Olmesartan medoxomil/Hydrochlorothiazide

Description

Olmesartan medoxomil and hydrochlorothiazide is a fixed-dose 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, 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 an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.7. It is presented as a white or practically white crystalline powder, slightly soluble in water and freely soluble in sodium hydroxide solution.

This combination is formulated for oral administration in tablet form, 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 hydroxypropylcellulose, hypromellose, lactose monohydrate, low-substituted hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, red iron oxide, talc, titanium dioxide, and yellow iron oxide.

Uses and Indications

Olmesartan medoxomil and hydrochlorothiazide is indicated for the treatment of hypertension to lower blood pressure. Effective management of hypertension is essential, as lowering blood pressure reduces the risk of both fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

Limitations of Use: This combination therapy is intended for use in patients whose blood pressure is not adequately controlled with monotherapy.

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 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 impairment.

Co-administration of aliskiren with olmesartan medoxomil and hydrochlorothiazide 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 should be discontinued immediately. Medications that act directly on the renin-angiotensin system have been associated with fetal toxicity, potentially leading to injury or death of the developing fetus.

General precautions must 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, olmesartan medoxomil and hydrochlorothiazide should be considered for discontinuation if no other etiology for gastrointestinal symptoms is identified.

Regular laboratory tests to monitor renal function and potassium levels are advised for patients at risk. This proactive approach will help ensure patient safety and the effective management of potential adverse effects.

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 of clinical significance 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 of sprue-like enteropathy, discontinuation of the medication should be considered if no other etiology is identified. Hypersensitivity reactions to any component of olmesartan medoxomil and hydrochlorothiazide have been noted, as well as anuria.

It is also important to note that aliskiren should not be co-administered with olmesartan medoxomil and hydrochlorothiazide in patients with diabetes. In neonates with a history of in utero exposure, if oliguria or hypotension occurs, immediate attention should be directed toward supporting blood pressure and renal perfusion, with exchange transfusions or dialysis potentially required to reverse hypotension and address disordered renal function.

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 recommended to avoid potential 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 of agents that 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 advised.

Pharmacokinetic Interactions

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

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

• Cholestyramine and Colestipol: The absorption of thiazide diuretics may be reduced when taken with cholestyramine or colestipol. It is advisable to monitor the therapeutic effects of thiazides and consider adjusting the dosing regimen if necessary.

Packaging & NDC

The table below lists all NDC Code configurations of Olmesartan Medoxomil-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, may experience complications such as oliguria or hypotension. In such cases, it is crucial to provide support for blood pressure and renal perfusion, which may necessitate interventions such as exchange transfusions or dialysis to address hypotension and restore renal function.

The safety and effectiveness of olmesartan medoxomil and hydrochlorothiazide 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 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.

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 and potential dose adjustments may be necessary for geriatric patients to mitigate these risks.

Pregnancy

The use of olmesartan medoxomil and hydrochlorothiazide during pregnancy is associated with significant risks, particularly during the second and third trimesters. This combination is classified as Pregnancy Category D, indicating evidence of risk to the fetus. Drugs that act on the renin-angiotensin system can lead to reduced fetal renal function, resulting in oligohydramnios, which may be linked to fetal lung hypoplasia and skeletal deformations. Adverse neonatal outcomes may include skull hypoplasia, anuria, hypotension, renal failure, and even death.

Healthcare providers are advised to discontinue olmesartan medoxomil and hydrochlorothiazide as soon as pregnancy is detected. The adverse effects associated with these medications are primarily observed when used in the later stages of pregnancy. While most epidemiologic studies have not specifically differentiated the effects of renin-angiotensin system inhibitors from other antihypertensive agents during the first trimester, appropriate management of maternal hypertension remains crucial for optimizing outcomes for both the mother and fetus.

In cases where there is no suitable alternative to therapy with renin-angiotensin system-affecting drugs, it is essential to inform the patient of the potential risks to the fetus. Serial ultrasound examinations should be performed to monitor the intraamniotic environment, and if oligohydramnios is detected, discontinuation of the medication is recommended unless it 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 should be closely monitored for signs of hypotension, oliguria, and hyperkalemia. Fetal testing may also be warranted, depending 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, which are components of the combination product, are known to appear in human milk.

Due to the potential for adverse effects on the nursing infant, healthcare professionals should consider the risks and benefits when advising lactating mothers. A decision should be made whether to discontinue nursing or to discontinue olmesartan medoxomil and hydrochlorothiazide, taking into account the importance of the medication to the mother.

Renal Impairment

Patients with renal impairment should have their renal function and potassium levels monitored, particularly in those with reduced kidney function. Dosing adjustments may be necessary based on the degree of 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 (vagal) stimulation. In the event of symptomatic hypotension, it is essential to initiate supportive treatment. The dialyzability of olmesartan medoxomil remains unknown, which may impact management strategies.

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 these animal models.

In contrast, the most common signs and symptoms associated with hydrochlorothiazide overdose 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 the risk of 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, suggesting a significant margin of safety in these species.

Healthcare professionals should remain vigilant for these potential symptoms and manage overdoses accordingly, ensuring appropriate supportive care and monitoring of electrolyte levels.

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.

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 the combination of olmesartan medoxomil and hydrochlorothiazide. However, olmesartan medoxomil was not found to be carcinogenic in a two-year dietary study in rats at the highest tested dose of 2000 mg/kg/day, approximately 480 times the MRHD. In two separate carcinogenicity studies in mice, including a 6-month gavage study in p53 knockout mice and a 6-month dietary study in Hras2 transgenic mice, doses up to 1000 mg/kg/day (about 120 times the MRHD) showed no evidence of carcinogenic effects.

In mutagenicity assessments, olmesartan medoxomil and hydrochlorothiazide were negative in the Salmonella-Escherichia coli/mammalian microsome reverse mutation test. Both compounds tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames test. However, they 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.

Animal studies conducted by the National Toxicology Program (NTP) revealed 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, equivocal evidence for hepatocarcinogenicity was noted 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 or Chinese hamster bone marrow chromosomes. 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. No studies of impairment of fertility with olmesartan medoxomil and hydrochlorothiazide have been conducted.

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 during pregnancy. It is important to discuss treatment options with women who are planning to become pregnant and to encourage patients 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. They should be instructed to report this symptom to their healthcare provider. Additionally, patients should be made 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.

Patients must be cautioned against using potassium supplements or salt substitutes that contain potassium without prior consultation with their healthcare provider.

Healthcare providers should instruct patients to discontinue olmesartan medoxomil and hydrochlorothiazide and seek immediate medical attention if they experience symptoms indicative of acute myopia or secondary angle-closure glaucoma.

For patients taking hydrochlorothiazide, it is essential to advise them 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 controlled room temperature of 20-25ºC (68-77ºF), as defined by the United States Pharmacopeia (USP) guidelines. Proper storage conditions are essential to maintain 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-Hydrochlorothiazide as submitted by AvKARE. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)