Irbesartan/Hydrochlorothiazide

Description

Irbesartan and hydrochlorothiazide tablets are a combination formulation consisting of irbesartan, an angiotensin II receptor antagonist (AT1 subtype), and hydrochlorothiazide (HCTZ), a thiazide diuretic. Irbesartan is a non-peptide compound with the chemical designation of 2-butyl-3-p-(o-1H-tetrazol-5-ylphenyl)benzyl-1,3-diazaspiro4.4non-1-en-4-one, exhibiting an empirical formula of C25H28N6O and a molecular weight of 428.5. It appears as a white to off-white crystalline powder, is nonpolar with a partition coefficient (octanol/water) of 10.1 at pH 7.4, and is slightly soluble in alcohol and methylene chloride, while being 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 297.7. It is presented as a white or practically white crystalline powder, slightly soluble in water and freely soluble in sodium hydroxide solution.

The tablets are formulated for oral administration and are available in film-coated forms containing either 150 mg or 300 mg of irbesartan combined with 12.5 mg of hydrochlorothiazide. Each dosage strength includes the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, magnesium stearate, polyvinyl alcohol-partially hydrolyzed, titanium dioxide, talc, macrogol/PEG 3350, lecithin, ferric oxide red, ferric oxide yellow, and ferric oxide black.

Uses and Indications

Irbesartan and hydrochlorothiazide tablets are indicated for the management of hypertension in adults. 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 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, method, and frequency of administration are not provided; therefore, healthcare professionals should refer to standard practices and guidelines for administration techniques.

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 to prevent adverse reactions. Furthermore, coadministration of aliskiren with irbesartan and hydrochlorothiazide tablets is contraindicated in patients with diabetes, as this combination may increase the risk of adverse effects.

Warnings and Precautions

The use of irbesartan and hydrochlorothiazide tablets necessitates careful consideration of several warnings and precautions 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 confirmed, irbesartan and hydrochlorothiazide tablets should be discontinued immediately. Medications that directly affect the renin-angiotensin system have been linked to serious injury or death in the developing fetus.

General Precautions Healthcare professionals should be vigilant regarding the following precautions:

• 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: The use of thiazide diuretics has been associated with the exacerbation or activation of systemic lupus erythematosus, necessitating careful patient evaluation.

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

While no specific laboratory tests are mandated for monitoring, healthcare providers should remain alert to the clinical status of patients receiving irbesartan and hydrochlorothiazide tablets, particularly those with the aforementioned risk factors.

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 the use of 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 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. Hypersensitivity reactions to any component of the product or to sulfonamide-derived drugs have also been reported. Anuria is another serious adverse reaction that may occur.

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

Drug Interactions

The concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors may diminish the diuretic and natriuretic effects of diuretics, potentially leading to an increased risk of renal impairment and a reduction in antihypertensive efficacy. It is advisable to monitor renal function periodically in patients receiving this combination.

When considering dual blockade of the renin-angiotensin system, there is an elevated risk of renal impairment, hypotension, and hyperkalemia. Close monitoring of renal function and serum potassium levels is recommended in patients undergoing this treatment.

Antidiabetic medications may require dosage adjustments when used concurrently, as their effectiveness can be influenced by the presence of other drugs.

The use of cholestyramine and colestipol can result in reduced absorption of thiazide diuretics, which may necessitate careful consideration of the timing of administration to optimize therapeutic outcomes.

Lithium levels may increase when used in conjunction with certain medications, leading to a heightened risk of lithium toxicity. Regular monitoring of serum lithium concentrations is essential to prevent adverse effects.

Carbamazepine may increase the risk of hyponatremia when used with other medications, necessitating monitoring of sodium levels to mitigate this risk.

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 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 medication 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 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 lead to increased 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. 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 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 signs of 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.

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 have shown that irbesartan crosses the placenta in rats and rabbits. In female rats administered irbesartan from prior to mating through gestation and lactation, increased incidences of hydroureter, renal pelvic cavitation, and absence of renal papilla were observed in fetuses. Additionally, subcutaneous edema occurred in fetuses at maternal doses of ≥180 mg/kg/day. However, these anomalies were not observed in pups postnatally or when irbesartan was administered only during organogenesis.

Pregnant rabbits receiving oral doses of irbesartan at 30 mg/kg/day 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. Conversely, studies in pregnant mice and rats given hydrochlorothiazide at doses up to 3000 and 1000 mg/kg/day, respectively, during their respective periods of major organogenesis did not demonstrate evidence of fetal harm.

Lactation

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 that lactating mothers discontinue the use of irbesartan and hydrochlorothiazide tablets as soon as possible.

Lactating mothers should closely observe breastfed infants who have a history of in utero exposure to irbesartan and hydrochlorothiazide tablets for signs of hypotension, oliguria, hyperkalemia, and other symptoms indicative of renal impairment. In cases where breastfed infants exhibit oliguria or hypotension, it is essential to provide support for blood pressure and renal perfusion.

