Olmesartan medoxomil/Hydrochlorothiazide

Description

Olmesartan medoxomil is 1H-Imidazole-5-Carboxylic Acid, 4-(1-Hydroxy-1-Methylethyl)-2-Propyl-1-[[2’-1H-Tetrazol-5yl)1, 1’-Biphenyl-4-yl]Methyl]-, (5-Methyl-2-Oxo-1, 3-Dioxol-4-yl) Methyl Ester. Its empirical formula is C29H30N6O6, and it has a molecular weight of 558.59. Olmesartan medoxomil appears as a white to off-white powder and is slightly soluble in acetone and methanol, very slightly soluble in ethanol, and practically insoluble in water.

Hydrochlorothiazide is 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 297.74. It is a white or practically white, practically odorless, crystalline powder. Hydrochlorothiazide is freely soluble in sodium hydroxide solution, n-butyl amine, and dimethylformamide; very slightly soluble in water; sparingly soluble in methanol; and insoluble in ether, chloroform, and dilute mineral acids.

Olmesartan medoxomil and hydrochlorothiazide tablets are formulated for oral administration, available 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 hydroxy propyl cellulose, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, low substituted hydroxy propyl cellulose, magnesium stearate, microcrystalline cellulose, talc, and titanium dioxide.

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.

There are no teratogenic or nonteratogenic effects associated with the use of this medication.

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.

Healthcare professionals should ensure that the dosing regimen is tailored to the individual patient's needs, taking into consideration their response to therapy and any potential side effects.

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 as soon as possible due to the risk of fetal toxicity. Medications that act directly on the renin-angiotensin system have the potential to cause injury or death to the developing fetus.

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 changes. 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 tablets if no other etiology for gastrointestinal symptoms is identified.

Laboratory tests should include regular monitoring of renal function and potassium levels in patients who may be at risk. This proactive approach is crucial for ensuring patient safety and optimizing therapeutic outcomes.

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 warnings associated with the use of this medication include fetal toxicity. It is imperative that olmesartan medoxomil and hydrochlorothiazide tablets 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 the correction of volume depletion prior to administration. Patients should have their renal function and potassium levels monitored, particularly those who are susceptible. There is also a need to observe for signs of fluid or electrolyte imbalance. 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 tablets have been noted, as well as anuria.

It is also important to note that olmesartan medoxomil and hydrochlorothiazide tablets should not be co-administered with aliskiren in patients with diabetes, due to potential adverse effects.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there are no known interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are necessary at this time.

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 necessary 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 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 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, 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%–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 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 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 a risk of fetal or neonatal jaundice or thrombocytopenia. Since thiazides do not prevent or alter the course of preeclampsia, they should not be used to treat hypertension in pregnant women, and their use for other indications, such as heart disease, should be avoided during pregnancy.

Lactation

There is limited information regarding the presence of olmesartan medoxomil and hydrochlorothiazide in human milk, as well as the effects on breastfed infants and milk production. However, olmesartan has been detected in rat milk following a single oral administration of 5 mg/kg to lactating rats. Hydrochlorothiazide is known to be present in human milk.

Due to the potential for adverse effects on the nursing infant, it is advised that lactating mothers refrain from breastfeeding during treatment with olmesartan medoxomil and hydrochlorothiazide tablets.

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 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, limited data are available regarding its effects in humans. The most likely clinical manifestations include hypotension and tachycardia; however, bradycardia may also occur due to vagal stimulation. Should symptomatic hypotension arise as a result of an overdose, it is imperative to initiate supportive treatment to manage the patient's condition effectively.

Toxicity studies conducted in mice and rats have demonstrated that no lethality was observed following acute exposure to single oral doses of olmesartan medoxomil up to 2000 mg/kg. In canine models, the minimum lethal oral dose was determined to be greater than 1500 mg/kg, indicating a relatively high threshold for toxicity in this species.

For hydrochlorothiazide, the most prevalent signs and symptoms of overdose are primarily associated with electrolyte depletion, which may manifest as hypokalemia, hypochloremia, and hyponatremia, alongside dehydration resulting from excessive diuresis. It is crucial to note that if digitalis has been administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias during hydrochlorothiazide overdose.

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 models. Healthcare professionals should remain vigilant for these potential symptoms and manage them accordingly in cases of suspected overdose.

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 as high as 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 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. In the in vitro Chinese hamster lung chromosomal aberration assay, both compounds were tested individually and in combination ratios of 40:12.5, 20:12.5, and 10:12.5, yielding positive responses for each component and combination; however, no synergistic clastogenic activity was observed.

In vivo testing revealed that olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio, administered orally, were 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 at the highest dose of 2000 mg/kg/day, approximately 480 times the MRHD, did not indicate carcinogenic potential. Additionally, 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), 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 the mouse bone marrow micronucleus test 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 also 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 and to encourage them to report any pregnancies to their physicians as soon as possible.

Patients should be informed that lightheadedness may occur, particularly during the initial days of therapy, and they should be instructed 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. Lastly, nursing women should be advised not to breastfeed while undergoing treatment with olmesartan medoxomil and hydrochlorothiazide tablets.

Storage and Handling

This product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It is essential to store the product at a temperature range of 20°-25°C (68°-77°F), in accordance with USP Controlled Room Temperature guidelines. Additionally, it is crucial to keep this product, along with all medications, out of the reach of children to ensure safety.

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.

Postmarketing experience has revealed that severe, chronic diarrhea with significant weight loss can occur in patients taking olmesartan, sometimes months to years after initiation of therapy. Intestinal biopsies in affected patients frequently show villous atrophy. If such symptoms arise during treatment, clinicians should rule out other causes and consider discontinuing olmesartan medoxomil and hydrochlorothiazide tablets if no alternative etiology is identified.

FDA Insert (PDF)

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

View full prescribing information (PDF)