Olmesartan medoxomil/Hydrochlorothiazide

Description

Olmesartan medoxomil is 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. Its molecular formula is C29H30N6O6, and it has a molecular weight of 558.6. Olmesartan medoxomil, USP appears as a white to light yellowish-white powder or crystalline powder and is practically insoluble in water, with sparing solubility in methanol.

Hydrochlorothiazide, USP is 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. It is a white or practically white crystalline powder that is slightly soluble in water but freely soluble in sodium hydroxide solution.

Olmesartan medoxomil and hydrochlorothiazide tablets are formulated for oral administration, available in strengths of 20 mg or 40 mg of olmesartan medoxomil, USP combined with 12.5 mg of hydrochlorothiazide, USP, or 40 mg of olmesartan medoxomil, USP combined with 25 mg of hydrochlorothiazide, USP. 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.

Limitations of use include that olmesartan medoxomil and hydrochlorothiazide tablets are not indicated for initial therapy. There are no teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

The recommended starting dose for patients who are not adequately controlled with olmesartan monotherapy is 40 mg of olmesartan combined with 12.5 mg of hydrochlorothiazide. This combination should be administered once daily.

Healthcare professionals should assess the patient's response to therapy and adjust the dosage as necessary to achieve optimal blood pressure control. It is important to monitor for any potential side effects and to consider the patient's overall treatment plan when determining the appropriate dosage.

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, as this combination may increase the risk of adverse effects.

Warnings and Precautions

When pregnancy is detected, olmesartan medoxomil and hydrochlorothiazide tablets should be discontinued as soon as possible. It is important to note that drugs acting directly on the renin-angiotensin system may cause injury or death to the developing fetus.

General precautions must be observed when administering this medication. Prior to administration, 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 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 olmesartan medoxomil and hydrochlorothiazide tablets. Furthermore, cases of sprue-like enteropathy have been reported; therefore, consideration should be given to discontinuing the medication if no other etiology is identified.

For patients at risk, regular monitoring of renal function and potassium levels is advised 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 at least 2% of participants, include nausea, hyperuricemia, dizziness, and upper respiratory infections.

Serious adverse reactions have been noted, including hypotension, which necessitates the correction of volume depletion prior to administration. Patients should be monitored for renal function and potassium levels, particularly those who are susceptible. Additionally, signs of fluid or electrolyte imbalance should be observed. Acute angle-closure glaucoma has also been reported in some cases.

A boxed warning highlights the risks associated with the use of olmesartan medoxomil and hydrochlorothiazide tablets during pregnancy. If pregnancy is detected, it is advised to discontinue the medication as soon as possible, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Other important considerations include the potential for sprue-like enteropathy, which has been reported in patients taking olmesartan medoxomil and hydrochlorothiazide tablets. Discontinuation of the medication should be considered if no other etiology is identified. Hypersensitivity reactions to any component of the tablets may occur, and anuria has been observed in some patients. Furthermore, it is contraindicated to co-administer aliskiren with olmesartan medoxomil and hydrochlorothiazide tablets in patients with diabetes.

Drug Interactions

The following drug interactions have been identified:

Lithium Concurrent use of olmesartan with lithium may increase the risk of lithium toxicity. Monitoring of lithium levels is recommended to avoid potential adverse effects.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) The co-administration of olmesartan with NSAIDs may lead to reduced diuretic, natriuretic, and antihypertensive effects. Additionally, there is an increased risk of renal toxicity. It is advisable to monitor renal function and blood pressure in patients receiving this combination.

Renin-Angiotensin System Inhibitors When olmesartan is used in conjunction with other agents that inhibit the renin-angiotensin system, there is an increased risk of renal impairment, hypotension, and hyperkalemia. Close monitoring of renal function and serum potassium levels is recommended.

Colesevelam Hydrochloride To minimize the potential for interaction, olmesartan should be administered at least 4 hours prior to the dose of colesevelam hydrochloride.

Antidiabetic Drugs Patients taking olmesartan alongside antidiabetic medications may require dosage adjustments. Blood glucose levels should be monitored to ensure effective glycemic control.

Cholestyramine and Colestipol The use of cholestyramine or colestipol may reduce the absorption of thiazide diuretics, including olmesartan. It is recommended to separate the administration of these agents to optimize therapeutic efficacy.

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 should be exercised when considering the use of this medication in children and adolescents. Further studies are needed to determine appropriate dosing and potential outcomes in this population.

