Irbesartan/Hydrochlorothiazide

Description

Irbesartan is a non-peptide compound, chemically described as 2-Butyl-3-p-(O-1H-tetrazol-5-yl-phenyl)benzyl-1,3-diazaspiro-4.4non-1-en-4-one. Its empirical formula is C25H28N6O, and it has a molecular weight of 428.5 g/mol. Irbesartan appears as a white to off-white crystalline powder with a partition coefficient (octanol/water) of 10.1 at a pH of 7.4. It is slightly soluble in alcohol and methylene chloride and is practically insoluble in water.

Hydrochlorothiazide is chemically defined 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 297.74 g/mol. This compound is a white or almost white crystalline powder that is slightly soluble in water and freely soluble in sodium hydroxide solution.

Irbesartan and Hydrochlorothiazide Tablets, USP are formulated for oral administration, containing either 150 mg or 300 mg of irbesartan, USP combined with 12.5 mg or 25 mg of hydrochlorothiazide, USP. Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, ferric oxide red (150 mg/12.5 mg and 300 mg/25 mg), ferric oxide yellow (300 mg/12.5 mg), lactose, magnesium stearate, microcrystalline cellulose, and povidone.

Uses and Indications

Irbesartan and hydrochlorothiazide is indicated for the treatment of hypertension in adult patients. This combination therapy is specifically designed 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 this medication.

Dosage and Administration

The initial dosage is 150 mg of the active component combined with 12.5 mg of the adjunctive component. Based on the patient's response and tolerability, the dosage may be titrated to 300 mg of the active component with 12.5 mg of the adjunctive component. If further adjustment is necessary, the dosage may be increased to 300 mg of the active component combined with 25 mg of the adjunctive component.

For patients requiring replacement therapy, this formulation may be substituted for the titrated components as clinically appropriate. Specific details regarding the route of administration, method, and frequency are not provided; therefore, healthcare professionals should refer to standard practices for administration of similar formulations.

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 is contraindicated in patients with diabetes, as it may increase the risk of adverse effects.

Warnings and Precautions

The use of irbesartan and hydrochlorothiazide is associated with significant warnings and precautions that healthcare professionals must consider to ensure patient safety.

Fetal Toxicity It is imperative to recognize the potential for fetal toxicity associated with the use of this medication. If pregnancy is detected, irbesartan and hydrochlorothiazide should be discontinued immediately. Medications that directly affect the renin-angiotensin system have been shown to cause injury or even death to the developing fetus.

General Precautions Healthcare providers should exercise caution in the following scenarios:

• Hypotension: Prior to initiating treatment, it is essential to correct any volume depletion to mitigate the risk of hypotension.

• Impaired Renal Function: Patients with compromised renal function should be monitored closely, as the medication may exacerbate their condition.

• Systemic Lupus Erythematosus: Thiazide diuretics, such as hydrochlorothiazide, may trigger or worsen systemic lupus erythematosus in susceptible individuals.

• Ocular Conditions: There is a risk of acute angle-closure glaucoma, acute myopia, and choroidal effusion, which should be considered when prescribing this combination therapy.

While no specific laboratory tests are mandated for monitoring, healthcare professionals should remain vigilant for any signs of the aforementioned conditions and adjust treatment as necessary.

Side Effects

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

Serious warnings associated with this medication include fetal toxicity. It is imperative that irbesartan 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 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 have been noted to potentially exacerbate or activate systemic lupus erythematosus.

Other serious conditions that have been reported include acute angle-closure glaucoma, acute myopia, and choroidal effusion. Hypersensitivity reactions may occur in patients with a known sensitivity to any component of this product or to sulfonamide-derived drugs. Anuria has also been observed in some cases.

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 until further data is available.

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 effects of the medication cannot be ruled out in some older individuals. Therefore, healthcare providers should exercise caution when prescribing this combination therapy to geriatric patients, considering potential variations in response and the need for careful monitoring. Dose adjustments may be warranted based on individual patient characteristics and clinical response.

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 tablets 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 increases the fetal risk for intrauterine growth restriction and intrauterine death, necessitating careful monitoring and management of pregnant women with hypertension.

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 appropriate 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 hypotension, oliguria, hyperkalemia, and other symptoms of renal impairment. In neonates exhibiting oliguria or hypotension, attention should be directed toward supporting blood pressure and renal perfusion, with exchange transfusion or dialysis considered as potential interventions for reversing hypotension and/or addressing disordered renal function.

