Irbesartan/Hydrochlorothiazide

Description

Irbesartan and Hydrochlorothiazide Tablets USP are a combination formulation consisting of irbesartan, an angiotensin II receptor antagonist (AT1 subtype), and hydrochlorothiazide, a thiazide diuretic. Irbesartan is chemically defined as 2-Butyl-3-p-(o-1H-tetrazol-5-ylphenyl)benzyl-1,3-diazaspiro4.4non-1-en-4-one, with a molecular weight of 428.5 and a structural formula of C25H28N6O. 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 identified as 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with a molecular weight of 297.7 and a structural formula of C7H8ClN3O4S2. It is a white or practically white, odorless crystalline powder that is very slightly soluble in water and freely soluble in sodium hydroxide solution.

These 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. Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, hypromellose, iron oxides (black, red, yellow), magnesium stearate, microcrystalline cellulose, poloxamer, polyethylene glycol, povidone, pregelatinized corn starch, and titanium dioxide.

Uses and Indications

Irbesartan and hydrochlorothiazide tablets are indicated for the management of hypertension in adults. This combination therapy is specifically recommended 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 teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

For the management of hypertension, treatment should be initiated with a dosage of 150 mg of the primary component and 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 and 12.5 mg of the secondary component. If further adjustment is necessary, the dosage may be increased to 300 mg of the primary component and 25 mg of the secondary component.

In cases of replacement therapy, this medication may be substituted for the titrated components as clinically appropriate. It is essential for healthcare professionals to monitor the patient's blood pressure and adjust the dosage accordingly to achieve optimal therapeutic outcomes.

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 function issues.

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 the potential to cause injury or death to the developing fetus.

Healthcare professionals should be aware of the following warnings associated with the use of this medication. Hypotension may occur; therefore, it is essential to correct any volume depletion prior to administration. Additionally, caution is advised in patients with impaired renal function, as this may exacerbate existing conditions. The use of thiazide diuretics has been linked to the exacerbation or activation of systemic lupus erythematosus, necessitating careful monitoring of patients with a history of this condition. Furthermore, there is a risk of acute angle-closure glaucoma, acute myopia, and choroidal effusion, which should be considered when prescribing this medication.

No specific general precautions or laboratory tests have been outlined in the provided information. However, healthcare professionals should remain vigilant and monitor patients for any adverse effects or complications associated with the use of irbesartan and hydrochlorothiazide tablets.

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 when pregnancy is detected, irbesartan and hydrochlorothiazide tablets be discontinued as soon as possible, 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 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 irbesartan and hydrochlorothiazide tablets should not be coadministered with aliskiren in patients with diabetes, as this may lead to further complications.

Drug Interactions

The concomitant use of certain drug classes may lead to significant interactions that require careful consideration and monitoring.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Selective COX-2 Inhibitors The use of NSAIDs and selective COX-2 inhibitors may diminish the diuretic and natriuretic effects of diuretics, potentially resulting in an increased risk of renal impairment and a reduced antihypertensive effect. It is advisable to monitor renal function periodically in patients receiving these combinations.

Renin-Angiotensin System Blockers Engaging in dual blockade of the renin-angiotensin system may elevate the risk of renal impairment, hypotension, and hyperkalemia. Close monitoring of renal function and serum potassium levels is recommended.

Antidiabetic Medications Patients on antidiabetic drugs may require dosage adjustments when used in conjunction with other medications. Regular monitoring of blood glucose levels is advised to ensure optimal glycemic control.

Bile Acid Sequestrants (Cholestyramine and Colestipol) The administration of cholestyramine or colestipol can lead to a reduction in the absorption of thiazide diuretics. It is recommended to separate the dosing of these agents to minimize interaction.

Lithium Concomitant use of lithium may result in increased serum lithium concentrations, raising the risk of lithium toxicity. Regular monitoring of serum lithium levels is essential to avoid adverse effects.

Carbamazepine The use of carbamazepine may increase the risk of hyponatremia. Patients should be monitored for sodium levels to prevent complications associated with low sodium concentrations.

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 geriatric patients and younger patients, 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 combination therapy to geriatric patients. Monitoring for potential adverse effects and therapeutic efficacy is recommended, and dose adjustments may be necessary based on individual patient response and tolerance.

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 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 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 indicative 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 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 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 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 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 crucial to evaluate the potential for multiple-drug interactions, drug-drug interactions, and any unusual drug kinetics that may be present in the patient.

For the most current information regarding the treatment of overdosage, healthcare professionals are advised to consult a certified regional Poison Control Center. Contact numbers for these centers can be found in the Physicians’ Desk Reference (PDR).

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 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.

Nonclinical Toxicology

Irbesartan and hydrochlorothiazide have been evaluated for their nonclinical toxicology profile, with specific attention to 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 human dose (MRHD) 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 in long-term studies where it was 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. The systemic exposure in male and female rats at 500 mg/kg/day was approximately three and eleven times, respectively, that of humans at the MRHD, while the 1000 mg/kg/day dose in females provided an exposure about twenty-one times that of humans. In 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 not found to be mutagenic in a series of in vitro tests, including the Ames microbial test and the rat hepatocyte DNA repair test, and was negative in tests for chromosomal aberrations both in vitro and in vivo. Hydrochlorothiazide also did not exhibit genotoxicity in various in vitro assays, including the Ames mutagenicity assay and tests for chromosomal aberrations. However, positive results were noted 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.

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. Nonetheless, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice.

The combination of irbesartan and hydrochlorothiazide has not been evaluated in definitive studies of fertility.

Postmarketing Experience

Postmarketing experience has identified additional adverse events reported voluntarily or through surveillance programs. These events include rare case reports of serious allergic reactions, including anaphylaxis, as well as instances of liver enzyme elevations. Reports of cardiovascular events, such as arrhythmias, have also been noted. Other adverse events include gastrointestinal disturbances, such as nausea and diarrhea, and central nervous system effects, including dizziness and headache. It is important to note that the frequency of these events is not well established, and the relationship to the drug has not been definitively determined.

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 during treatment.

Discuss the importance of adherence to the prescribed treatment regimen. Emphasize that missing doses can affect the effectiveness of the medication and may lead to complications in their condition.

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

Encourage patients to maintain regular follow-up appointments to monitor their progress and adjust treatment as necessary. This ongoing communication is vital for ensuring the safety and effectiveness of the therapy.

Remind patients to store the medication properly, keeping it out of reach of children and in accordance with the storage instructions provided. This helps prevent accidental ingestion or misuse.

Finally, advise patients to consult their healthcare provider before making any changes to their treatment plan or if they have any questions or concerns regarding their medication. Open dialogue is essential for successful management of their health condition.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with the United States Pharmacopeia (USP) standards, featuring a child-resistant closure as required. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper handling and storage conditions are essential to maintain the integrity 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 Teva Pharmaceuticals USA, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)