Olmesartan medoxomil/Hydrochlorothiazide

Description

Olmesartan medoxomil and hydrochlorothiazide tablets are a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a thiazide diuretic, hydrochlorothiazide (HCTZ). 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 to light yellowish-white powder or crystalline powder and is practically insoluble in water, with sparing solubility in methanol.

Hydrochlorothiazide is identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, having an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.7. It is a white, or practically white, crystalline powder that is practically odourless, slightly soluble in water, and freely soluble in sodium hydroxide solution.

These tablets are formulated for oral administration and are 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 hydroxypropylcellulose, hypromellose, lactose monohydrate, low-substituted hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, iron oxide red, talc, titanium dioxide, polyethylene glycol, and iron oxide yellow.

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.

There are no teratogenic or nonteratogenic effects associated with 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.

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 patients with hypersensitivity to any component of the formulation. Additionally, the medication should not be used in individuals with anuria, as this condition may exacerbate renal impairment. Co-administration of aliskiren with olmesartan medoxomil and hydrochlorothiazide tablets is contraindicated in patients with diabetes due to the potential for adverse effects on renal function.

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. It is essential to correct any volume depletion prior to initiation 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 olmesartan medoxomil and hydrochlorothiazide tablets. Furthermore, cases of sprue-like enteropathy have been reported; therefore, consideration should be given to discontinuing the medication if no other etiology for gastrointestinal symptoms is identified.

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

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 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. In cases where no other etiology is identified, discontinuation of olmesartan medoxomil and hydrochlorothiazide tablets should be considered. Hypersensitivity reactions to any component of the medication 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.

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

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

Pregnancy Category D. 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 potential death. Oligohydramnios resulting from such drug use can lead to fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, olmesartan medoxomil and hydrochlorothiazide tablets should be discontinued as soon as possible. These adverse outcomes are primarily linked to the use of these medications during the second and third trimesters. Most epidemiologic studies examining fetal abnormalities following antihypertensive use in the first trimester have not differentiated between drugs affecting the renin-angiotensin system and other antihypertensive agents.

Appropriate management of maternal hypertension during pregnancy is crucial to optimize outcomes for both the mother and fetus. In cases where there is no suitable alternative to therapy with renin-angiotensin system-affecting drugs, healthcare providers should inform the mother of the potential risks to the fetus. Serial ultrasound examinations should be performed to assess the intraamniotic environment, and if oligohydramnios is observed, olmesartan medoxomil and hydrochlorothiazide tablets should be discontinued unless deemed lifesaving for the mother.

Fetal testing may be warranted based on the gestational age. It is important for patients and healthcare providers to recognize 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 hypotension, oliguria, and hyperkalemia.

Lactation

It is not known whether olmesartan is excreted in human milk; however, olmesartan is secreted at low concentrations in the milk of lactating rats. Thiazides, which are components of olmesartan medoxomil and hydrochlorothiazide tablets, 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 the drug to the mother when making a decision to either discontinue nursing or discontinue the use of 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

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 stimulation.

In the event of symptomatic hypotension, it is recommended that supportive treatment be initiated to manage the condition effectively. The dialyzability of olmesartan medoxomil remains unknown, which may influence the management approach in cases of overdose.

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 canine studies, the minimum lethal oral dose was determined 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 are primarily due to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. It is important to note that if digitalis has also been administered, hypokalemia may exacerbate the risk of cardiac arrhythmias.

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 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 dosage 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. In vitro testing revealed that olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio were negative in the Salmonella-Escherichia coli/mammalian microsome reverse mutation test. Additionally, clastogenic activity was assessed in the in vitro Chinese hamster lung chromosomal aberration assay, where positive responses were observed for each component and combination ratio tested. However, no synergistic clastogenic activity was detected 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.

Olmesartan medoxomil was not found to be carcinogenic in a two-year dietary study in rats at doses up to 2000 mg/kg/day, which is 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 showed 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 tested 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 did find 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. It also did not exhibit genotoxicity 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 obtained 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. Patients should be instructed 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 tablets. Additionally, patients should be made aware that lightheadedness may occur, particularly during the initial days of therapy, and they should report this symptom to their healthcare provider.

Patients must 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.

Healthcare providers should caution patients against using potassium supplements or salt substitutes that contain potassium without prior consultation. Patients should also 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, it is essential to advise patients 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 temperature range of 20°C to 25°C (68°F to 77°F), adhering to the guidelines set forth by the United States Pharmacopeia (USP) for Controlled Room Temperature. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Clinicians should periodically monitor renal function in patients whose renal status may be influenced by the renin-angiotensin system, as well as assess serum electrolytes and calcium levels. In cases of hypotension, patients should be positioned supine and may require intravenous normal saline. For acute angle-closure glaucoma, it is critical to discontinue hydrochlorothiazide promptly, and further medical or surgical intervention may be necessary if intraocular pressure remains elevated.

Postmarketing reports indicate that severe, chronic diarrhea with significant weight loss has occurred in patients taking olmesartan, sometimes months to years after initiation of therapy. Intestinal biopsies in these cases frequently reveal villous atrophy.

FDA Insert (PDF)

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

View full prescribing information (PDF)