Geriatric Use

Elderly patients may not respond differently to olmesartan medoxomil and hydrochlorothiazide tablets compared to younger patients, as clinical studies did not include a sufficient number of subjects aged 65 and over to draw definitive conclusions. However, other clinical experiences have not identified significant differences in responses between these age groups.

In general, dose selection for geriatric 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 primarily excreted by the kidneys, there is an elevated risk of toxic reactions in elderly patients with impaired renal function. Therefore, careful monitoring of renal function is recommended when prescribing these medications to geriatric patients.

Pregnancy

Olmesartan medoxomil and hydrochlorothiazide tablets 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, increased fetal and neonatal morbidity, and a heightened risk of death. Therefore, when pregnancy is detected, olmesartan medoxomil and hydrochlorothiazide tablets 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 increases maternal risks for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, including the need for cesarean section and postpartum hemorrhage. Additionally, hypertension poses risks to the fetus, including intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be closely monitored and managed accordingly.

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 tablets 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 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 risks 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 the use of this drug in lactating mothers or its effects on breastfed infants in the provided prescribing information. 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. 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 cases of overdosage with olmesartan medoxomil, limited data are available regarding its effects in humans. The most likely clinical manifestations include hypotension and tachycardia, with the potential for bradycardia resulting from vagal stimulation. Should symptomatic hypotension occur, it is imperative that supportive treatment be initiated promptly to manage the patient's condition effectively.

Toxicity studies conducted in animal models have shown no lethality in acute toxicity assessments for olmesartan medoxomil, with single oral doses of up to 2000 mg/kg administered to mice and rats resulting in survival. In canine models, the minimum lethal oral dose was determined to be greater than 1500 mg/kg, indicating a relatively high threshold for toxicity in this species.

In the case of hydrochlorothiazide overdose, the predominant signs and symptoms are typically associated with electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. It is important to note that if digitalis has been administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias, necessitating careful monitoring and management.

The oral LD50 for hydrochlorothiazide has been established as greater than 10 g/kg in both mice and rats, suggesting a significant margin of safety in these animal models. Healthcare professionals should remain vigilant for the signs of overdose and implement appropriate management strategies to mitigate potential complications.

Nonclinical Toxicology

No studies have been conducted to evaluate the impairment of fertility associated with olmesartan medoxomil and hydrochlorothiazide. However, fertility assessments in rats indicated that administration of olmesartan medoxomil at doses up to 1000 mg/kg/day, which is approximately 240 times the maximum recommended human dose (MRHD), did not adversely affect fertility when dosing commenced 2 weeks prior to mating for females and 9 weeks prior for males. Similarly, hydrochlorothiazide did not demonstrate any negative effects 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 performed with olmesartan medoxomil and hydrochlorothiazide. In mutagenicity testing, olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio were found to be negative in the Salmonella-Escherichia coli/mammalian microsome reverse mutation test at the maximum recommended plate concentration. When tested individually and in combination ratios of 40:12.5, 20:12.5, and 10:12.5 for clastogenic activity in the in vitro Chinese hamster lung chromosomal aberration assay, a positive response was observed for each component and combination ratio; however, no synergistic clastogenic activity was detected between the two compounds.

In vivo testing revealed that olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio, administered orally, tested negative in the mouse bone marrow erythrocyte micronucleus assay at doses up to 3144 mg/kg. Long-term dietary administration of olmesartan medoxomil to rats for up to 2 years did not indicate carcinogenic potential, with the highest tested dose of 2000 mg/kg/day being 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 carcinogenicity.

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 the mouse bone marrow micronucleus test at oral doses up to 2000 mg/kg, while olmesartan was not tested.

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 involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, or the Drosophila sex-linked recessive lethal trait gene. 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

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.

Nursing women should be informed not to breastfeed while undergoing treatment with olmesartan medoxomil and hydrochlorothiazide tablets. Additionally, patients should be made aware that lightheadedness may occur, particularly during the initial days of therapy, and they should report this symptom to their healthcare provider.

Patients should be informed that dehydration resulting from inadequate fluid intake, excessive perspiration, vomiting, or diarrhea may lead to a significant drop in blood pressure. In the event of syncope, patients are advised to contact their healthcare provider immediately.

Healthcare providers should caution patients against using potassium supplements or salt substitutes that contain potassium without prior consultation. Patients must 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, 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 a plastic bottle containing 90 units. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions 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 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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)