Irbesartan/Hydrochlorothiazide

Description

Irbesartan and hydrochlorothiazide tablets, USP are a combination of an angiotensin II receptor antagonist, irbesartan, and a thiazide diuretic, hydrochlorothiazide (HCTZ). Irbesartan, USP is a non-peptide compound, chemically described as 2-butyl-3-p-(o-1H-tetrazol-5-ylphenyl) benzyl-1,3-diazaspiro4.4non-1-en-4-one, with an empirical formula of C25H28N6O. It appears as a white to off-white crystalline powder and has a molecular weight of 428.5. Irbesartan is a nonpolar compound 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, USP is chemically identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2. This compound is a white or practically white crystalline powder with a molecular weight of 297.7. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution.

Irbesartan and hydrochlorothiazide tablets, USP are available for oral administration in film-coated tablets containing either 150 mg or 300 mg of irbesartan combined with 12.5 mg of hydrochlorothiazide. Each dosage strength includes the following inactive ingredients: mannitol, croscarmellose sodium, poloxamer 188, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol, lecithin, ferric oxide red, and ferric oxide yellow.

Uses and Indications

Irbesartan and hydrochlorothiazide tablets are indicated for the management of hypertension in adult patients. This combination therapy is appropriate for patients 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 specific teratogenic or nonteratogenic effects associated with this medication as per the available data.

Dosage and Administration

The initial dosage is 150 mg/12.5 mg. Based on the patient's response and clinical judgment, the dosage may be titrated to 300 mg/12.5 mg, and if further adjustment is necessary, to 300 mg/25 mg.

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

No specific route, method, or frequency of administration details are provided; therefore, healthcare professionals should determine the appropriate administration technique based on individual patient needs and clinical guidelines.

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

When pregnancy is detected, it is imperative to discontinue the use of irbesartan and hydrochlorothiazide tablets as soon as possible. Medications that act directly on the renin-angiotensin system have been associated with potential injury and death to the developing fetus, necessitating immediate cessation of treatment.

Healthcare professionals should exercise caution in patients with hypotension; it is essential to correct any volume depletion prior to the administration of this medication. Additionally, patients with impaired renal function require careful monitoring, as the use of thiazide diuretics may exacerbate or activate systemic lupus erythematosus.

There is also a risk of acute angle-closure glaucoma, acute myopia, and choroidal effusion associated with thiazide diuretics, which should be considered when prescribing this medication. Regular assessment of renal function and blood pressure is recommended to ensure patient safety during treatment.

Side Effects

Patients receiving irbesartan and hydrochlorothiazide tablets 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 tablets be discontinued as soon as pregnancy is detected, as drugs that act directly on the renin-angiotensin system can cause injury and death to 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 the potential to exacerbate or activate systemic lupus erythematosus. Other serious conditions that may arise 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 reported. It is important to note that aliskiren should not be coadministered with irbesartan and hydrochlorothiazide tablets in patients with diabetes.

In cases of overdose, the most likely manifestations include hypotension and tachycardia, with bradycardia also potentially occurring. The most common signs and symptoms observed in humans due to overdose are those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis.

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 geriatric patients and their younger counterparts, it is important to note that greater sensitivity to the effects of the medication in some elderly individuals cannot be ruled out. Therefore, healthcare providers should exercise caution when prescribing this combination therapy to elderly patients, considering potential variations in response and the need for careful monitoring.

Dose adjustments may be necessary based on individual patient characteristics, particularly in those who are older, to ensure optimal therapeutic outcomes while minimizing the risk of adverse effects.

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 lead to increased 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 increases the fetal risk for intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be closely monitored and managed accordingly.

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 are recommended to assess the intra-amniotic environment, and fetal testing may be appropriate based on the gestational age. It is important for patients and healthcare providers to recognize 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.

Thiazides, including hydrochlorothiazide, cross the placenta, and their use during pregnancy is associated with risks such as fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions observed in adults. Animal studies indicate that irbesartan crosses the placenta in rats and rabbits, with findings of increased incidences of hydroureter and renal pelvic cavitation, as well as absence of renal papilla in fetuses of female rats given irbesartan during gestation and lactation. Additionally, subcutaneous edema was observed in fetuses at maternal doses of ≥180 mg/kg/day. Pregnant rabbits receiving oral doses of irbesartan experienced a high rate of maternal mortality and abortion. Conversely, studies in pregnant mice and rats given hydrochlorothiazide during major organogenesis did not demonstrate 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 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 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 and Manifestations The most likely manifestations of overdosage include hypotension and tachycardia, with the potential for bradycardia to occur as well. Acute oral toxicity studies have shown that 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.

In cases of hydrochlorothiazide overdose, the predominant signs and symptoms are typically related to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has been co-administered, hypokalemia may further exacerbate the risk of cardiac arrhythmias.

Toxicity Levels The oral LD50 of hydrochlorothiazide has been established as greater than 10 g/kg in both mice and rats, indicating a significant margin of safety in animal models.

Management of Overdosage It is critical to note that irbesartan is not removed by hemodialysis, and the extent to which hydrochlorothiazide is removed by this method has not been determined. In the event of an overdosage, healthcare professionals are advised to contact a certified regional Poison Control Center for the most current information regarding treatment protocols and management strategies.

Nonclinical Toxicology

No teratogenic effects have been observed with the administration of irbesartan or hydrochlorothiazide. Irbesartan did not exhibit adverse effects on fertility or mating in male or female rats at oral doses 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 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 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, both compounds were negative in tests for the induction of chromosomal aberrations, as demonstrated in the in vitro human lymphocyte assay and the in vivo 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, while the 1000 mg/kg/day dose for females resulted in an exposure approximately twenty-one times that of humans. In male and female mice, the 1000 mg/kg/day dose provided exposures approximately three and five times, respectively, that of the human exposure at 300 mg/day.

Hydrochlorothiazide was evaluated in two-year feeding studies conducted by the National Toxicology Program (NTP), which found no evidence of carcinogenic potential 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 only observed in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

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 essential 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 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 prior consultation with 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 accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20 to 25 °C (68 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 before starting antihypertensive therapy. Awareness of potential hypersensitivity reactions is crucial, particularly for those with a history of allergies or bronchial asthma. Patients should also be educated on the signs and symptoms 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 Unichem Pharmaceuticals (USA) , Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)