Irbesartan/Hydrochlorothiazide

Description

Irbesartan is a non-peptide compound, chemically described as a 2-butyl-3-p-(o-1H-tetrazol-5-ylphenyl)benzyl-1,3-diazaspiro 4.4non-1-en-4-one. Its empirical formula is C25H28N6O, and it has a molecular weight of 428.5 g/mol. Irbesartan appears as a white to off-white crystalline powder and is slightly soluble in alcohol and methylene chloride, while being practically insoluble in water.

Hydrochlorothiazide is characterized 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 g/mol. It is a white or practically white crystalline powder, slightly soluble in water and freely soluble in sodium hydroxide solution.

Irbesartan and Hydrochlorothiazide Tablets USP are formulated for oral administration, available in strengths of 150 mg or 300 mg of irbesartan combined with 12.5 mg of hydrochlorothiazide, or 300 mg of irbesartan combined with 25 mg of hydrochlorothiazide. Inactive ingredients include lactose monohydrate, croscarmellose sodium, povidone, magnesium stearate, iron oxide red, and iron oxide yellow. The 300/25 mg pinkish brown film-coated tablet contains titanium dioxide, hypromellose, iron oxide black, and polyethylene glycol.

Uses and Indications

Irbesartan and Hydrochlorothiazide Tablets USP are indicated for the management of hypertension in adults. This combination therapy is specifically designed for patients who are not adequately controlled with monotherapy. Additionally, it may be utilized as initial therapy in patients who are likely to require multiple antihypertensive agents to achieve their blood pressure goals.

There are no teratogenic or nonteratogenic effects associated with 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 tolerability, the dosage may be titrated to 300 mg of the active component with 12.5 mg of the adjunctive component, and if further adjustment is necessary, to 300 mg of the active component with 25 mg of the adjunctive component.

For patients requiring replacement therapy, this formulation may be substituted for the titrated components as clinically indicated. The specific route, method, and frequency of administration are not detailed in the provided information; therefore, healthcare professionals should refer to additional prescribing information or clinical guidelines for these details.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with hypersensitivity to any component of this product, as well as those with anuria, should not use this medication. Additionally, individuals with a known hypersensitivity to sulfonamide-derived drugs are also contraindicated. Furthermore, coadministration of aliskiren with Irbesartan and Hydrochlorothiazide Tablets is contraindicated in patients with diabetes due to potential 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 tablets 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 regarding hypotension. It is essential to correct any volume depletion prior to the administration of this medication to mitigate the risk of adverse effects. Additionally, patients with impaired renal function should be closely monitored, as the use of this medication may exacerbate their condition.

The use of thiazide diuretics, such as Hydrochlorothiazide, may lead to the exacerbation or activation of systemic lupus erythematosus. Therefore, clinicians should be vigilant in monitoring patients with a history of this condition.

Furthermore, there is a risk of acute angle-closure glaucoma, acute myopia, and choroidal effusion associated with the use of this medication. Patients should be informed of these potential risks and monitored accordingly.

While no specific laboratory tests are mandated for the safe use of Irbesartan and Hydrochlorothiazide Tablets, healthcare providers should remain attentive to the overall clinical status of their patients, particularly those with the aforementioned conditions.

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 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 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 the 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 Tablets in patients with diabetes, as this may lead to further complications.

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 younger patients, 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 elderly 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 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 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 are recommended to assess the intra-amniotic environment, and fetal testing may be warranted based on 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 experiencing 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 that have been 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 or absence of renal papilla in fetuses of female rats exposed to irbesartan throughout gestation and lactation. 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 Tablets in breastfeeding women is not recommended.

Renal Impairment

Patients with renal impairment may require careful consideration regarding dosing adjustments and monitoring. It is essential to evaluate the degree of renal function reduction, as impaired renal function can significantly affect drug clearance. Healthcare professionals should assess the patient's creatinine clearance and adjust the dosage accordingly to avoid potential toxicity or subtherapeutic effects. Regular monitoring of renal function is recommended to ensure safe and effective use in this population.

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. 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. It is crucial to monitor patients for these symptoms and manage them accordingly.

