Irbesartan/Hydrochlorothiazide

Description

Irbesartan is a non-peptide compound, chemically described as a 2-butyl-3-p-(o-1H-tetrazol-5-ylphenyl)benzyl]-1,3-diazaspiro4.4non-1-en-4-one, with a molecular formula of C25H28N6O and a molecular weight of 428.5. It appears as a white to off-white, crystalline powder and is classified as a nonpolar compound, exhibiting a partition coefficient (octanol/water) of 10.1 at a pH of 7.4. Irbesartan is slightly soluble in alcohol and methylene chloride, while being practically insoluble in water.

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

Irbesartan and hydrochlorothiazide, USP is formulated for oral administration in film-coated tablets. These tablets are available in two combinations: either 150 mg or 300 mg of irbesartan USP combined with 12.5 mg of hydrochlorothiazide USP, or 300 mg of irbesartan USP combined with 25 mg of hydrochlorothiazide USP. The inactive ingredients in the formulation include colloidal silicon dioxide, hypromellose, iron oxide red, lactose monohydrate, polyethylene glycol, povidone, sodium stearyl fumarate, sodium starch glycolate, talc, and titanium dioxide. Additionally, the 150 mg/12.5 mg and 300 mg/12.5 mg formulations contain iron oxide yellow, while the 300 mg/25 mg formulation contains iron oxide black.

Uses and Indications

Irbesartan and hydrochlorothiazide tablets are indicated for the management of hypertension in adult patients. This combination therapy is specifically recommended for individuals who have not achieved adequate blood pressure control with monotherapy. Additionally, it may be utilized as initial therapy in patients who are anticipated to require multiple antihypertensive agents to reach their blood pressure targets.

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

Dosage and Administration

The initial dosage for the treatment is 150 mg of the primary component combined with 12.5 mg of the secondary component. Based on the patient's response and clinical judgment, the dosage may be titrated to 300 mg of the primary component with 12.5 mg of the secondary component. If further adjustment is necessary, the dosage can be increased to 300 mg of the primary component with 25 mg of the secondary component.

For patients requiring replacement therapy, this formulation may be substituted for the titrated components as clinically indicated.

The specific route of administration, method, and frequency have not been detailed in the provided information and should be determined based on standard clinical practices and individual patient needs.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with hypersensitivity to any component of the product should not use it due to the risk of severe allergic reactions. Additionally, the product is contraindicated in individuals with anuria, as it may exacerbate renal complications.

Patients with a known hypersensitivity to sulfonamide-derived drugs should avoid this product to prevent potential adverse reactions. Furthermore, coadministration of aliskiren with irbesartan and hydrochlorothiazide tablets is contraindicated in patients with diabetes, as it may increase the risk of adverse effects.

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of irbesartan and hydrochlorothiazide. It is imperative that these medications be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can lead to serious injury or death of the developing fetus (5.1, 8.1).

Healthcare professionals should be vigilant regarding the potential for hypotension in patients. It is essential to correct any volume depletion prior to the administration of these medications to mitigate this risk (5.2). Additionally, caution is warranted in patients with impaired renal function, as the use of these agents may exacerbate renal issues (5.7).

The use of thiazide diuretics, such as hydrochlorothiazide, may lead to the exacerbation or activation of systemic lupus erythematosus (5.4). Furthermore, patients should be monitored for the development of acute angle-closure glaucoma, acute myopia, and choroidal effusion, which are potential adverse effects associated with these medications (5.8).

No specific general precautions or laboratory tests have been identified in the provided information. However, healthcare providers should remain alert to any emerging concerns and ensure appropriate monitoring of patients receiving these treatments.

Side Effects

Patients may experience a range of adverse reactions while using irbesartan and hydrochlorothiazide. The most common adverse events reported include dizziness, fatigue, and musculoskeletal pain.

Serious warnings associated with this medication include fetal toxicity. It is critical to discontinue the use of irbesartan and hydrochlorothiazide 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 may also experience impaired renal function. Furthermore, thiazide diuretics, such as hydrochlorothiazide, have been noted to potentially exacerbate or activate systemic lupus erythematosus.

