Irbesartan/Hydrochlorothiazide

Description

Irbesartan and hydrochlorothiazide tablets are a combination 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, having 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 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 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 in film-coated forms, available in two dosage strengths: 150 mg of irbesartan combined with 12.5 mg of hydrochlorothiazide, and 300 mg of irbesartan combined with 25 mg of hydrochlorothiazide. Each dosage strength contains 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. Additionally, the 300/25 mg film-coated tablets include FD&C Blue #2/Indigo Carmine Aluminum Lake.

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 for the treatment 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, 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, the medication may be substituted for the titrated components as clinically indicated.

The specific route, method, and frequency of administration have not been 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 patients with hypersensitivity to any component of the formulation. Additionally, it should not be administered to individuals with anuria, as this condition may exacerbate renal function.

Patients with a known hypersensitivity to sulfonamide-derived drugs should also avoid this product due to the potential for cross-reactivity. 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

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 been associated with potential injury and death to 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 this medication to mitigate the risk of exacerbating low blood pressure.

Patients with impaired renal function require careful monitoring, as the use of this combination therapy may pose additional risks. Furthermore, thiazide diuretics, such as hydrochlorothiazide, have been known to potentially exacerbate or activate systemic lupus erythematosus, necessitating vigilance in patients with a history of this condition.

There is also a risk of secondary acute angle-closure glaucoma and/or acute myopia associated with the use of thiazide diuretics. Patients should be monitored for any visual disturbances or symptoms indicative of these conditions.

While no specific laboratory tests are mandated for the safe use of irbesartan and hydrochlorothiazide tablets, healthcare providers should remain alert to the clinical status of their patients and adjust treatment as necessary based on individual health parameters.

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. 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 the potential to exacerbate or activate systemic lupus erythematosus. Other serious reactions include secondary acute angle-closure glaucoma and/or acute myopia, as well as hypersensitivity reactions to any component of the product or to sulfonamide-derived drugs. Anuria has also been reported.

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

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 influenced by the presence of other drugs.

The use of cholestyramine and colestipol can result in reduced absorption of thiazide diuretics, which may necessitate adjustments in therapy to maintain desired therapeutic outcomes.

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 agents, necessitating careful monitoring of sodium levels in patients receiving this combination.

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 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 lead to increased 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. 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 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 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 observed in adults. Animal studies have shown that irbesartan crosses the placenta in rats and rabbits. In female rats administered irbesartan prior to mating through gestation and lactation, increased incidences of hydroureter and renal pelvic cavitation, as well as absence of renal papilla, were observed in fetuses. 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. Conversely, studies in pregnant mice and rats given hydrochlorothiazide during major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, did not demonstrate evidence of fetal harm.

Lactation

Irbesartan and hydrochlorothiazide are known to cross the placenta and may pose risks to the fetus when administered to pregnant women. 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 morbidity and mortality in both fetuses and neonates. Therefore, it is recommended that irbesartan and hydrochlorothiazide tablets be discontinued as soon as pregnancy is detected.

Lactating mothers should be aware that infants with a history of in utero exposure to irbesartan and hydrochlorothiazide should be closely monitored for signs of hypotension, oliguria, hyperkalemia, and other symptoms indicative of renal impairment. In cases where these symptoms are observed, immediate attention should be directed toward supporting blood pressure and renal perfusion.

Additionally, thiazides, including hydrochlorothiazide, have been associated with risks such as fetal or neonatal jaundice and thrombocytopenia when used during pregnancy. While specific data on the excretion of irbesartan and hydrochlorothiazide in human breast milk are not provided, the potential for adverse effects in breastfed infants should be considered, particularly in those with a history of in utero exposure.

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 and minimize the risk of adverse effects.

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 overdosage in humans. 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 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 demonstrated no adverse effects on 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 observed in humans receiving the maximum recommended dose of 300 mg/day. Hydrochlorothiazide also showed no adverse effects on fertility in both male and female mice and rats 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 conducted specifically for the combination of irbesartan and hydrochlorothiazide. However, irbesartan was not found to be carcinogenic when administered at doses of up to 500 mg/kg/day for males and 1000 mg/kg/day for females in rats, and at 1000 mg/kg/day in mice over a period of up to two years. Hydrochlorothiazide also exhibited no evidence of carcinogenic potential in two-year feeding studies conducted by the National Toxicology Program (NTP) in female mice at doses of up to approximately 600 mg/kg/day and in male and female rats at doses of up to approximately 100 mg/kg/day. The NTP did report equivocal evidence for hepatocarcinogenicity in male mice.

Both irbesartan and hydrochlorothiazide were not mutagenic in standard in vitro tests, including the Ames microbial test and the Chinese hamster mammalian-cell forward gene-mutation assay. Additionally, they were negative in tests for the induction of chromosomal aberrations, as demonstrated in both in vitro human lymphocyte assays and in vivo mouse micronucleus studies. Hydrochlorothiazide was also not genotoxic in various in vitro assays, including the Ames mutagenicity assay across multiple Salmonella typhimurium strains and the Chinese Hamster Ovary test for chromosomal aberrations, nor in vivo in assays involving mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes.

Positive results were observed in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays at concentrations ranging from 43 to 1300 µg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration. 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 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, 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. 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 a plastic bottle containing 90 units. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C and 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines. Proper 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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)