Olmesartan medoxomil/Hydrochlorothiazide

Uses and Indications

Olmesartan medoxomil and hydrochlorothiazide is indicated for the treatment of hypertension, aimed at lowering blood pressure. Lowering blood pressure is associated with a reduced risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

Limitations of Use

Olmesartan medoxomil and hydrochlorothiazide is not indicated for initial therapy.

Teratogenic and Nonteratogenic Effects

No teratogenic or nonteratogenic effects are mentioned in the provided information.

Dosage and Administration

The recommended starting dose of Olmesartan Medoxomil and Hydrochlorothiazide is 40 mg/12.5 mg for patients not adequately controlled with olmesartan monotherapy and 20 mg/12.5 mg for those not adequately controlled with hydrochlorothiazide monotherapy.

Dosage adjustments may be made after 2 to 4 weeks, as necessary, with a maximum allowable dose of 40 mg of olmesartan and 25 mg of hydrochlorothiazide.

The medication is available in film-coated tablets. It is important for healthcare professionals to monitor patients' responses to therapy and adjust the dosage accordingly to achieve optimal blood pressure control.

Contraindications

Use of olmesartan medoxomil and hydrochlorothiazide is contraindicated in patients with hypersensitivity to any component of the formulation. It is also contraindicated in individuals with anuria. Additionally, co-administration of aliskiren with olmesartan medoxomil and hydrochlorothiazide is not recommended in patients with diabetes due to the associated risks.

Warnings and Precautions

WARNING: FETAL TOXICITY When pregnancy is detected, olmesartan medoxomil and hydrochlorothiazide should be discontinued as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

General Precautions

• Hypotension: Correct volume-depletion prior to administration.

• Renal Function Monitoring: Monitor renal function and potassium levels in susceptible patients.

• Fluid and Electrolyte Imbalance: Observe for signs of fluid or electrolyte imbalance.

• Acute Angle-Closure Glaucoma: Patients should be monitored for this condition.

• Sprue-like Enteropathy: This condition has been reported; consider discontinuation of olmesartan medoxomil and hydrochlorothiazide in cases where no other etiology is found.

Laboratory Tests

• Regular monitoring of renal function and potassium levels is recommended for susceptible patients.

Get Emergency Medical Help No specific instructions are provided in the text.

Stop Taking and Call Your Doctor No specific instructions are provided in the text.

Side Effects

Most common adverse reactions (incidence ≥2%) reported in patients include:

• Nausea

• Hyperuricemia

• Dizziness

• Upper respiratory infection

Warnings: Fetal Toxicity

• When pregnancy is detected, olmesartan medoxomil and hydrochlorothiazide should be discontinued as soon as possible.

• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Additional Adverse Reactions or Important Notes

• Hypotension: Correct volume-depletion prior to administration.

• Renal Function: Monitor renal function and potassium in susceptible patients.

• Fluid or Electrolyte Imbalance: Observe for signs of fluid or electrolyte imbalance.

• Acute Angle-Closure Glaucoma: Has been reported.

• Sprue-like Enteropathy: Has been reported; consider discontinuation of olmesartan medoxomil and hydrochlorothiazide in cases where no other etiology is found.

• Hypersensitivity: To any component of olmesartan medoxomil and hydrochlorothiazide.

• Anuria: Reported.

• Co-administration with Aliskiren: Do not co-administer aliskiren with olmesartan medoxomil and hydrochlorothiazide in patients with diabetes.

Overdosage Effects:

• Most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur if parasympathetic (vagal) stimulation occurs.

• Common signs and symptoms of hydrochlorothiazide overdose observed in humans include those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis.

Drug Interactions

Olmesartan Medoxomil and Hydrochlorothiazide may interact with several other medications, leading to significant clinical effects.

Pharmacokinetic Interactions

• Lithium: There is a risk of lithium toxicity when olmesartan is co-administered with lithium-containing products. Monitoring of lithium levels is recommended.

• Colesevelam Hydrochloride: It is advised to administer olmesartan at least 4 hours before colesevelam hydrochloride to avoid reduced absorption.

