Olmesartan medoxomil/Hydrochlorothiazide

Description

Olmesartan medoxomil and hydrochlorothiazide tablets are a combination formulation consisting of olmesartan medoxomil, an angiotensin II receptor antagonist (AT1 subtype), and hydrochlorothiazide (HCTZ), a thiazide diuretic. Olmesartan medoxomil, a prodrug, is converted to its active form, olmesartan, during gastrointestinal absorption. The chemical structure of 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, with an empirical formula of C29H30N6O6 and a molecular weight of 558.6. It appears as a white or almost white crystalline powder that is practically insoluble in water and sparingly soluble in methanol.

Hydrochlorothiazide is characterized by the chemical structure 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. It is also a white or practically white crystalline powder, slightly soluble in water and freely soluble in sodium hydroxide solution.

These 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 lactose, microcrystalline cellulose, low substituted hydroxypropyl cellulose, magnesium stearate, hydroxypropyl cellulose, hypromellose, titanium dioxide, PEG 4000, and iron oxide yellow.

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.

There are no teratogenic effects associated with this medication. Additionally, no nonteratogenic effects have been reported.

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.

Dose 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.

Administration should be performed orally, and the medication can be taken with or without food. It is advisable to monitor blood pressure regularly to assess the effectiveness of the treatment and to adjust the dosage as necessary.

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.

Co-administration with aliskiren 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 to discontinue the medication 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.

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. Healthcare professionals are advised to monitor renal function and potassium levels in patients who may be susceptible to imbalances. Additionally, vigilance for signs of fluid or electrolyte imbalance is recommended.

There is a risk of acute angle-closure glaucoma associated with this medication, necessitating careful patient assessment. Furthermore, cases of sprue-like enteropathy have been reported; therefore, consideration should be given to discontinuing olmesartan medoxomil and hydrochlorothiazide tablets in instances where no other etiology for gastrointestinal symptoms is identified.

For patients at risk, regular monitoring of renal function and potassium levels is crucial to prevent complications.

Side Effects

Patients receiving olmesartan medoxomil and hydrochlorothiazide may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

The most common adverse reactions, occurring in at least 2% of participants, include nausea, hyperuricemia, dizziness, and upper respiratory infections.

Serious adverse reactions warranting attention include fetal toxicity, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. It is crucial to discontinue olmesartan medoxomil and hydrochlorothiazide as soon as pregnancy is detected.

Additional adverse reactions that may occur include hypotension, which necessitates correction of volume depletion prior to administration. Patients should have their renal function and potassium levels monitored, particularly those who are susceptible. Signs of fluid or electrolyte imbalance should be observed, and acute angle-closure glaucoma has been reported in some cases. Sprue-like enteropathy has also been noted; discontinuation of the medication should be considered if no other etiology is identified. Hypersensitivity reactions to any component of the medication have been documented, as well as instances of anuria.

It is important to note that co-administration with aliskiren is contraindicated in patients with diabetes.

In cases of overdosage, the most likely manifestations associated with olmesartan medoxomil include hypotension and tachycardia, with bradycardia potentially occurring due to parasympathetic (vagal) stimulation. For hydrochlorothiazide, the most common signs and symptoms of overdose are related to electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia, along with dehydration resulting from excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias.

Drug Interactions

The following drug interactions have been identified, categorized by their pharmacodynamic and pharmacokinetic effects, along with recommendations for monitoring and dosage adjustments where applicable.

Pharmacodynamic Interactions

• Lithium: Co-administration with olmesartan may increase the risk of lithium toxicity. Monitoring of lithium levels is advised to prevent adverse effects.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs may lead to reduced diuretic, natriuretic, and antihypotensive effects of olmesartan. Additionally, there is an increased risk of renal toxicity. Patients should be monitored for renal function and blood pressure.

• Dual Inhibition of the Renin-Angiotensin System: Concurrent use with agents that also inhibit the renin-angiotensin system may elevate the risk of renal impairment, hypotension, and hyperkalemia. Regular monitoring of renal function and serum potassium levels is recommended.

Pharmacokinetic Interactions

• Colesevelam Hydrochloride: It is recommended that olmesartan be administered at least 4 hours prior to the dose of colesevelam hydrochloride to minimize the potential for reduced absorption.

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used in conjunction with olmesartan. Close monitoring of blood glucose levels is advised to ensure effective glycemic control.

• Cholestyramine and Colestipol: The absorption of thiazide diuretics may be reduced when taken with cholestyramine or colestipol. Monitoring of blood pressure and electrolyte levels is suggested to assess 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

Pediatric patients, particularly neonates with a history of in utero exposure to olmesartan medoxomil and hydrochlorothiazide tablets, may experience complications such as oliguria or hypotension. In such cases, it is crucial to provide support for blood pressure and renal perfusion, as exchange transfusions or dialysis may be necessary to address hypotension and restore renal function.

