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 and a molecular weight of 428.5. It appears as a white to off-white crystalline powder, is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH 7.4, and is slightly soluble in alcohol and methylene chloride, but 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 and a molecular weight of 297.7. It is a white or practically white crystalline powder, slightly soluble in water, and freely soluble in sodium hydroxide solution.

Irbesartan and hydrochlorothiazide tablets 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. All dosage strengths include the following inactive ingredients: carboxymethylcellulose calcium, sodium starch glycolate, talc, povidone, colloidal silicon dioxide, and magnesium stearate. The 300/12.5 and 150/12.5 mg peach film-coated tablets also contain ferric oxide red, ferric oxide yellow, hypromellose-2910, PEG-3000, titanium dioxide, and lactose monohydrate.

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 is 150 mg of the active component combined with 12.5 mg of the adjunctive component. Based on the patient's response and clinical judgment, 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 previously used. The specific route of administration, method, and frequency have not been detailed; therefore, healthcare professionals should refer to standard practices and individual patient needs when determining these parameters.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with hypersensitivity to any component of the product should not use it, as this may lead to severe allergic reactions. Additionally, the product is contraindicated in individuals with anuria, due to the potential for exacerbating renal impairment.

Patients with a known hypersensitivity to sulfonamide-derived drugs should avoid this product, as cross-reactivity may occur. Furthermore, coadministration of aliskiren with irbesartan and hydrochlorothiazide tablets is contraindicated in patients with diabetes, due to the increased risk of adverse effects.

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of irbesartan and hydrochlorothiazide tablets. 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.

Healthcare professionals should exercise caution in patients with hypotension. It is essential to correct any volume depletion prior to the administration of these tablets to mitigate the risk of exacerbating low blood pressure. Additionally, caution is warranted in patients with impaired renal function, as the use of these medications may further compromise renal status.

Thiazide diuretics, such as hydrochlorothiazide, have been associated with the exacerbation or activation of systemic lupus erythematosus. Therefore, careful monitoring of patients with a history of this condition is advised.

Patients may also be at risk for acute angle-closure glaucoma, acute myopia, and choroidal effusion. It is crucial for healthcare providers to be vigilant for symptoms indicative of these conditions and to provide appropriate management as necessary.

While no specific laboratory tests are recommended for monitoring the use of irbesartan and hydrochlorothiazide tablets, healthcare professionals should remain attentive to the overall clinical status of their patients to ensure safe and effective treatment.

Side Effects

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

Serious warnings associated with the use of this medication include fetal toxicity, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. Therefore, it is imperative to discontinue the use of irbesartan and hydrochlorothiazide tablets as soon as pregnancy is detected.

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 reactions include acute angle-closure glaucoma, acute myopia, and choroidal effusion. Hypersensitivity reactions to any component of this product or to sulfonamide-derived drugs have also been reported. Anuria is another potential adverse reaction.

It is important to note that the coadministration of aliskiren with irbesartan and hydrochlorothiazide tablets is contraindicated in patients with diabetes.

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 tablets, 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 medication may be present in some elderly individuals. Therefore, healthcare providers should exercise caution when prescribing this medication to geriatric patients, considering potential variations in response and the need for careful monitoring. Dose adjustments may be warranted based on individual patient assessment and clinical judgment.

Pregnancy

Irbesartan and hydrochlorothiazide tablets 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 the use of 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 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 tablets 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. Animal studies have shown that irbesartan crosses the placenta in rats and rabbits, with female rats exposed to irbesartan during mating through gestation and lactation exhibiting increased incidences of hydroureter and renal pelvic cavitation and/or absence of renal papilla. Pregnant rabbits receiving oral doses of irbesartan experienced a high rate of maternal mortality and abortion, with surviving females showing a slight increase in early resorptions and a corresponding decrease in live fetuses. In contrast, 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. Thiazides, which are also components of the combination, are known to appear in human milk.

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

Renal Impairment

Patients with renal impairment may experience altered pharmacokinetics, necessitating careful consideration of dosing adjustments and monitoring. It is essential to correct any volume depletion prior to administration to ensure optimal therapeutic outcomes. For patients with reduced kidney function, healthcare professionals should refer to Section 5.7 for specific guidance on the implications of impaired renal function on treatment.

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 there is currently no available data regarding human overdosage. However, clinical experience indicates that daily doses of up to 900 mg for a duration of 8 weeks have been well tolerated.

Expected Symptoms and Manifestations The most likely manifestations of an overdose include hypotension and tachycardia. Additionally, bradycardia may occur as a result of overdose. In cases where hydrochlorothiazide is involved, the most common signs and symptoms are associated with electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration due to excessive diuresis. It is important to note that if digitalis has also been administered, hypokalemia may exacerbate cardiac arrhythmias.

Management of Overdosage Irbesartan is not removed by hemodialysis, which should be taken into consideration when managing an overdose. For acute oral toxicity, studies have indicated 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 contrast, the oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

For up-to-date information regarding the treatment of overdosage, healthcare professionals are advised to consult a certified regional Poison Control Center. This resource can provide critical guidance on the management of overdose cases and associated complications.

Nonclinical Toxicology

No carcinogenicity studies have been conducted with the combination of irbesartan and hydrochlorothiazide. In standard in vitro tests, including the Ames microbial test and the Chinese hamster mammalian-cell forward gene-mutation assay, the combination was not found to be mutagenic. Additionally, it was negative in tests for the induction of chromosomal aberrations, both in vitro using a human lymphocyte assay and in vivo in a mouse micronucleus study.

Irbesartan has been evaluated for carcinogenicity in rats and mice, with no evidence of carcinogenicity observed 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 up to two years. In these studies, male and female rats receiving 500 mg/kg/day exhibited systemic exposure to irbesartan approximately 3 and 11 times, respectively, that of humans receiving the maximum recommended human dose (MRHD) of 300 mg/day. Similarly, male and female mice receiving 1000 mg/kg/day showed exposures about 3 and 5 times, respectively, that of human exposure at the same MRHD.

Irbesartan was also evaluated in a battery of in vitro tests, including the Ames microbial test, rat hepatocyte DNA repair test, and V79 mammalian-cell forward gene-mutation assay, and was found to be non-mutagenic. It was negative in several tests for chromosomal aberrations, reinforcing the absence of mutagenic potential. Furthermore, irbesartan did not adversely affect fertility or mating in male or female rats at oral doses of up to 650 mg/kg/day, with the highest dose providing systemic exposure approximately 5 times that found in humans at the MRHD.

Hydrochlorothiazide has been assessed for carcinogenic potential in two-year feeding studies conducted by the National Toxicology Program (NTP). These studies revealed no evidence of carcinogenicity 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.

In terms of mutagenicity, hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay using 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 observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay.

Hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex in studies where these species were exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation. The combination of irbesartan and hydrochlorothiazide has not been evaluated in definitive studies of fertility.

Postmarketing Experience

No specific postmarketing experience details have been reported. 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 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 feel lightheaded or faint. In cases 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 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 various package configurations, with specific NDC numbers available upon request. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C and 30°C (59°F to 86°F) in accordance with USP guidelines. Proper container requirements must be adhered to, and special handling needs should be observed to maintain product integrity.

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 of acute angle-closure glaucoma and the importance of seeking immediate medical attention if such symptoms arise.

FDA Insert (PDF)

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

View full prescribing information (PDF)