Management of Overdosage Irbesartan is not removed by hemodialysis; therefore, this method is not effective in the management of overdose. For the most current information regarding the treatment of overdosage, healthcare professionals are advised to consult a certified regional Poison Control Center.

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 where hydrochlorothiazide is involved, the most common signs and symptoms of overdose are related to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. It is important to note that if digitalis has also been administered, hypokalemia may exacerbate cardiac arrhythmias.

The oral LD50 of hydrochlorothiazide has been determined to be greater than 10 g/kg in both mice and rats, indicating a significant margin of safety in animal models. However, clinical vigilance is warranted in cases of suspected overdose.

Nonclinical Toxicology

No teratogenic effects have been identified in the studies conducted. Irbesartan did not demonstrate adverse effects on fertility or mating in male or female rats at oral doses of up to 650 mg/kg/day, which 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 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 performed on the combination of irbesartan and hydrochlorothiazide. However, both agents were found to be non-mutagenic in standard in vitro tests, including the Ames microbial test and the Chinese hamster mammalian-cell forward gene-mutation assay. Additionally, the combination did not induce chromosomal aberrations in either in vitro assays using human lymphocytes or in vivo studies involving mouse micronuclei.

Irbesartan was administered at doses of up to 500 mg/kg/day for males and 1000 mg/kg/day for females in rats, and up to 1000 mg/kg/day in mice for a duration of two years, with no evidence of carcinogenicity observed. It was also negative in various in vitro tests for mutagenicity and chromosomal aberration induction.

Two-year feeding studies conducted by the National Toxicology Program (NTP) revealed no 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. However, the NTP did find equivocal evidence of hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay across several Salmonella typhimurium strains, nor 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 noted only in the in vitro CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays, as well as in the Aspergillus nidulans non-disjunction assay, under specific conditions.

The combination of irbesartan and hydrochlorothiazide has not been evaluated in definitive studies regarding fertility. No specific animal pharmacology details are available in the provided data.

Postmarketing Experience

During postapproval use of Irbesartan and Hydrochlorothiazide Tablets, various adverse reactions have been reported voluntarily or through surveillance programs. Due to the nature of these reports, which originate from a population of uncertain size, it is not always feasible to reliably estimate their frequency or establish a causal relationship to drug exposure. The inclusion of these reactions in labeling is generally based on factors such as the seriousness of the reaction, frequency of reporting, or the strength of the causal connection to the medications.

Adverse reactions associated with Irbesartan and Hydrochlorothiazide include:

Irbesartan and Hydrochlorothiazide:

• Blood and lymphatic system: Thrombocytopenia

• Hepatobiliary: Hepatitis, Jaundice

• Renal and urinary: Impaired renal function, including renal failure

• Skin and subcutaneous tissue: Urticaria

Irbesartan:

• Blood and lymphatic system: Anemia

• Ear and labyrinth: Tinnitus

• Gastrointestinal: Intestinal angioedema

• Skin and subcutaneous tissue: Angioedema (involving swelling of the face, lips, pharynx, and/or tongue)

• Immune system: Anaphylactic reaction, including anaphylactic shock

• Investigations: Increased CPK (Creatine Phosphokinase)

• Metabolism and nutrition: Hyperkalemia, Hypoglycemia in diabetic patients

Hydrochlorothiazide:

• Eye: Acute angle-closure glaucoma, acute myopia, and choroidal effusion

• Non-melanoma Skin Cancer: Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. A study conducted in the Sentinel System indicated that the increased risk was predominantly for squamous cell carcinoma (SCC) and was observed in white patients taking large cumulative doses. The overall increased risk for SCC was approximately 1 additional case per 16,000 patients per year, while for white patients taking a cumulative dose of ≥50,000 mg, the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

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 treatment options with women who are planning to become pregnant and to encourage patients 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. 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.

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.

For patients taking hydrochlorothiazide, it is crucial to advise them to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Patients should be encouraged to contact their doctor for medical advice regarding any side effects they may experience. Additionally, they may report side effects to the FDA at 1-800-FDA-1088.

For further information, patients can also reach out to Alembic Pharmaceuticals Limited at 1-866-210-9797.

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 to 30°C (59°F to 86°F) in accordance with USP guidelines. Proper storage conditions are essential to maintain 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 Alembic Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)