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 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 a molecular formula of C25H28N6O and a molecular weight of 428.5. It appears as a white to off-white crystalline powder, characterized as a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH 7.4. Irbesartan 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-sulfonamide1,1-dioxide, with a molecular 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.

These tablets are formulated for oral administration and are available in film-coated forms containing either 150 mg or 300 mg of irbesartan, USP, combined with 12.5 mg of hydrochlorothiazide, USP. Each dosage strength includes the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, magnesium stearate, colloidal silicon dioxide, ferric oxide red, ferric oxide yellow, polyethylene glycol, and titanium dioxide.

Uses and Indications

Irbesartan and hydrochlorothiazide tablets are indicated for the management of hypertension in adult patients. 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 the use of this medication.

Dosage and Administration

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

For patients requiring replacement therapy, this medication 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 for administration and adjust based on individual patient needs and responses.

Contraindications

Use of this product is contraindicated in the following situations:

• Patients with hypersensitivity to any component of the product.

• Patients with anuria, due to the risk of renal complications.

• Patients with hypersensitivity to sulfonamide-derived drugs, as cross-reactivity may occur.

• Coadministration of aliskiren with irbesartan and hydrochlorothiazide is contraindicated in patients with diabetes, due to the potential for adverse renal effects.

Warnings and Precautions

Fetal toxicity is a significant concern associated with the use of ibesartan and hydrochlorothiazide. 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 medications to mitigate the risk of exacerbating hypotensive episodes. Additionally, patients with impaired renal function require careful monitoring, as the use of these agents may further compromise renal status.

The use of thiazide diuretics, such as hydrochlorothiazide, may lead to the exacerbation or activation of systemic lupus erythematosus in susceptible individuals. Furthermore, there is a risk of secondary acute angle-closure glaucoma and/or acute myopia, which should be monitored in patients presenting with visual disturbances.

While no specific laboratory tests are mandated for the monitoring of patients on ibesartan and hydrochlorothiazide, healthcare providers should remain vigilant for any signs of adverse effects 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 may arise include secondary acute angle-closure glaucoma and/or acute myopia.

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 in some cases. It is important to note that aliskiren should not be coadministered with irbesartan and hydrochlorothiazide in patients with diabetes due to the risk of adverse effects.

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.

Antidiabetic medications may require dosage adjustments when used concurrently, as their effectiveness can be altered.

The use of cholestyramine and colestipol can result in reduced absorption of thiazide diuretics, which may necessitate monitoring of therapeutic efficacy and potential dose adjustments.

Lithium levels may increase when used in conjunction with certain medications, leading to a 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. Monitoring of sodium levels is recommended 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. In neonates with a history of in utero exposure to Irbesartan and Hydrochlorothiazide, if oliguria or hypotension occurs, it is crucial to provide support for blood pressure and renal perfusion. In such cases, exchange transfusions or dialysis may be necessary to reverse hypotension and/or address impaired renal function.

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 medication may be present in some older individuals. Therefore, healthcare providers should exercise caution when prescribing this combination therapy to geriatric patients. Monitoring for potential adverse effects and considering dose adjustments may be warranted to ensure optimal therapeutic outcomes in this population.

Pregnancy

The use of irbesartan and hydrochlorothiazide during pregnancy is associated with significant risks, particularly during the second and third trimesters. Pregnancy Category D indicates that there is positive evidence of risk to the fetus. Specifically, drugs that act on the renin-angiotensin system can reduce fetal renal function, leading to increased morbidity and mortality in both the fetus and neonate. Oligohydramnios, a potential consequence of such drug use, may result in fetal lung hypoplasia and skeletal deformations. Adverse neonatal outcomes may include skull hypoplasia, anuria, hypotension, renal failure, and death.

Healthcare providers are advised to discontinue irbesartan and hydrochlorothiazide as soon as pregnancy is detected. The adverse effects associated with these medications are primarily linked to their use in the later stages of pregnancy. While most epidemiologic studies have not specifically differentiated between antihypertensive agents affecting the renin-angiotensin system and other classes during the first trimester, appropriate management of maternal hypertension remains crucial for optimizing outcomes for both mother and fetus.

In cases where there are no suitable alternatives to therapy with renin-angiotensin system-affecting drugs, it is essential to inform the mother of the potential risks to the fetus. Serial ultrasound examinations should be performed to monitor the intra-amniotic environment. If oligohydramnios is detected, discontinuation of irbesartan and hydrochlorothiazide is recommended unless the treatment is deemed lifesaving for the mother. It is important to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. Infants with in utero exposure to these medications should be closely monitored for hypotension, oliguria, and hyperkalemia.

