Olmesartan medoxomil/Hydrochlorothiazide

Uses and Indications

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

These tablets are not indicated for initial therapy in the management of hypertension.

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 of treatment, based on the patient's response and tolerability. 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 previous treatment history and response to therapy.

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 immediately. This medication can cause fetal toxicity, including injury and death to the developing fetus, due to its action on the renin-angiotensin system.

General precautions must 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 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 in instances where no other etiology for gastrointestinal symptoms is identified.

Regular laboratory tests to monitor renal function and potassium levels are advised for patients at risk. 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 this medication include the potential for fetal toxicity. Drugs that act directly on the renin-angiotensin system, such as olmesartan, can cause injury and death to the developing fetus. Therefore, it is crucial to avoid use during pregnancy.

Additional adverse reactions that may occur include 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. It is also important to observe for signs of fluid or electrolyte imbalance.

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

Co-administration of aliskiren with olmesartan medoxomil and hydrochlorothiazide is contraindicated in patients with diabetes.

In the event of overdosage, the most likely manifestations include hypotension and tachycardia, although bradycardia may occur if there is parasympathetic (vagal) stimulation. Common signs and symptoms of hydrochlorothiazide overdose observed in humans are primarily those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia, as well as dehydration due to 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 with certain medications. Monitoring of blood glucose levels is advised to ensure effective glycemic control.

Cholestyramine and colestipol can reduce the absorption of thiazide diuretics. It is recommended to monitor the therapeutic effects of thiazides and consider adjusting the dosage if necessary.

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 necessary 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 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.

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

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, which can lead to increased fetal and neonatal morbidity and mortality. 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 poses additional risks, including increased maternal risk for 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. 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 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.

Thiazides, including hydrochlorothiazide, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. Hydrochlorothiazide can also cause placental hypoperfusion and accumulates 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 and thrombocytopenia. Additionally, these medications do not prevent or alter the course of preeclampsia and should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications, such as heart disease, during pregnancy should also 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 and 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. 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 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. The dialyzability of olmesartan medoxomil remains unknown, which may impact management strategies.

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, indicating a relatively high threshold for toxicity in this species.

In contrast, the most common signs and symptoms associated with hydrochlorothiazide 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 the risk of cardiac arrhythmias. The extent to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD50 of hydrochlorothiazide is reported to be 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 these potential symptoms and manage them accordingly in cases of suspected overdose.

Nonclinical Toxicology

No teratogenic effects have been reported in studies involving olmesartan medoxomil and hydrochlorothiazide. Investigations into the effects of olmesartan medoxomil on fertility demonstrated that administration at doses as high as 1000 mg/kg/day, which is 240 times the maximum recommended human dose (MRHD), did not adversely affect the fertility of rats when dosing commenced 2 weeks prior to mating for females and 9 weeks for males. Similarly, hydrochlorothiazide did not exhibit 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. 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. Both compounds were evaluated for clastogenic activity in the in vitro Chinese hamster lung chromosomal aberration assay at various combination ratios, revealing positive responses for each component and combination; however, no synergistic clastogenic activity was observed. In vivo testing in the mouse bone marrow erythrocyte micronucleus assay with the 20:12.5 ratio showed negative results at doses up to 3144 mg/kg.

Long-term studies indicated that olmesartan medoxomil was not carcinogenic when administered in the diet to rats for up to 2 years, 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 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 demonstrate 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 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. 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

During post-approval use of olmesartan medoxomil and hydrochlorothiazide, several adverse reactions have been reported voluntarily or through surveillance programs. These include asthenia, vomiting, hyperkalemia, rhabdomyolysis, alopecia, and pruritus. Due to the voluntary nature of these reports and the uncertain size of the population, it is not always feasible to reliably estimate the frequency of these events or establish a causal relationship to drug exposure.

