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: 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 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, including strokes and myocardial infarctions.

This drug is not indicated for initial therapy. There are no teratogenic or nonteratogenic effects associated with the use of olmesartan medoxomil and hydrochlorothiazide tablets.

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 account 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 function issues in these patients.

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. 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 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 advised. 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 recommended for patients who may be at risk. This proactive approach can help in identifying potential complications early and ensuring patient safety.

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, particularly in patients with volume depletion, and acute angle-closure glaucoma. It is essential to correct any volume depletion prior to administration and to monitor renal function and potassium levels in susceptible patients. Additionally, patients should be observed for signs of fluid or electrolyte imbalance.

A boxed warning highlights the risks associated with the use of these tablets 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 sprue-like enteropathy, which has been reported in some cases. Discontinuation of the medication should be considered if no other etiology is found. Hypersensitivity reactions to any component of the tablets may also occur, along with anuria. Furthermore, it is contraindicated to co-administer aliskiren with olmesartan medoxomil and hydrochlorothiazide tablets in patients with diabetes.

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 concurrently, necessitating careful monitoring of blood glucose levels to maintain glycemic control.

Cholestyramine and colestipol can reduce the absorption of thiazide diuretics. It is advisable 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

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. Further studies are needed to determine appropriate dosing and therapeutic 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 from 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.

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, 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 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% to 4% and 15% to 20%, respectively. Hypertension during pregnancy can increase 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, including hydrochlorothiazide, 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 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. The potential for excretion of these medications in breast milk has not been addressed in the provided data. Additionally, there are no specific recommendations or precautions mentioned for women who are breastfeeding.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored closely, as they may be at increased risk for complications. Dosing adjustments may be necessary based on the degree of reduced kidney function 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

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 recommended that supportive treatment be initiated promptly. The dialyzability of olmesartan is currently 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, indicating a relatively high threshold for toxicity in this species.

In cases where hydrochlorothiazide is involved, the most common signs and symptoms of overdose observed 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. However, it is noted that the oral LD50 of hydrochlorothiazide exceeds 10 g/kg in both mice and rats, suggesting a significant margin of safety in these animal models.

Nonclinical Toxicology

No teratogenic effects have been identified in studies involving olmesartan medoxomil and hydrochlorothiazide. Investigations into the effects of olmesartan medoxomil on fertility revealed 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 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 for olmesartan medoxomil and hydrochlorothiazide. In mutagenicity testing, 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. When tested for clastogenic activity in the in vitro Chinese hamster lung chromosomal aberration assay, both compounds, individually and in combination ratios of 40:12.5, 20:12.5, and 10:12.5, showed positive responses; however, no synergistic clastogenic activity was observed between the two agents at any combination ratio. In the in vivo mouse bone marrow erythrocyte micronucleus assay, olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio were administered orally and tested negative at doses up to 3144 mg/kg.

Long-term studies indicated that olmesartan medoxomil was not 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 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, 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 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, healthcare providers should emphasize the importance of protecting their skin from sun exposure and undergoing regular skin cancer screenings to monitor for any potential issues.

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 container requirements must be adhered to, and special handling needs should be followed to ensure product integrity.

Additional Clinical Information

Clinicians are advised to monitor renal function periodically in patients at risk of developing acute renal failure, as well as to assess serum electrolytes and calcium levels regularly. In cases of hypotension, patients should be positioned supine and may require intravenous normal saline. Additionally, patients should be informed about the symptoms of acute transient myopia or acute angle-closure glaucoma, which include a sudden decrease in visual acuity or ocular pain; hydrochlorothiazide should be discontinued promptly if these symptoms arise.

Postmarketing reports have indicated that severe, chronic diarrhea with significant weight loss may occur in patients taking olmesartan, sometimes months to years after initiation of therapy. Intestinal biopsies in these cases have shown villous atrophy. Clinicians should consider discontinuing olmesartan medoxomil and hydrochlorothiazide tablets if no other cause for these symptoms is identified.

FDA Insert (PDF)

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

View full prescribing information (PDF)