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.

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.

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 olmesartan medoxomil and hydrochlorothiazide tablets to mitigate potential adverse effects.

Pregnancy

The use of olmesartan medoxomil and hydrochlorothiazide tablets during pregnancy is classified as Pregnancy Category D. Administration of drugs that act on the renin-angiotensin system during the second and third trimesters is associated with significant risks, including reduced fetal renal function, increased fetal and neonatal morbidity, and potential mortality. Oligohydramnios resulting from such use can lead to serious fetal complications, including lung hypoplasia and skeletal deformations.

Neonates exposed to these medications may experience adverse effects such as skull hypoplasia, anuria, hypotension, renal failure, and death. Therefore, it is imperative to discontinue olmesartan medoxomil and hydrochlorothiazide tablets as soon as pregnancy is confirmed. The adverse outcomes are primarily linked to the use of these drugs during the later stages of pregnancy.

While most epidemiologic studies investigating fetal abnormalities following antihypertensive exposure in the first trimester do not specifically differentiate between drugs affecting the renin-angiotensin system and other antihypertensive agents, appropriate management of maternal hypertension is crucial to optimize outcomes for both the mother and fetus. In rare cases where no suitable alternative therapy exists, healthcare providers should inform the patient of the potential risks to the fetus.

Healthcare professionals are advised to perform serial ultrasound examinations to monitor the intraamniotic environment. If oligohydramnios is detected, olmesartan medoxomil and hydrochlorothiazide tablets should be discontinued unless their use is deemed lifesaving for the mother. 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 tablets should be closely monitored for signs of hypotension, oliguria, and hyperkalemia. Fetal testing may also be warranted based on the gestational age.

Lactation

It is not known whether olmesartan is excreted in human milk; however, olmesartan has been detected at low concentrations in the milk of lactating rats. Thiazides are known to appear in human milk.

Due to the potential for adverse effects on the nursing infant, healthcare professionals should consider the importance of olmesartan medoxomil and hydrochlorothiazide tablets to the mother when making a decision to either discontinue nursing or discontinue the medication.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored, particularly in those who are susceptible to changes in these parameters. Regular assessment is essential to ensure safe and effective use of the medication in this population.

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 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 symptoms and manage them accordingly, ensuring appropriate supportive care is provided.

Nonclinical Toxicology

No teratogenic effects were observed in pregnant mice or rats administered combinations of olmesartan medoxomil and hydrochlorothiazide at oral doses up to 1625 mg/kg/day. This dosage corresponds to 122 times the maximum recommended human dose (MRHD) on a mg/m² basis for mice and 280 times the MRHD for rats. However, in rats, fetal body weights at this dose were significantly lower than those of the control group. The no observed effect dose for developmental toxicity in rats was determined to be 162.5 mg/kg/day, which is approximately 28 times the MRHD of olmesartan medoxomil and hydrochlorothiazide tablets.

Fertility assessments in rats indicated that olmesartan medoxomil did not adversely affect reproductive capabilities at doses as high as 1000 mg/kg/day, which is 240 times the MRHD. 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 conducted for olmesartan medoxomil and hydrochlorothiazide. However, 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. In the in vitro Chinese hamster lung chromosomal aberration assay, both olmesartan medoxomil and hydrochlorothiazide were tested individually and in combination ratios of 40:12.5, 20:12.5, and 10:12.5, yielding positive responses for clastogenic activity, although no synergistic effects were observed between the two compounds.

In vivo testing in the mouse bone marrow erythrocyte micronucleus assay showed that olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio were negative at doses up to 3144 mg/kg. No studies have been conducted to assess the impairment of fertility with these compounds.

Long-term studies indicated that olmesartan medoxomil was not carcinogenic when administered to rats via diet for up to 2 years at the highest tested dose of 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, also revealed no evidence of carcinogenic effects at doses up to 1000 mg/kg/day, about 120 times the MRHD.

Both olmesartan medoxomil and hydrochlorothiazide tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of 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.

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 using 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

Reports of side effects have been received through voluntary submissions and surveillance programs. Patients are encouraged to consult their healthcare provider for medical advice regarding any adverse effects experienced. Additionally, side effects can be reported to the FDA at 1-800-FDA-1088.

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, which can result 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.

It is crucial to inform patients not to use potassium supplements or salt substitutes containing potassium without prior consultation with their healthcare provider. Furthermore, patients 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.

Patients should be encouraged to call their doctor for medical advice regarding any side effects they may experience. They may also report side effects to the FDA at 1-800-FDA-1088.

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

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 Alembic Pharmaceuticals Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)