Data from a controlled trial and an epidemiologic study have indicated a potential increase in cardiovascular (CV) risk associated with high-dose olmesartan in diabetic patients, although the overall data remain inconclusive. The ROADMAP trial, a randomized, placebo-controlled, double-blind study involving 4,447 patients with type 2 diabetes mellitus, demonstrated that while olmesartan delayed the onset of microalbuminuria, it did not show a beneficial effect on the decline in glomerular filtration rate (GFR). Notably, there was an observed increase in CV mortality in the olmesartan group compared to placebo (15 vs. 3), with a hazard ratio of 4.9 (95% CI 1.4, 17). Conversely, the risk of non-fatal myocardial infarction was lower in the olmesartan group (HR 0.64, 95% CI 0.35, 1.18).

In an epidemiologic study involving patients aged 65 years and older, with over 300,000 patient-years of exposure, high-dose olmesartan (40 mg/d) for more than six months was associated with an increased risk of death in diabetic patients (HR 2.0, 95% CI 1.1, 3.8) compared to those taking other angiotensin receptor blockers. In contrast, non-diabetic patients receiving high-dose olmesartan appeared to have a decreased risk of death (HR 0.46, 95% CI 0.24, 0.86). No significant differences were noted between groups receiving lower doses of olmesartan or those treated for less than six months.

These findings raise concerns regarding a possible increased CV risk associated with high-dose olmesartan in diabetic patients. However, the credibility of these findings is tempered by the observation of a survival benefit in non-diabetic patients that is comparable in magnitude to the adverse findings in diabetic patients.

Additionally, hydrochlorothiazide has been linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), as identified in a study conducted within the Sentinel System. The increased risk was predominantly observed in white patients receiving large cumulative doses, with an estimated increase of approximately one additional case of SCC per 16,000 patients per year in the overall population. For white patients taking a cumulative dose of ≥50,000 mg, the risk increase was approximately one additional SCC case for every 6,700 patients per year.

Patient Counseling

Healthcare providers should advise patients that if pregnancy is detected, olmesartan medoxomil and hydrochlorothiazide tablets should be discontinued as soon as possible. It is important to communicate that medications acting directly on the renin-angiotensin system can pose significant risks, including injury and death to the developing fetus.

Providers should inform patients that the use of these medications during the second and third trimesters of pregnancy can lead to reduced fetal renal function, increasing the risks of fetal and neonatal morbidity and mortality. Patients should be made aware that oligohydramnios, which may occur as a result of these medications, can be associated with serious complications such as fetal lung hypoplasia and skeletal deformations.

Additionally, potential neonatal adverse effects should be discussed, including skull hypoplasia, anuria, hypotension, renal failure, and even death. It is crucial to note that thiazides can cross the placental barrier and may appear in cord blood, with possible adverse reactions including fetal or neonatal jaundice and thrombocytopenia.

Healthcare providers should emphasize the importance of closely monitoring infants who have been exposed in utero to olmesartan medoxomil and hydrochlorothiazide for signs of hypotension, oliguria, and hyperkalemia. In cases where oliguria or hypotension is observed, providers should be prepared to implement measures to maintain adequate blood pressure and renal perfusion, which may include exchange transfusions or dialysis as necessary.

Finally, it is essential to advise nursing women that breastfeeding is not recommended during treatment with olmesartan medoxomil and hydrochlorothiazide, ensuring that patients are fully informed of the risks associated with this medication during lactation.

Storage and Handling

The product is supplied in accordance with the following specifications. It should be stored at a temperature range of 20º to 25º C (68º to 77º F), in compliance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients receiving olmesartan medoxomil and hydrochlorothiazide should be counseled that breastfeeding is not recommended during treatment. Clinicians should be aware of potential postmarketing experiences associated with this medication, which include asthenia, vomiting, hyperkalemia, rhabdomyolysis, alopecia, pruritus, and an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients who have taken large cumulative doses.

FDA Insert (PDF)

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

View full prescribing information (PDF)