Other serious conditions that may arise include acute angle-closure glaucoma, acute myopia, and choroidal effusion. There is also a risk of hypersensitivity reactions to any component of the product, as well as anuria. Patients with a known hypersensitivity to sulfonamide-derived drugs should exercise caution.

It is important to note that aliskiren should not be coadministered with irbesartan and hydrochlorothiazide in patients with diabetes, as this combination may pose additional risks.

Drug Interactions

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

Packaging & NDC

The table below lists all NDC Code configurations of Irbesartan and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution, as there is insufficient data to support its use in these populations. Healthcare professionals are advised to consider the potential risks and benefits before prescribing this medication to pediatric patients.

Geriatric Use

In controlled clinical studies of hypertension involving 1,694 patients treated with irbesartan and hydrochlorothiazide, 264 patients (15.6%) were aged 65 years and older, and 45 patients (2.7%) were aged 75 years and older.

While no overall differences in safety or effectiveness were observed between elderly patients and their younger counterparts, it is important to note that greater sensitivity to the medication may be present in some older individuals. Therefore, healthcare providers should exercise caution when prescribing this combination therapy to geriatric patients. Monitoring for potential adverse effects and considering dose adjustments may be warranted to ensure optimal therapeutic outcomes in this population.

Pregnancy

Irbesartan and hydrochlorothiazide can cause fetal harm when administered to a pregnant woman. 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 increase fetal and neonatal morbidity and mortality. Therefore, when pregnancy is detected, it is recommended to discontinue irbesartan and hydrochlorothiazide as soon as possible.

All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes, regardless of drug exposure. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Hypertension during pregnancy poses additional risks, including increased maternal risk for preeclampsia, 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. Therefore, pregnant women with hypertension should be closely monitored and managed appropriately.

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 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 irbesartan and hydrochlorothiazide should be closely observed for signs of hypotension, oliguria, hyperkalemia, and other symptoms of renal impairment. In neonates experiencing oliguria or hypotension, attention should be directed toward supporting blood pressure and renal perfusion, with exchange transfusion or dialysis considered as potential interventions to address hypotension and/or substitute for impaired renal function.

Additionally, thiazides cross the placenta, and their use during pregnancy is associated with risks of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults.

Lactation

There are no specific statements regarding the use of this drug in nursing mothers or its effects on lactation. Consequently, the safety and efficacy of this medication in lactating mothers and its potential impact on breastfed infants have not been established. Healthcare professionals should consider the lack of data when advising lactating mothers on the use of this medication.

Renal Impairment

Patients with renal impairment may experience altered pharmacokinetics, necessitating careful consideration of dosing adjustments. It is essential to correct any volume depletion prior to administration to ensure optimal therapeutic outcomes. Monitoring of renal function is recommended to assess the need for further adjustments in dosing or to implement additional precautions as necessary.

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 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 the event of an overdosage, it is important to note that no specific data are available regarding human overdosage; however, daily doses of 900 mg for a duration of 8 weeks have been reported to be well tolerated.

Expected Symptoms The most likely manifestations of overdosage include hypotension and tachycardia, with the potential for bradycardia to occur as well. In cases involving hydrochlorothiazide, the most common signs and symptoms are associated with electrolyte depletion, which may present as hypokalemia, hypochloremia, and hyponatremia, alongside dehydration resulting from excessive diuresis. If digitalis has been co-administered, hypokalemia may further exacerbate the risk of cardiac arrhythmias.

Toxicity Data Acute oral toxicity studies have indicated that the acute lethal doses of irbesartan exceed 2000 mg/kg, which is approximately 25-fold to 50-fold the maximum recommended human dose (MRHD) of 300 mg when adjusted for body surface area. For hydrochlorothiazide, the oral LD50 is greater than 10 g/kg in both mice and rats, suggesting a significant margin of safety in animal models.

Management Recommendations In the case of suspected overdosage, it is crucial to seek immediate medical attention. Healthcare professionals are advised to contact a certified regional Poison Control Center for the most current information regarding the management of overdosage. Prompt intervention may be necessary to mitigate the effects of electrolyte imbalances and cardiovascular symptoms.

