Irbesartan/Hydrochlorothiazide

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.

Limitations of use: There are no teratogenic or nonteratogenic effects associated with 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 and guidelines for administration techniques and schedules.

Contraindications

Use of this product is contraindicated in patients with hypersensitivity to any component of the formulation. Additionally, it is contraindicated in individuals with anuria, as well as those with hypersensitivity to sulfonamide-derived drugs.

Coadministration of aliskiren with irbesartan and hydrochlorothiazide tablets is contraindicated in patients with diabetes due to the potential for 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 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 regarding hypotension. It is essential to correct any volume depletion prior to the administration of these tablets to mitigate the risk of significant blood pressure drops.

Patients with impaired renal function require careful monitoring, as the use of these medications may exacerbate their condition. Additionally, thiazide diuretics, which are components of this combination therapy, have been associated with the exacerbation or activation of systemic lupus erythematosus, necessitating vigilance in patients with a history of this autoimmune disorder.

There is also a risk of acute angle-closure glaucoma, acute myopia, and choroidal effusion, which should be considered when prescribing this medication. Regular assessment of patients for these conditions is advisable to ensure timely intervention if symptoms arise.

While no specific laboratory tests are mandated for monitoring the 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 needs.

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 this medication include the potential for 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 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, exacerbation or activation of systemic lupus erythematosus due to thiazide diuretics, and ocular conditions such as 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. Furthermore, it is advised that aliskiren not be coadministered with irbesartan and hydrochlorothiazide tablets in patients with diabetes.

In cases of overdosage, the most likely manifestations for irbesartan include hypotension and tachycardia, with bradycardia potentially occurring as well. For hydrochlorothiazide, the most common signs and symptoms observed in humans are those resulting from electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia, along with dehydration due to excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias.

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 on this regimen.

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 therapeutic efficacy.

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

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, 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 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 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 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 or higher. Pregnant rabbits given 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, when pregnant mice and rats were given hydrochlorothiazide during their respective periods of major organogenesis, there was no evidence of fetal harm.

Lactation

Irbesartan crosses the placenta in animal studies, specifically in rats and rabbits. Data indicate that there were no adverse effects on kidney development in pups from dams administered irbesartan from Gestation Day 15 through Lactation Day 24 at doses of 50, 180, or 650 mg/kg/day, which corresponds to up to 21.1 times the maximum recommended human dose (MRHD). Additionally, radioactivity was detected in the fetuses of both rats and rabbits during late gestation following oral doses of radiolabeled irbesartan.

Currently, there is no specific information available regarding the excretion of irbesartan in human breast milk or its effects on breastfed infants. Therefore, healthcare professionals should exercise caution when considering the use of irbesartan in lactating mothers.

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 of irbesartan, it is important to note that no specific data are available 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.

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

The combination of irbesartan and hydrochlorothiazide has not been evaluated in definitive studies of fertility. 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 corresponds to a systemic exposure approximately five times that observed in humans receiving the maximum recommended dose (MRD) of 300 mg/day. Similarly, hydrochlorothiazide did not adversely affect the fertility of 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 conducted specifically on the combination of irbesartan and hydrochlorothiazide. However, irbesartan 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. It was also negative in tests for the induction of chromosomal aberrations, both in vitro (human lymphocyte assay) and in vivo (mouse micronucleus study). In long-term studies, no evidence of carcinogenicity was observed when irbesartan 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 over a period of up to two years. The systemic exposure for 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 for females provided an exposure about twenty-one times that of humans at the MRHD. For male and female mice, the 1000 mg/kg/day dose resulted in exposures approximately three and five times, respectively, that of humans at 300 mg/day.

Hydrochlorothiazide was also not found to be genotoxic in vitro in the Ames mutagenicity assay across various Salmonella typhimurium strains 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 did not indicate genotoxicity. However, positive results were observed in the in vitro CHO Sister Chromatid Exchange assay and the Mouse Lymphoma Cell assay at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration. Two-year feeding studies conducted by the National Toxicology Program (NTP) found 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, although equivocal evidence for hepatocarcinogenicity was noted in male mice.

Postmarketing Experience

In postmarketing surveillance, various adverse events have been reported voluntarily in association with the use of irbesartan and hydrochlorothiazide.

In double-blind clinical trials, the incidence of hypokalemia (serum potassium <3.5 mEq/L) among hypertensive patients was observed at 7.5% for those receiving the combination therapy compared to 6.0% for placebo. The incidence of hyperkalemia (serum potassium >5.7 mEq/L) was reported at <1.0% for the treatment group versus 1.7% for placebo. No patients discontinued treatment due to fluctuations in serum potassium levels, and the combination therapy generally had no significant effect on serum potassium. Higher doses of irbesartan were noted to mitigate the hypokalemic response associated with hydrochlorothiazide.

Coadministration of irbesartan and hydrochlorothiazide with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medications that elevate serum potassium levels may lead to hyperkalemia, which can be severe. Monitoring of serum potassium levels is recommended in these patients.

Additional adverse events reported with irbesartan, without regard to causality, include:

• Body as a Whole: fever, chills, orthostatic effects, facial edema, upper extremity edema

• Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, hypotension, syncope, arrhythmic/conduction disorder, cardiorespiratory arrest, heart failure, hypertensive crisis

• Dermatologic: pruritus, dermatitis, ecchymosis, erythema of the face, urticaria

• Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout

• Gastrointestinal: diarrhea, constipation, gastroenteritis, flatulence, abdominal distention

• Musculoskeletal/Connective Tissue: musculoskeletal trauma, extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, joint stiffness, bursitis, muscle weakness

• Nervous System: anxiety/nervousness, sleep disturbance, numbness, somnolence, vertigo, emotional disturbance, depression, paresthesia, tremor, transient ischemic attack, cerebrovascular accident

• Renal/Genitourinary: prostate disorder

• Respiratory: cough, upper respiratory infection, epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea, wheezing

• Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain, conjunctivitis

Similarly, adverse events associated with hydrochlorothiazide, also reported without regard to causality, include:

• Body as a Whole: weakness

• Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation

• Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia

• Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions

• Metabolic: hyperglycemia, glycosuria, hyperuricemia

• Musculoskeletal: muscle spasm

• Nervous System/Psychiatric: restlessness

• Renal: renal failure, renal dysfunction, interstitial nephritis

• Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis

• Special Senses: transient blurred vision, xanthopsia

Patient Counseling

Healthcare providers should advise patients that if pregnancy is detected, it is essential to discontinue the use of irbesartan and hydrochlorothiazide tablets as soon as possible. Patients should be informed that medications acting directly on the renin-angiotensin system, including this combination, have the potential to cause injury or even death to the developing fetus. It is crucial for patients to understand the risks associated with these medications during pregnancy and to discuss any concerns or questions they may have regarding their treatment options.

Storage and Handling

The product is supplied in a plastic bottle containing 90 units. The National Drug Code (NDC) numbers are not specified.

For optimal storage, the product should be maintained at a temperature range of 20°C to 25°C (68°F to 77°F). Temporary excursions outside this range are permissible, provided the temperature does not exceed 30°C (86°F) or fall below 15°C (59°F), in accordance with USP Controlled Room Temperature guidelines.

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)