• Cholestyramine and Colestipol: These agents may reduce the absorption of thiazides, which could affect the efficacy of olmesartan.

Pharmacodynamic Interactions

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The use of NSAIDs may lead to reduced diuretic, natriuretic, and antihypertensive effects of olmesartan, as well as an increased risk of renal toxicity.

• Dual Inhibition of the Renin-Angiotensin System: Co-administration with other agents that inhibit the renin-angiotensin system may increase the risk of renal impairment, hypotension, and hyperkalemia.

• Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used in conjunction with olmesartan.

• Agents Increasing Potassium Levels: Co-administration with agents that increase potassium levels may lead to elevated serum potassium levels, necessitating monitoring.

These interactions highlight the importance of careful medication management and monitoring when prescribing olmesartan medoxomil and hydrochlorothiazide in conjunction with other therapies.

Pediatric Use

Neonates with a history of in utero exposure to olmesartan medoxomil and hydrochlorothiazide may experience oliguria or hypotension. In such cases, it is crucial to provide support for blood pressure and renal perfusion. Exchange transfusions or dialysis may be necessary to reverse hypotension and address disordered renal function.

The safety and effectiveness of olmesartan medoxomil and hydrochlorothiazide in pediatric patients have not been established.

Geriatric Use

Clinical studies of olmesartan medoxomil and hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

In general, dose selection for elderly patients should be cautious, typically starting at the low end of the dosing range. This approach reflects the greater frequency of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in this population.

Olmesartan and hydrochlorothiazide are substantially excreted by the kidneys, and the risk of toxic reactions may be greater in patients with impaired renal function. Therefore, careful monitoring and potential dose adjustments are recommended for geriatric patients, particularly those with renal impairment.

Pregnancy

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

When pregnancy is detected, olmesartan medoxomil and hydrochlorothiazide should be discontinued as soon as possible, and alternative antihypertensive therapies should be considered. The estimated background risk of major birth defects and miscarriage in the U.S. general population is approximately 2% to 4% and 15% to 20%, respectively. Pregnant patients with hypertension are at increased risk for complications such as pre-eclampsia, gestational diabetes, and delivery complications, which necessitates careful monitoring and management.

Serial ultrasound examinations are recommended to assess the intra-amniotic environment, and fetal testing may be warranted based on gestational age. It is important to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. Infants with in utero exposure to olmesartan medoxomil and hydrochlorothiazide should be closely monitored for hypotension, oliguria, and hyperkalemia. If these conditions arise, measures to maintain adequate blood pressure and renal perfusion should be implemented, which may include exchange transfusions or dialysis.

Thiazides, including hydrochlorothiazide, can cross the placenta, achieving concentrations in the umbilical vein that are comparable to maternal plasma levels. Hydrochlorothiazide may cause placental hypoperfusion and can accumulate in amniotic fluid, with concentrations reported to be up to 19 times higher than in umbilical vein plasma. The use of thiazides during pregnancy is also associated with risks of fetal or neonatal jaundice and thrombocytopenia. Given that thiazides do not prevent or alter the course of preeclampsia, their use for treating hypertension in pregnant women is not recommended, and alternative therapies should be sought.

Lactation

It is not known whether olmesartan is excreted in human milk; however, studies indicate that olmesartan is secreted at low concentrations in the milk of lactating rats. Hydrochlorothiazide, a component of the combination, is known to appear in human milk. Due to the potential for adverse effects on breastfed infants, healthcare providers should carefully consider whether to discontinue breastfeeding or to discontinue olmesartan medoxomil and hydrochlorothiazide therapy, weighing the importance of the medication to the mother.

There is limited information regarding the effects of olmesartan medoxomil and hydrochlorothiazide on breastfed infants or on milk production. Given the potential risks, it is advisable to inform nursing mothers that breastfeeding is not recommended during treatment with this medication.

Renal Impairment

Patients with renal impairment should be closely monitored for renal function and potassium levels, particularly those who are susceptible to changes in these parameters. It is essential to correct any volume depletion prior to the administration of Olmesartan Medoxomil and Hydrochlorothiazide. Additionally, healthcare providers should observe patients for signs of fluid or electrolyte imbalance throughout the treatment process.