Animal studies have shown that irbesartan crosses the placenta, with pregnant rats exhibiting increased incidences of renal pelvic cavitation and other anomalies when exposed to doses exceeding the maximum recommended human dose (MRHD). In pregnant rabbits, exposure to doses equivalent to 1.5 times the MRHD resulted in high maternal mortality and abortion rates. Conversely, hydrochlorothiazide has not demonstrated evidence of fetal harm in studies conducted on pregnant mice and rats at doses significantly higher than the MRHD. A developmental toxicity study involving a combination of irbesartan and hydrochlorothiazide did not indicate increased toxicity to developing embryos, despite higher toxicity observed in the dams at elevated doses.

Given these findings, healthcare professionals should exercise caution when prescribing these medications to pregnant patients and consider the potential risks to fetal health.

Lactation

It is not known whether irbesartan is excreted in human milk; however, studies in lactating rats indicate that irbesartan or some of its metabolites are secreted at low concentrations in breast milk.

Thiazides are known to appear in human milk. Due to the potential for adverse effects on the nursing infant, healthcare professionals should consider whether to discontinue breastfeeding or to discontinue the medication, weighing the importance of the drug to the mother against the potential risks to the breastfed infant.

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 dosing accordingly to mitigate the risk of adverse effects 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 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 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 when managing an overdose. 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 of irbesartan exceed 2000 mg/kg, which is approximately 25-fold and 50-fold the maximum recommended human dose (MRHD) of 300 mg on a mg/m² basis.

Nonclinical Toxicology

Pregnancy Category D. The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with reduced fetal renal function, leading to increased fetal and neonatal morbidity and mortality. Oligohydramnios resulting from such use can contribute to fetal lung hypoplasia and skeletal deformations. Potential adverse effects in neonates may include skull hypoplasia, anuria, hypotension, renal failure, and death. It is recommended to discontinue the use of irbesartan and hydrochlorothiazide as soon as pregnancy is detected.

Thiazides are known to cross the placenta, and their use during pregnancy carries a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults.

No carcinogenicity studies have been conducted with the irbesartan-hydrochlorothiazide combination. Irbesartan-hydrochlorothiazide 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, it was negative in tests for the induction of chromosomal aberrations, both in vitro (human lymphocyte assay) and in vivo (mouse micronucleus study). The combination has not been evaluated in definitive studies regarding fertility.

Irbesartan has shown no evidence of carcinogenicity 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. It was also not mutagenic in a series of in vitro tests, including the Ames microbial test, rat hepatocyte DNA repair test, and V79 mammalian-cell forward gene-mutation assay. Irbesartan was negative in several tests for chromosomal aberrations.

Irbesartan did not adversely affect fertility or mating in male or female rats at oral doses of up to 650 mg/kg/day, which provided a systemic exposure approximately five times that found in humans receiving the maximum recommended dose of 300 mg/day.

Two-year feeding studies conducted under the auspices of the National Toxicology Program (NTP) found no evidence of carcinogenic potential for hydrochlorothiazide 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 NTP did find equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay using various strains of Salmonella typhimurium and 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 (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.

When pregnant rats were treated with irbesartan from Day 0 to Day 20 of gestation at oral doses of 50, 180, and 650 mg/kg/day, increased incidences of renal pelvic cavitation, hydroureter, and/or absence of renal papilla were observed in fetuses at doses of 50 mg/kg/day and above. Subcutaneous edema was noted in fetuses at doses of 180 mg/kg/day and higher. These anomalies were not observed in rats exposed to irbesartan during gestation days 6 to 15, indicating that they may reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg/kg/day of irbesartan were associated with maternal mortality and abortion, with surviving females showing an increase in early resorptions and a decrease in live fetuses. Irbesartan was found to cross the placental barrier in both rats and rabbits.

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, the relationship between the drug and the reported events has not been definitively established.

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 specific foods, alcohol, or other medications that could affect the efficacy or safety of the treatment.

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. Encourage patients to communicate openly with their healthcare provider about their progress and any concerns they may have.

Finally, remind patients to keep the medication out of reach of children and to store it according to the instructions provided, ensuring its safety and effectiveness.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permitted between 15° to 30°C (59° to 86°F), in accordance with USP Controlled Room Temperature 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 levels. Additionally, periodic monitoring of serum electrolytes is recommended to ensure patient safety and effective management.

FDA Insert (PDF)

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

View full prescribing information (PDF)