Benicar Hct

Description

BENICAR HCT (olmesartan medoxomil and hydrochlorothiazide) is a pharmaceutical formulation that combines an angiotensin II receptor antagonist, olmesartan medoxomil, with 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, which is 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. This compound is a white or practically white crystalline powder, slightly soluble in water and freely soluble in sodium hydroxide solution.

BENICAR HCT 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. The tablets contain inactive ingredients including hydroxypropylcellulose, hypromellose, lactose monohydrate, low-substituted hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, red iron oxide, talc, titanium dioxide, and yellow iron oxide.

Uses and Indications

BENICAR HCT is indicated for the treatment of hypertension to lower blood pressure. Effective management of blood pressure 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 BENICAR HCT.

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 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 previous treatment history and response to therapy.

Contraindications

Use of BENICAR HCT is contraindicated in patients with hypersensitivity to any component of the formulation. Additionally, the drug should not be administered to patients with anuria. Co-administration of aliskiren with BENICAR HCT is contraindicated in patients with diabetes due to potential adverse effects.

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of BENICAR HCT. It is imperative that the medication be discontinued as soon as pregnancy is detected, as drugs that directly affect the renin-angiotensin system may lead to serious injury or death in the developing fetus.

In terms of general precautions, it is essential to correct any volume depletion prior to the administration of BENICAR HCT 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 also a risk of acute angle-closure glaucoma, which necessitates careful patient assessment. Furthermore, cases of sprue-like enteropathy have been reported; therefore, consideration should be given to discontinuing BENICAR HCT in instances where no other etiology for gastrointestinal symptoms can be identified.

Regular laboratory tests to monitor renal function and potassium levels are advised for patients at risk, ensuring timely identification and management of potential adverse effects.

Side Effects

Patients receiving BENICAR HCT 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 adverse reactions include warnings regarding fetal toxicity. It is imperative that BENICAR HCT 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. There have also been reports of acute angle-closure glaucoma and sprue-like enteropathy; in cases where no other etiology is identified, discontinuation of BENICAR HCT should be considered. Hypersensitivity reactions to any component of BENICAR HCT have been noted, as well as instances of anuria.

It is also important to note that aliskiren should not be co-administered with BENICAR HCT in patients with diabetes, as this may exacerbate adverse effects. Patients should be observed for signs of fluid or electrolyte imbalance during treatment.

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 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 with 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 recommended.

Pharmacokinetic Interactions

• Colesevelam Hydrochloride: It is advisable to administer olmesartan at least 4 hours prior to the dose of colesevelam hydrochloride to minimize potential interactions.

• Cholestyramine and Colestipol: These agents may reduce the absorption of thiazide diuretics. Monitoring of blood pressure and renal function is recommended, and dosage adjustments may be necessary.

• Antidiabetic Drugs: Co-administration may necessitate dosage adjustments of antidiabetic medications. Close monitoring of blood glucose levels is recommended to ensure effective glycemic control.

Packaging & NDC

The table below lists all NDC Code configurations of Benicar Hct (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 BENICAR HCT, may require careful monitoring. In cases of oliguria or hypotension, it is essential to support 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 BENICAR HCT in pediatric patients have not been established, indicating a need for caution when considering its use in this population.

Geriatric Use

Clinical studies of BENICAR HCT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported clinical experience has not identified significant differences in responses between elderly patients and younger patients.

In general, dose selection for geriatric 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 to BENICAR HCT in patients with impaired renal function. Therefore, careful monitoring of renal function is recommended in elderly patients to mitigate potential risks associated with this medication.

Pregnancy

The use of BENICAR HCT during pregnancy is associated with significant risks, particularly during the second and third trimesters. It is classified as Pregnancy Category D, indicating that there is positive evidence of risk to the fetus. Drugs that act on the renin-angiotensin system can lead to reduced fetal renal function, resulting in increased morbidity and mortality for both the fetus and neonate.

Oligohydramnios, a potential consequence of such drug use, may be linked to fetal lung hypoplasia and skeletal deformations. Adverse neonatal effects may include skull hypoplasia, anuria, hypotension, renal failure, and death. Therefore, when pregnancy is detected, it is crucial to discontinue BENICAR HCT as soon as possible.

Most epidemiologic studies assessing fetal abnormalities following antihypertensive exposure in the first trimester have not specifically differentiated between drugs affecting the renin-angiotensin system and other antihypertensive agents. Nonetheless, appropriate management of maternal hypertension during pregnancy is essential 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 monitor the intraamniotic environment, and if oligohydramnios is detected, BENICAR HCT should be discontinued unless it is deemed lifesaving for the mother.

Fetal testing may be warranted depending on the gestational age. 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 BENICAR HCT 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 are known to appear in human milk.

Due to the potential for adverse effects on the nursing infant, lactating mothers should make a decision regarding the continuation of breastfeeding or the discontinuation of BENICAR HCT, considering 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 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 potential symptoms and manage them accordingly in cases of suspected overdosage.

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 and 280 times the maximum recommended human dose (MRHD) on a mg/m² basis for mice and rats, respectively. 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 BENICAR HCT.

Fertility assessments in rats indicated that administration of olmesartan medoxomil at doses as high as 1000 mg/kg/day, initiated two weeks prior to mating for females and nine weeks for males, did not adversely affect reproductive capabilities. Similarly, hydrochlorothiazide did not demonstrate any negative impact 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 with olmesartan medoxomil and hydrochlorothiazide. In mutagenicity testing, olmesartan medoxomil and hydrochlorothiazide in a 20:12.5 ratio were negative in the Salmonella-Escherichia coli/mammalian microsome reverse mutation test. When tested individually and in various combinations for clastogenic activity in the in vitro Chinese hamster lung chromosomal aberration assay, a positive response was observed for each component and combination ratio, although no synergistic clastogenic activity was detected. In vivo testing in the mouse bone marrow erythrocyte micronucleus assay at doses up to 3144 mg/kg also yielded negative results.

Olmesartan medoxomil was not found to be carcinogenic in a two-year dietary study in rats, with the highest tested dose being 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 at doses up to 1000 mg/kg/day, revealed no evidence of carcinogenic effects. Both olmesartan medoxomil and hydrochlorothiazide tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no 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 mouse bone marrow 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, 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. In vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also indicated a lack of genotoxicity. 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

Postmarketing experience has identified a potential association between hydrochlorothiazide and non-melanoma skin cancer. It is recommended that patients receiving hydrochlorothiazide be advised to take protective measures against sun exposure and to participate in regular skin cancer screenings.

Patient Counseling

Healthcare providers should advise female patients of childbearing age about the potential consequences of exposure to BENICAR HCT 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 BENICAR HCT 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

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 starting the medication. Intestinal biopsies from affected patients frequently show villous atrophy.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Benicar Hct as submitted by Cosette Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)