Olmesartan medoxomil/Hydrochlorothiazide

Description

Olmesartan medoxomil, USP is 1H-imidazole-5-carboxylic acid, 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl) 1, 1’-biphenyl-4-yl] methyl]-, (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl ester, with a molecular formula of C29H30N6O6 and a molecular weight of 558.59. It appears as a white to off-white crystalline powder that is practically insoluble in water and sparingly soluble 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 297.74. This compound is a white or practically white, practically odourless, crystalline powder. It is very slightly soluble in water, freely soluble in sodium hydroxide solution, n-butylamine, and dimethyl formamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids.

The olmesartan medoxomil and hydrochlorothiazide tablet is available for oral administration in strengths of 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, lactose monohydrate, low-substituted hydroxypropylcellulose, microcrystalline cellulose, stearic acid, red iron oxide, talc, titanium dioxide, hypromellose, and yellow iron oxide.

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.

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

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 is contraindicated in patients with hypersensitivity to any component of the formulation. Additionally, the drug should not be administered to patients with anuria. Co-administration of aliskiren with olmesartan medoxomil and hydrochlorothiazide is contraindicated in patients with diabetes due to the potential for adverse effects.

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of olmesartan medoxomil and hydrochlorothiazide. It is imperative that these medications be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system may cause injury or death to the developing fetus (5.1, 8.1).

General precautions should be observed to ensure patient safety. Prior to administration, it is essential to correct any volume-depletion to mitigate the risk of hypotension (5.2). Healthcare professionals should monitor renal function and potassium levels in patients who are susceptible to these changes (5.3). Additionally, vigilance for signs of fluid or electrolyte imbalance is recommended (5.5). There is also a risk of acute angle-closure glaucoma associated with this medication (5.6). Furthermore, cases of sprue-like enteropathy have been reported; therefore, consideration should be given to discontinuing olmesartan medoxomil and hydrochlorothiazide if no other etiology is identified (5.8).

To ensure safe use, it is crucial to monitor renal function and potassium levels in susceptible patients, as these parameters can indicate potential adverse effects.

Side Effects

Patients receiving olmesartan medoxomil and hydrochlorothiazide 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 warnings associated with 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 or 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 reported adverse reactions include acute angle-closure glaucoma and sprue-like enteropathy, which may warrant discontinuation of the medication if no other etiology is identified. Hypersensitivity reactions to any component of the drug have been noted, as well as anuria.

It is important to note that co-administration of aliskiren with olmesartan medoxomil and hydrochlorothiazide is contraindicated in patients with diabetes. Overdosage of this medication may lead to hypotension and tachycardia, with bradycardia potentially occurring due to parasympathetic (vagal) stimulation. Symptoms of hydrochlorothiazide overdose can include electrolyte depletion (such as hypokalemia, hypochloremia, and hyponatremia) and dehydration resulting from 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) may 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 can 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.

Colesevelam hydrochloride should be administered at least 4 hours prior to olmesartan to avoid potential interactions that may affect the efficacy of olmesartan.

Antidiabetic drugs may require dosage adjustments when used in conjunction with other medications. Monitoring of blood glucose levels is recommended to ensure appropriate management.

Cholestyramine and colestipol can reduce the absorption of thiazide diuretics. It is advisable to separate the administration of these agents to optimize therapeutic outcomes.

Packaging & NDC

The table below lists all NDC Code configurations of Olmesartan Medoxomil-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 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 safety profiles in this population.

Geriatric Use

Clinical studies of olmesartan medoxomil and hydrochlorothiazide 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 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 of renal function is recommended in geriatric patients receiving these medications to mitigate potential adverse effects.

Pregnancy

Olmesartan medoxomil and hydrochlorothiazide 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 should be discontinued as soon as possible, and alternative antihypertensive therapy should be considered.

The estimated background risk of major birth defects and miscarriage in the general 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%–4% and 15%–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 can increase 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, 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 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.

Hydrochlorothiazide, a thiazide diuretic, can cross the placenta, with concentrations in the umbilical vein approaching those in maternal plasma. It may cause placental hypoperfusion and 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 and 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 is no specific information available regarding the use of olmesartan medoxomil and hydrochlorothiazide in lactating mothers or the potential for excretion in breast milk. Additionally, there is no data concerning the effects on breastfed infants or the potential for adverse reactions in infants who are breastfed while the mother is taking this medication. Healthcare professionals should consider the lack of information 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, 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 these patients for signs of fluid or electrolyte imbalance throughout the treatment process.

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 olmesartan medoxomil overdosage, the most likely clinical manifestations include hypotension and tachycardia. It is important to note that bradycardia may also occur, particularly with parasympathetic stimulation. Should symptomatic hypotension arise, it is recommended that supportive treatment be promptly initiated to manage the patient's condition.

Toxicity studies conducted in mice and rats have demonstrated that no lethality was observed following the administration of 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, indicating a relatively high threshold for acute toxicity in these animal models.

In the case of hydrochlorothiazide overdose, the predominant signs and symptoms are typically associated with electrolyte depletion, which may include hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. It is critical to monitor patients closely, as the presence of hypokalemia can exacerbate cardiac arrhythmias, particularly in individuals who have been administered digitalis.

The oral LD50 of hydrochlorothiazide has been established as greater than 10 g/kg in both mice and rats, suggesting a significant margin of safety in these animal studies. However, healthcare professionals should remain vigilant in assessing and managing potential complications arising from overdose situations.

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 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 vitro testing revealed that a combination of olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio was negative in the Salmonella-Escherichia coli/mammalian microsome reverse mutation test at the maximum recommended plate concentration. Further testing for clastogenic activity in the Chinese hamster lung chromosomal aberration assay showed positive responses for each component and combination ratios of 40:12.5, 20:12.5, and 10:12.5; however, no synergistic clastogenic activity was observed between the two compounds at any combination ratio. 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.

In animal studies, olmesartan medoxomil was not found to be carcinogenic when administered via 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 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 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 across various Salmonella typhimurium strains 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

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 during pregnancy. It is important to discuss treatment options with women who are planning to become pregnant and to encourage them 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.

Patients should be made aware that lightheadedness may occur, particularly during the initial days of therapy. They should be instructed to report this symptom to their healthcare provider. Additionally, patients should be informed 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.

Healthcare providers should instruct patients to discontinue olmesartan medoxomil and hydrochlorothiazide and seek immediate medical attention if they experience symptoms indicative of acute myopia or secondary angle-closure glaucoma.

For patients taking hydrochlorothiazide, it is essential to advise them to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20 to 25°C (68 to 77°F), as defined by the United States Pharmacopeia (USP). Proper storage conditions are essential to maintain 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 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. Postmarketing reports indicate that severe, chronic diarrhea with substantial weight loss has occurred in patients taking olmesartan, sometimes months to years after initiation of therapy, with intestinal biopsies frequently showing villous atrophy.

FDA Insert (PDF)

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

View full prescribing information (PDF)