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 2-Butyl-3-p-(o-1H-tetrazol-5-ylphenyl)benzyl-1,3-diazaspiro4.4non-1-en-4-one, having a structural 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 a structural formula of C7H8ClN3O4S2 and a molecular weight of 297.7. It is presented as a white or practically white, practically odorless crystalline powder, very slightly soluble in water, and freely soluble in sodium hydroxide solution.

The tablets are formulated for oral administration, containing either 150 mg or 300 mg of irbesartan combined with 12.5 mg of hydrochlorothiazide. Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, ferric oxide red, ferric oxide yellow, magnesium stearate, microcrystalline cellulose, poloxamer, povidone, and pregelatinized starch.

Uses and Indications

Irbesartan and hydrochlorothiazide tablets USP are indicated for the management of hypertension in adult patients. This combination therapy is specifically indicated for patients who have not achieved adequate blood pressure control with monotherapy. Additionally, it may be utilized as initial therapy in patients who are likely 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

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. If further adjustment is necessary, the dosage may be increased to 300 mg of the active component combined with 25 mg of the adjunctive component.

For patients requiring replacement therapy, this formulation may be substituted for the titrated components as clinically appropriate. The specific route of administration, method, and frequency have not been detailed in the provided information and should be determined based on clinical judgment and individual patient needs.

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

Warnings and Precautions

The use of irbesartan and hydrochlorothiazide tablets necessitates careful consideration of several warnings and precautions to ensure patient safety.

Fetal Toxicity It is imperative to recognize the potential for fetal toxicity associated with the use of this medication. If pregnancy is detected, irbesartan and hydrochlorothiazide tablets should be discontinued immediately. Medications that directly affect the renin-angiotensin system have been shown to cause injury or even death to the developing fetus.

General Precautions Healthcare professionals should be vigilant regarding the following precautions:

• Hypotension: Prior to initiating treatment, it is essential to correct any volume depletion to mitigate the risk of hypotension.

• Impaired Renal Function: Patients with compromised renal function should be monitored closely, as the use of this medication may exacerbate their condition.

• Systemic Lupus Erythematosus: Thiazide diuretics, such as hydrochlorothiazide, have the potential to exacerbate or activate systemic lupus erythematosus in susceptible individuals.

• Acute Myopia and Glaucoma: There is a risk of acute myopia and secondary angle-closure glaucoma associated with thiazide diuretics, which should be considered when prescribing this medication.

While no specific laboratory tests are mandated for monitoring, healthcare providers should remain alert to the clinical status of patients receiving irbesartan and hydrochlorothiazide tablets, particularly in the context of the aforementioned warnings and precautions.

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, with musculoskeletal pain occurring in 5% or more of patients treated with the combination compared to those receiving placebo.

Serious warnings associated with the use of 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, exacerbation or activation of systemic lupus erythematosus due to thiazide diuretics, acute myopia, and secondary angle-closure glaucoma. Hypersensitivity reactions to any component of the product or to sulfonamide-derived drugs have been noted, as well as anuria.

In cases of overdose, the most likely manifestations include hypotension and tachycardia, with bradycardia also potentially occurring. The common signs and symptoms of overdose observed in humans are primarily 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

Irbesartan may interact with nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, potentially leading to an increased risk of renal impairment and a reduction in the antihypertensive effect. It is advisable to monitor renal function periodically in patients receiving this combination.

Hydrochlorothiazide has several notable interactions. When administered with antidiabetic drugs, dosage adjustments of the antidiabetic medication may be necessary to maintain glycemic control. The concomitant use of cholestyramine or colestipol can result in reduced absorption of thiazides, which may diminish their effectiveness.

Lithium clearance may be significantly reduced when used alongside diuretics, leading to an elevated risk of lithium toxicity; therefore, the combination of lithium and diuretics is contraindicated. Additionally, NSAIDs can diminish the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide, while also increasing the risk of renal impairment.

Lastly, the use of carbamazepine in conjunction with hydrochlorothiazide may elevate the risk of hyponatremia, necessitating careful monitoring of sodium levels in patients receiving both medications.

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

Pediatric patients, particularly neonates with a history of in utero exposure to irbesartan and hydrochlorothiazide, may experience complications such as oliguria or hypotension. In such cases, it is crucial to provide support for blood pressure and renal perfusion. Interventions such as exchange transfusions or dialysis may be necessary to address hypotension and/or to compensate for impaired renal function.

The safety and effectiveness of this medication in pediatric patients have not been established. Therefore, caution is advised when considering treatment in this population.

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 assessing the need for dosage adjustments based on individual patient response is recommended.

Pregnancy

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy is associated with significant risks to fetal renal function, leading to increased morbidity and mortality in both the fetus and neonate. Oligohydramnios, a potential consequence of such drug use, can result in fetal lung hypoplasia and skeletal deformations. Adverse neonatal outcomes may include skull hypoplasia, anuria, hypotension, renal failure, and death. Therefore, when pregnancy is detected, it is imperative to discontinue the use of irbesartan and hydrochlorothiazide as soon as possible. The majority of epidemiologic studies assessing fetal abnormalities following antihypertensive exposure in the first trimester have not differentiated between drugs affecting the renin-angiotensin system and other antihypertensive agents. Effective management of maternal hypertension during pregnancy is crucial to optimize outcomes for both the mother and fetus.