Regular assessment of renal function is crucial to ensure the safe use of this medication in patients with compromised kidney function. Adjustments to dosing may be necessary based on the patient's renal status, although specific dosing adjustments are not detailed in the provided data. Therefore, careful clinical judgment is advised when managing these patients.

Hepatic Impairment

Patients with hepatic impairment have no specific dosage adjustments, special monitoring requirements, or precautions outlined for the use of Olmesartan Medoxomil and Hydrochlorothiazide, including its formulations as Benicar Hct. The available data does not provide any information regarding the safety or efficacy of these medications in this patient population. Therefore, healthcare providers should exercise caution and consider individual patient factors when prescribing these medications to patients with liver problems.

Overdosage

Limited data are available regarding the overdosage of olmesartan medoxomil in humans. The most likely manifestations of overdosage include hypotension and tachycardia; bradycardia may occur if parasympathetic (vagal) stimulation is present. In cases of symptomatic hypotension, supportive treatment should be initiated. The dialyzability of olmesartan is currently unknown.

Acute toxicity studies in mice and rats have shown no lethality with single oral doses of olmesartan medoxomil up to 2000 mg/kg. The minimum lethal oral dose in dogs is greater than 1500 mg/kg.

For hydrochlorothiazide, the most common signs and symptoms of overdose observed in humans are primarily due to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias. The extent to which hydrochlorothiazide is removed by hemodialysis has not been established, and the oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

Nonclinical Toxicology

Teratogenic Effects

No teratogenic effects were observed when combinations of olmesartan medoxomil and hydrochlorothiazide in a 1.6:1 ratio were administered to pregnant mice at oral doses up to 1625 mg/kg/day (122 times the maximum recommended human dose MRHD on a mg/m² basis) or to pregnant rats at oral doses up to 1625 mg/kg/day (280 times the MRHD on a mg/m² basis). However, in rats, fetal body weights at 1625 mg/kg/day (a toxic, sometimes lethal dose in the dams) were significantly lower than control. 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 (40 mg olmesartan medoxomil / 25 mg hydrochlorothiazide/day).

Non-Teratogenic Effects

Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in studies where dosing commenced 2 weeks (females) or 9 weeks (males) prior to mating. Hydrochlorothiazide also demonstrated no adverse effects on the fertility of mice and rats of either sex when these species were exposed, via their diet, to doses of up to 100 mg/kg (mice) and 4 mg/kg (rats), respectively, prior to mating and throughout gestation. No studies of impairment of fertility with olmesartan medoxomil and hydrochlorothiazide have been conducted.

Nonclinical Toxicology

No carcinogenicity studies with olmesartan medoxomil and hydrochlorothiazide have been conducted. 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 up to the maximum recommended plate concentration for standard assays. Both compounds were tested individually and in combination ratios of 40:12.5, 20:12.5, and 10:12.5 for clastogenic activity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay, where a positive response was observed for each component and combination ratio. However, no synergism in clastogenic activity was detected between olmesartan medoxomil and hydrochlorothiazide at any combination ratio.

In vivo, olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio, administered orally, tested negative in the mouse bone marrow erythrocyte micronucleus assay at administered doses of up to 3144 mg/kg.

Olmesartan medoxomil was not carcinogenic when administered by dietary administration to rats for up to 2 years, with the highest dose tested being 2000 mg/kg/day (approximately 480 times the MRHD). Two carcinogenicity studies conducted in mice, including a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan medoxomil.

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 (bacterial mutagenicity) test. However, both compounds induced chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay.

Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney, and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested).

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538, or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. It was also not 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 test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) assay, the Mouse Lymphoma Cell (mutagenicity) assay, and the Aspergillus nidulans non-disjunction assay.

Storage and Handling

Olmesartan Medoxomil and Hydrochlorothiazide is supplied in tablet form, specifically as film-coated tablets. The product is packaged in plastic bottles containing 90 tablets each.

The recommended storage conditions for this product are at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature guidelines. It is essential to keep this and all medications out of the reach of children. When dispensing, the product should be placed in a tight, light-resistant container that complies with USP standards and includes a child-resistant closure.