It is important to note that thiazides, including hydrochlorothiazide, can cross the placenta, and their use during pregnancy has been linked to risks such as fetal or neonatal jaundice and thrombocytopenia, as well as other adverse reactions observed in adults. Additionally, irbesartan has been shown to cross the placenta in animal studies, with radioactivity detected in the fetuses of rats and rabbits during late gestation following oral doses of radiolabeled irbesartan.

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. Healthcare professionals should assess renal function and adjust treatment protocols accordingly to mitigate potential risks associated with reduced kidney function.

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 with irbesartan. However, clinical experience indicates that daily doses of up to 900 mg for a duration of 8 weeks have been well tolerated.

Potential Symptoms of Overdosage The most likely manifestations of an overdose include hypotension and tachycardia. Additionally, bradycardia may also occur as a result of overdose.

Management of Overdosage Irbesartan is not removed by hemodialysis, which should be taken into consideration during management. In cases of suspected overdose, it is advisable to consult a certified regional Poison Control Center for the most current treatment recommendations. Contact information for these centers can be found in the Physicians’ Desk Reference (PDR).

When managing an overdose, healthcare professionals should be vigilant about the potential for multiple-drug interactions, drug-drug interactions, and any unusual drug kinetics that may be present in the patient. It is important to note that laboratory determinations of serum levels of irbesartan are not widely available, and such measurements do not have an established role in the management of irbesartan overdose.

Acute oral toxicity studies conducted in mice and rats have shown that 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. This information underscores the importance of careful monitoring and management in cases of suspected overdose.

Nonclinical Toxicology

Irbesartan and hydrochlorothiazide have been evaluated for their nonclinical toxicology profile, with a focus on teratogenic effects, fertility, carcinogenicity, and mutagenicity.

No information is available regarding teratogenic effects associated with irbesartan or hydrochlorothiazide.

In terms of non-teratogenic effects, studies indicate that irbesartan does not adversely affect fertility or mating in male or female rats at oral doses up to 650 mg/kg/day. This highest dose corresponds to a systemic exposure approximately five times that observed in humans receiving the maximum recommended dose of 300 mg/day. Similarly, hydrochlorothiazide did not demonstrate adverse effects on 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 has shown no evidence of carcinogenicity when administered at doses 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. Hydrochlorothiazide also did not exhibit carcinogenic potential in two-year feeding studies conducted by the National Toxicology Program (NTP), which found 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. Nonetheless, the NTP reported equivocal evidence for hepatocarcinogenicity in male mice.

Both irbesartan and hydrochlorothiazide were 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. They were also negative in tests for chromosomal aberrations, including the in vitro human lymphocyte assay and the in vivo mouse micronucleus study. However, positive results were observed in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays for hydrochlorothiazide at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay.

Irbesartan was not mutagenic in a comprehensive 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 negative in several tests for chromosomal aberrations. The combination of irbesartan and hydrochlorothiazide has not been evaluated in definitive studies of fertility.

Postmarketing Experience

The postmarketing experience for the drug associated with SPL code 90375-7 includes reports of additional adverse events received through voluntary reporting and surveillance programs. These events encompass a range of conditions, some of which are rare and may not have been observed during clinical trials.

Healthcare professionals and patients have reported various cases, contributing to the understanding of the drug's safety profile in a broader population. The nature of these reports varies, and while they provide valuable insights, they do not establish a definitive causal relationship between the drug and the reported events.

Continued monitoring and evaluation of postmarketing data are essential to ensure ongoing safety and efficacy of the drug in the general population.

Patient Counseling

Advise patients to take the medication exactly as prescribed by their healthcare provider. It is important for patients to understand the dosage and frequency of administration to ensure optimal therapeutic outcomes.

Inform patients about the potential side effects associated with the medication. Patients should be made aware of common side effects, as well as any serious adverse reactions that may require immediate medical attention. Encourage patients to report any unusual symptoms or side effects they experience while taking the medication.

Discuss the importance of adherence to the prescribed treatment regimen. Patients should be counseled on the potential consequences of missed doses and the appropriate steps to take if a dose is forgotten.

Instruct patients to avoid certain activities or substances that may interact with the medication. This may include alcohol consumption, specific foods, or other medications that could lead to adverse effects or reduced efficacy.

Emphasize the need for regular follow-up appointments to monitor the patient's response to the medication and to make any necessary adjustments to the treatment plan. Patients should be encouraged to communicate openly with their healthcare provider about their treatment experience.

Finally, provide patients with information on how to store the medication properly, including keeping it out of reach of children and away from excessive heat or moisture.

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 20°C to 25°C (68°F to 77°F). Temporary excursions outside this range are permissible, provided they remain between 15°C and 30°C (59°F to 86°F), 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

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)