In cases where there is no suitable alternative to therapy with drugs affecting the renin-angiotensin system, healthcare providers should inform the mother of the potential risks to the fetus. Serial ultrasound examinations should be conducted 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. Fetal testing may be warranted depending on the gestational age; however, 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 should be closely monitored for hypotension, oliguria, and hyperkalemia.

Animal studies indicate that irbesartan crosses the placenta in rats and rabbits. In pregnant rats administered irbesartan at doses exceeding the maximum recommended human dose (MRHD), fetuses exhibited increased incidences of renal pelvic cavitation, hydroureter, and/or absence of renal papilla. Additionally, subcutaneous edema was observed in fetuses at doses approximately four times the MRHD. These anomalies were noted when irbesartan was administered through Day 20 of gestation, but not when treatment was halted on Day 15. The effects observed are believed to be late gestational consequences of the drug. Pregnant rabbits receiving oral doses of irbesartan equivalent to 1.5 times the MRHD experienced a high rate of maternal mortality and abortion, with surviving females showing a slight increase in early resorptions and a decrease in live fetuses.

Radioactivity from irbesartan was detected in the rat and rabbit fetus during late gestation, as well as in rat milk following oral administration of radiolabeled irbesartan. In contrast, when pregnant mice and rats were given hydrochlorothiazide at doses up to 3000 and 1000 mg/kg/day, respectively (approximately 600 and 400 times the MRHD) during critical periods of organogenesis, no evidence of fetal harm was observed. A developmental toxicity study involving a combination of irbesartan and hydrochlorothiazide at doses of 50/50 mg/kg/day and 150/150 mg/kg/day indicated that while the higher dose combination appeared more toxic to the dams, there was no corresponding increase in toxicity to the developing embryos.

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 mitigate the risk of hypotension. Healthcare professionals should refer to section 5.8 for further details on the implications of impaired renal function and to section 5.2 for guidance on managing volume status in these patients.

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 to 50 times the maximum recommended human dose (MRHD) of 300 mg on a mg/m² basis.

Nonclinical Toxicology

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 drug use can contribute to fetal lung hypoplasia and skeletal deformations. Potential adverse neonatal outcomes include skull hypoplasia, anuria, hypotension, renal failure, and death. It is recommended that irbesartan and hydrochlorothiazide be discontinued as soon as pregnancy is detected. In cases where no appropriate alternative therapy exists, the mother should be informed of the potential risks to the fetus, and serial ultrasound examinations should be performed to monitor the intra-amniotic environment. If oligohydramnios is detected, discontinuation of the drugs should be considered unless deemed lifesaving for the mother. Close monitoring of infants with in utero exposure to these medications is advised for signs of hypotension, oliguria, and hyperkalemia.

Irbesartan has been shown to cross the placenta in both rats and rabbits. In pregnant rats administered irbesartan at doses exceeding the maximum recommended human dose (MRHD), fetuses exhibited increased incidences of renal pelvic cavitation, hydroureter, and/or absence of renal papilla. Subcutaneous edema was also noted in fetuses at doses approximately four times the MRHD. These anomalies were observed when treatment continued through Day 20 of gestation but not when treatment was halted by Day 15, suggesting that the effects are related to late gestational exposure. Pregnant rabbits receiving oral doses of irbesartan equivalent to 1.5 times the MRHD experienced a high incidence of maternal mortality and abortion, with surviving females showing a slight increase in early resorptions and a decrease in live fetuses. In contrast, administration of hydrochlorothiazide to pregnant mice and rats at doses up to 3000 and 1000 mg/kg/day, respectively, during major organogenesis did not result in fetal harm. A developmental toxicity study involving a combination of irbesartan and hydrochlorothiazide indicated that while the higher dose appeared more toxic to the dams, there was no increase in toxicity to the developing embryos.

No carcinogenicity studies have been conducted with the irbesartan-hydrochlorothiazide combination. However, 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. It was also negative in tests for chromosomal aberrations both in vitro and in vivo. Irbesartan has not demonstrated carcinogenic potential in long-term studies, with no evidence of carcinogenicity observed in rats at doses up to 500/1000 mg/kg/day and in mice at 1000 mg/kg/day over a two-year period. Additionally, irbesartan did not adversely affect fertility or mating in male or female rats at oral doses up to 650 mg/kg/day.

Two-year feeding studies conducted by the National Toxicology Program (NTP) revealed no evidence of carcinogenicity 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, equivocal evidence for hepatocarcinogenicity was noted in male mice. Hydrochlorothiazide was not genotoxic in various in vitro assays, including the Ames mutagenicity assay and tests for chromosomal aberrations. Positive results were only observed in specific in vitro assays, including the CHO Sister Chromatid Exchange and Mouse Lymphoma Cell assays.

Postmarketing Experience

Postmarketing experience has identified additional adverse events reported voluntarily or through surveillance programs. These events include, but are not limited to, rare case reports of hypersensitivity reactions, including anaphylaxis, and instances of liver enzyme elevations. Reports of gastrointestinal disturbances, such as nausea and diarrhea, have also been noted. Other events include skin reactions, such as rash and urticaria. It is important to recognize that these events were reported in the postmarketing setting and do not imply a causal relationship with the drug.

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 ask questions and express any concerns they may have regarding their treatment. Open communication can help ensure that patients feel supported and informed throughout their therapy.

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 Legacy Pharmaceutical Packaging. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)