood pressure and renal perfusion, as exchange transfusions or dialysis may be necessary to address hypotension and restore renal function.

The safety and effectiveness of olmesartan medoxomil and hydrochlorothiazide tablet in pediatric patients have not been established. Therefore, caution is advised when considering this medication for use 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 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.

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 in geriatric patients receiving olmesartan medoxomil and hydrochlorothiazide tablets to mitigate potential adverse effects.

Pregnancy

The use of olmesartan medoxomil and hydrochlorothiazide tablet 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 fetal and neonatal morbidity, and potential mortality. Oligohydramnios, a condition that may arise from such drug use, can lead to serious fetal complications such as lung hypoplasia and skeletal deformations.

Neonates exposed to these medications may experience adverse effects, including skull hypoplasia, anuria, hypotension, renal failure, and death. Therefore, it is imperative to discontinue olmesartan medoxomil and hydrochlorothiazide tablet as soon as pregnancy is confirmed. The adverse outcomes are primarily linked to the use of these agents 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 medications, appropriate management of maternal hypertension remains crucial for optimizing outcomes for both the mother and fetus. In rare cases where no suitable alternative therapy exists, healthcare providers should inform the patient of the potential risks to the fetus.

Healthcare professionals are advised to perform serial ultrasound examinations to monitor the intraamniotic environment. If oligohydramnios is detected, discontinuation of olmesartan medoxomil and hydrochlorothiazide tablet should be considered, unless the medication 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 olmesartan medoxomil and hydrochlorothiazide tablet should be closely monitored for signs of 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 are known to appear in human milk.

Due to the potential for adverse effects on the nursing infant, healthcare professionals should consider the risks and benefits when advising lactating mothers. A decision should be made whether to discontinue breastfeeding or to discontinue olmesartan medoxomil and hydrochlorothiazide tablets, taking into account the importance of the medication to the mother.

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 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 overdosage include hypotension and tachycardia; however, bradycardia may occur if there is parasympathetic (vagal) stimulation. In the event of symptomatic hypotension, it is recommended that supportive treatment be initiated. The dialyzability of olmesartan medoxomil remains unknown.

Acute toxicity studies conducted in mice and rats have shown no lethality with single oral doses of olmesartan medoxomil up to 2000 mg/kg. In dogs, the minimum lethal oral dose was found to be greater than 1500 mg/kg.

In contrast, the most common signs and symptoms associated with hydrochlorothiazide overdose in humans are primarily due to electrolyte depletion, which includes hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may exacerbate cardiac arrhythmias. The extent to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

Healthcare professionals should remain vigilant for these potential symptoms and manage them accordingly in cases of suspected overdosage.

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. 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.

Fertility assessments in rats indicated that administration of olmesartan medoxomil at doses as high as 1000 mg/kg/day, initiated two weeks prior to mating for females and nine weeks for males, 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 specifically for olmesartan medoxomil and hydrochlorothiazide. However, in vitro testing revealed that a combination of these agents at a ratio of 20:12.5 was negative in the Salmonella-Escherichia coli/mammalian microsome reverse mutation test. Further assessments for clastogenic activity in the Chinese hamster lung chromosomal aberration assay indicated positive responses for each component and combination ratio tested, although no synergistic clastogenic activity was observed. In vivo testing in the mouse bone marrow erythrocyte micronucleus assay showed that the combination at a ratio of 20:12.5 was negative at doses up to 3144 mg/kg.

Olmesartan medoxomil was not found to be carcinogenic in a two-year dietary study in rats, with the highest tested dose being 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, also showed no evidence of carcinogenic effects at doses up to 1000 mg/kg/day. 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 agents induced chromosomal aberrations in cultured cells 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.

Animal studies conducted by the National Toxicology Program (NTP) over two years revealed 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, equivocal evidence for hepatocarcinogenicity was noted in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay or in the Chinese Hamster Ovary 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 a lack of genotoxicity. Positive results were observed in the in vitro CHO Sister Chromatid Exchange assay, the Mouse Lymphoma Cell mutagenicity assay, and the Aspergillus nidulans non-disjunction assay.

Postmarketing Experience

No specific postmarketing experience details are available in the extracted data. As such, there are no additional adverse events or rare case reports to summarize.

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, 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 the use of olmesartan medoxomil and hydrochlorothiazide 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.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It is essential to store the product at a controlled room temperature of 20-25°C (68-77°F), in accordance with USP guidelines. Proper storage conditions must be maintained to ensure 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 activity of the renin-angiotensin system. Additionally, it is important to periodically assess serum electrolytes and calcium levels in these patients.

Patients should be counseled to report any occurrence of severe, chronic diarrhea accompanied by significant weight loss during treatment with olmesartan. In such cases, it is essential to exclude other potential causes and consider discontinuation of olmesartan medoxomil and hydrochlorothiazide 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 Ascend Laboratories, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)