Nonclinical Toxicology

No teratogenic effects were observed in studies involving irbesartan and hydrochlorothiazide. Irbesartan did not exhibit adverse effects on fertility or mating in male or female rats at oral doses of up to 650 mg/kg/day, which corresponds to a systemic exposure approximately five times that seen in humans receiving the maximum recommended human dose (MRHD) of 300 mg/day. Similarly, hydrochlorothiazide did not adversely affect fertility in mice and rats of either sex when administered dietary doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

No carcinogenicity studies have been conducted specifically on the combination of irbesartan and hydrochlorothiazide. However, irbesartan was not found to be mutagenic in standard in vitro tests, including the Ames microbial test and the Chinese hamster mammalian-cell forward gene-mutation assay. Additionally, it was negative in tests for chromosomal aberrations, both in vitro using human lymphocytes and in vivo in a mouse micronucleus study. The combination has not been evaluated in definitive studies regarding fertility.

In long-term studies, no evidence of carcinogenicity was observed with irbesartan when administered at doses of up to 500 mg/kg/day for males and 1000 mg/kg/day for females in rats, and 1000 mg/kg/day in mice over a period of up to two years. For male and female rats, the 500 mg/kg/day dose provided systemic exposure approximately three and eleven times, respectively, that of humans at the MRHD of 300 mg/day. For male and female mice, the 1000 mg/kg/day dose resulted in exposures approximately three and five times, respectively, that of human exposure at 300 mg/day.

Irbesartan was also not mutagenic in a comprehensive array of in vitro tests, including the Ames microbial test, rat hepatocyte DNA repair test, and V79 mammalian-cell forward gene-mutation assay. It was consistently negative in tests for chromosomal aberrations.

Two-year feeding 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, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay across various Salmonella typhimurium strains or in the Chinese Hamster Ovary (CHO) 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 showed no genotoxicity. Positive results were noted only in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays, as well as in the Aspergillus nidulans non-disjunction assay, under specific conditions.

Postmarketing Experience

No specific postmarketing experience details are available. As such, there are no additional adverse events or rare case reports to summarize at this time.

Patient Counseling

Healthcare providers should inform female patients of childbearing age about the potential consequences of exposure to irbesartan and hydrochlorothiazide tablets during pregnancy. It is essential to discuss treatment options with women who are planning to become pregnant and to encourage patients to report any pregnancies to their physician as soon as possible.

Patients using irbesartan and hydrochlorothiazide tablets should be made aware that they may experience lightheadedness, particularly during the initial days of treatment. They should be advised to inform their physician if they feel lightheaded or faint. In the event of fainting, patients must discontinue the use of irbesartan and hydrochlorothiazide tablets and contact their prescribing doctor immediately.

It is important to educate patients about the risks of dehydration, which can lead to excessively low blood pressure, resulting in lightheadedness and potential fainting. Dehydration may occur due to excessive sweating, diarrhea, vomiting, or inadequate fluid intake.

Patients should be cautioned against using potassium supplements or salt substitutes that contain potassium without first consulting their healthcare provider.

Healthcare providers must instruct patients to discontinue irbesartan and hydrochlorothiazide tablets and seek immediate medical attention if they experience symptoms indicative of acute angle-closure glaucoma, acute myopia, or choroidal effusion.

Additionally, patients taking hydrochlorothiazide should be advised to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It is essential to store the product at a temperature range of 20ºC to 25ºC (68ºF to 77ºF), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions must be maintained to ensure the integrity and efficacy of the product.

Additional Clinical Information

Clinicians should monitor serum potassium levels in patients who are coadministered potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medications that may elevate serum potassium. Periodic monitoring of serum electrolytes is also recommended.

Postmarketing reports have indicated cases of acute angle-closure glaucoma associated with hydrochlorothiazide use. Symptoms may include a sudden decrease in visual acuity or ocular pain, typically manifesting within hours to weeks after initiation of the drug. If left untreated, acute angle-closure glaucoma can lead to permanent vision loss. The primary course of action is to discontinue the medication promptly, and if intraocular pressure remains uncontrolled, immediate medical or surgical intervention may be necessary. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing this condition.

FDA Insert (PDF)

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

View full prescribing information (PDF)