Olmesartan medoxomil/Hydrochlorothiazide

Description

Olmesartan medoxomil and hydrochlorothiazide tablets comprise a combination 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 or almost white crystalline powder, which 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 also a white or practically white crystalline powder, exhibiting slight solubility in water and free solubility in sodium hydroxide solution.

The tablets are formulated for oral administration and are 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 hydroxypropyl cellulose, hypromellose, iron oxide yellow, lactose, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, PEG 4000, and titanium dioxide.

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.

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

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 allowable dose is 40 mg of olmesartan combined with 25 mg of hydrochlorothiazide. It is essential to monitor the patient's blood pressure and overall response to treatment during this adjustment period 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 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

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 even death to the developing fetus.

General precautions should be observed when administering this combination therapy. Prior to initiation, it is essential to correct any volume depletion to mitigate the risk of hypotension. Healthcare professionals should closely 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 this medication. Furthermore, cases of sprue-like enteropathy have been reported; therefore, if no other etiology is identified, consideration should be given to discontinuing olmesartan medoxomil and hydrochlorothiazide tablets.

For patients at risk, regular monitoring of renal function and potassium levels is advised to ensure safe use of this therapy.

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 lead to injury or death of the developing fetus.

Additional adverse reactions that may occur 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 olmesartan medoxomil and hydrochlorothiazide tablets have been noted, as well as anuria.

It is also important to note that co-administration of aliskiren with olmesartan medoxomil and hydrochlorothiazide is contraindicated 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.

Lithium co-administration 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.

For patients taking colesevelam hydrochloride, it is recommended to administer olmesartan at least 4 hours prior to the colesevelam hydrochloride dose to ensure optimal absorption and efficacy.

Antidiabetic drugs may require dosage adjustments when used in conjunction with other medications. Regular 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 separate the administration of these agents to minimize the impact on thiazide absorption.

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 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 patients and their younger counterparts.

In general, dose selection for elderly patients should be approached with caution. It is advisable to start 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 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, which can lead to increased fetal and neonatal morbidity and mortality. Therefore, when pregnancy is detected, it is recommended to discontinue olmesartan medoxomil and hydrochlorothiazide tablets as soon as possible and to consider alternative antihypertensive therapy.

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 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 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.

Hydrochlorothiazide, a component of this combination therapy, 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 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, 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 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 considered as part of standard clinical practice.

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 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, when combined in a ratio of 20:12.5, yielded negative results in the Salmonella-Escherichia coli/mammalian microsome reverse mutation test at the maximum recommended plate concentration. Individual and combined testing of olmesartan medoxomil and hydrochlorothiazide in various ratios for clastogenic activity in the in vitro Chinese hamster lung chromosomal aberration assay showed positive responses for each component and combination. However, no synergistic clastogenic activity was observed between the two compounds at any tested ratio.

In vivo testing of olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio, administered orally, was 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 (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 revealed no evidence of carcinogenicity for olmesartan medoxomil.

Both olmesartan medoxomil and hydrochlorothiazide tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no 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 assay, and the Aspergillus nidulans non-disjunction assay.

Postmarketing Experience

Postmarketing experience has identified cases of acute myopia and secondary angle-closure glaucoma associated with the use of olmesartan medoxomil and hydrochlorothiazide tablets. Patients experiencing symptoms of these conditions are advised to discontinue the medication and seek immediate medical attention.

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. Additionally, healthcare providers should inform patients that lightheadedness may occur, particularly during the initial days of therapy, and they should report this symptom if it arises.

Providers should also make patients aware 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 are advised to contact their healthcare provider immediately.

Furthermore, patients should be cautioned against using potassium supplements or salt substitutes that contain potassium without prior consultation with their healthcare provider. Lastly, healthcare providers should instruct patients 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.

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 temperature range of 20 to 25°C (68 to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions must be maintained to ensure the integrity and efficacy of the product.

Additional Clinical Information

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

Additionally, postmarketing reports have indicated that severe, chronic diarrhea with significant weight loss can occur in patients taking olmesartan, sometimes months to years after starting the medication.

FDA Insert (PDF)

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

View full prescribing information (PDF)