Thiazides, including Hydrochlorothiazide, cross the placenta, and their use during pregnancy is associated with risks of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions observed in adults. Irbesartan also crosses the placenta, as demonstrated in animal studies where pregnant rats and rabbits exhibited adverse fetal outcomes, including increased incidences of hydroureter and renal pelvic cavitation, as well as high rates of maternal mortality and abortion in rabbits. However, studies in pregnant mice and rats given Hydrochlorothiazide during major organogenesis did not show evidence of fetal harm.

Lactation

There are no available data on the presence of irbesartan in human milk, effects on milk production, or the breastfed infant. However, studies in lactating rats indicate that irbesartan or some metabolite of irbesartan is secreted in milk. Additionally, thiazides are known to appear in human milk.

Due to the potential for adverse effects on the nursing infant, the use of irbesartan and hydrochlorothiazide in breastfeeding women is not recommended.

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 advised 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 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

In the event of an overdosage, it is important to note that no specific data are available regarding human overdosage. However, clinical experience indicates that daily doses of 900 mg for 8 weeks have been well tolerated.

Expected Symptoms The most likely manifestations of overdosage include hypotension and tachycardia. Additionally, bradycardia may occur as a result of overdose. For hydrochlorothiazide, the most common signs and symptoms are associated with electrolyte depletion, which may lead to hypokalemia, hypochloremia, and hyponatremia, as well as dehydration due to excessive diuresis. If digitalis has been co-administered, hypokalemia may further exacerbate the risk of cardiac arrhythmias.

Toxicity Data Acute oral toxicity studies have demonstrated 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 based on body surface area. For hydrochlorothiazide, the oral LD50 is greater than 10 g/kg in both mice and rats, indicating a significant margin of safety in animal models.

Management Recommendations In cases 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 address the potential complications associated with electrolyte imbalances and cardiovascular effects.

Nonclinical Toxicology

No information is available regarding teratogenic effects associated with the combination of irbesartan and hydrochlorothiazide.

The combination of irbesartan and hydrochlorothiazide has not undergone carcinogenicity studies. In standard in vitro tests, including the Ames microbial test and the Chinese hamster mammalian-cell forward gene-mutation assay, the combination was found to be non-mutagenic. Additionally, it was negative in tests for the induction of chromosomal aberrations, as demonstrated in both the in vitro human lymphocyte assay and the in vivo mouse micronucleus study. Definitive studies evaluating the fertility effects of this combination have not been conducted.

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 for a duration of up to two years, showed no evidence of carcinogenicity. It was also non-mutagenic in a series of in vitro tests, including the Ames microbial test, the rat hepatocyte DNA repair test, and the V79 mammalian-cell forward gene-mutation assay. Furthermore, irbesartan did not induce chromosomal aberrations in several tests, including the in vitro human lymphocyte assay and the in vivo mouse micronucleus study. No adverse effects on fertility or mating were observed in male or female rats at oral doses of up to 650 mg/kg/day.

Hydrochlorothiazide has been evaluated in two-year feeding studies in mice and rats, revealing no evidence of carcinogenic potential 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. However, the National Toxicology Program (NTP) reported equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was also found to be non-genotoxic in vitro, as evidenced by results from the Ames mutagenicity assay and the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. In studies where mice and rats were exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation, no adverse effects on fertility were noted in either sex.

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

Patients using irbesartan and hydrochlorothiazide tablets may experience lightheadedness, particularly during the initial days of treatment. Healthcare providers should advise patients to inform their physician if they experience feelings of lightheadedness or fainting. In the event of fainting, patients should discontinue the use of irbesartan and hydrochlorothiazide tablets and contact their prescribing doctor immediately.

Patients should also be made aware that dehydration 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.

It is essential to advise patients against using potassium supplements or salt substitutes that contain potassium without first consulting their healthcare provider.

Patients should be instructed to discontinue the use of 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 counseled on the importance of protecting their skin from sun exposure and undergoing 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 20º to 25°C (68º to 77°F), 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 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. Additionally, periodic monitoring of serum electrolytes is recommended.

Patients should be counseled to discontinue the medication upon detection of pregnancy. They should be informed about the risk of hypotension and the necessity to correct any volume depletion prior to administration. It is also important to alert patients to the potential for hypersensitivity reactions, particularly those with a history of allergies or bronchial asthma. Patients should be educated on the signs of acute angle-closure glaucoma and advised to stop the medication if such symptoms arise.

FDA Insert (PDF)

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

View full prescribing information (PDF)