Irbesartan/Hydrochlorothiazide

Description

Irbesartan and Hydrochlorothiazide Tablets are a combination formulation consisting 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-diazaspiro 4.4non-1-en-4-one, exhibiting 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 defined 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.

Irbesartan and Hydrochlorothiazide Tablets USP are formulated for oral administration, available in two strengths: 150 mg or 300 mg of irbesartan combined with 12.5 mg of hydrochlorothiazide, and 300 mg of irbesartan combined with 25 mg of hydrochlorothiazide. The tablets contain inactive ingredients including lactose monohydrate, croscarmellose sodium, povidone, magnesium stearate, iron oxide red, and iron oxide yellow. The 300/25 mg formulation is a pinkish brown film-coated tablet that includes titanium dioxide, hypromellose, iron oxide black, and polyethylene glycol.

Uses and Indications

Irbesartan and Hydrochlorothiazide Tablets USP is indicated for the treatment of hypertension in patients who are not adequately controlled with monotherapy. This combination therapy may also be utilized as initial treatment in patients who are likely to require multiple medications to achieve their blood pressure goals.

There are no specific teratogenic or nonteratogenic effects associated with this medication as per the available data.

Dosage and Administration

For the management of hypertension, treatment should be initiated with a dosage of 150 mg/12.5 mg. Based on the patient's response and tolerability, the dosage may be titrated to 300 mg/12.5 mg. If further adjustment is necessary, the dosage can be increased to 300 mg/25 mg.

It is important to note that the maximum therapeutic effects are typically observed within 2 to 4 weeks following any change in dosage. Additionally, this medication is not recommended for use in patients with severe renal impairment, specifically those with a creatinine clearance of less than 30 mL/min. Healthcare professionals should assess renal function prior to initiation and during treatment to ensure patient safety.

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. Co-administration 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 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 myopia and secondary angle-closure glaucoma associated with the use of this medication. Patients should be informed of these potential side effects and advised to report any visual disturbances promptly.

While no specific laboratory tests are mandated for monitoring, healthcare providers should remain attentive to the overall clinical status of patients receiving Irbesartan and Hydrochlorothiazide Tablets, particularly those with pre-existing conditions that may be affected by the medication.

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 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 important adverse reactions include acute myopia and secondary angle-closure glaucoma, as well as hypersensitivity reactions to any component of the product. Anuria has also been reported. Patients with a known hypersensitivity to sulfonamide-derived drugs should exercise caution. It is also advised that aliskiren not be co-administered with Irbesartan and Hydrochlorothiazide Tablets in patients with diabetes to avoid potential 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 in patients undergoing this treatment.

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 medications, 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

Pediatric patients, particularly neonates with a history of in utero exposure to Irbesartan and Hydrochlorothiazide Tablets, 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 Irbesartan and Hydrochlorothiazide Tablets in pediatric patients have not been established. Therefore, caution is advised when considering the use of this medication in children and adolescents.

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 effects of the medication in some older individuals cannot be ruled out. 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 characteristics and clinical response.

Pregnancy

The use of Irbesartan and Hydrochlorothiazide Tablets during pregnancy is classified as Pregnancy Category D. Administration of drugs that act on the renin-angiotensin system during the second and third trimesters is associated with reduced fetal renal function, leading to increased morbidity and mortality in both the fetus and neonate. Oligohydramnios resulting from such use can contribute to fetal lung hypoplasia and skeletal deformations. Potential adverse neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

It is recommended that Irbesartan and Hydrochlorothiazide Tablets be discontinued as soon as pregnancy is detected. The adverse outcomes are primarily linked to the use of these medications during the later stages of pregnancy. While most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive agents in the first trimester have not specifically differentiated drugs affecting the renin-angiotensin system from other antihypertensive medications, appropriate management of maternal hypertension is crucial to optimize outcomes for both mother and fetus.

In cases where there is no suitable alternative to therapy with renin-angiotensin system-affecting drugs, healthcare providers should inform the mother of the potential risks to the fetus. Serial ultrasound examinations should be performed to monitor the intra-amniotic environment, and if oligohydramnios is detected, discontinuation of Irbesartan and Hydrochlorothiazide Tablets is advised 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 a history of in utero exposure to Irbesartan and Hydrochlorothiazide Tablets should be closely monitored for hypotension, oliguria, and hyperkalemia. Animal studies indicate that irbesartan crosses the placenta in rats and rabbits, with pregnant rats exposed to doses exceeding the maximum recommended human dose (MRHD) showing increased incidences of renal pelvic cavitation, hydroureter, and absence of renal papilla. Additionally, subcutaneous edema was observed in fetuses at doses approximately four times the MRHD. These effects were noted when treatment continued through Day 20 of gestation but not when discontinued by Day 15.

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 radiolabeled irbesartan was detected in the fetuses of rats and rabbits during late gestation and in rat milk. In contrast, administration of hydrochlorothiazide to pregnant mice and rats at doses significantly higher than the MRHD did not demonstrate evidence of fetal harm. A developmental toxicity study involving a combination of irbesartan and hydrochlorothiazide indicated that while the higher dose combination was 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 require careful consideration regarding dosing adjustments and monitoring. It is essential to assess renal function prior to initiating treatment and periodically thereafter, as impaired renal function can affect drug clearance. Healthcare professionals should be vigilant in evaluating the patient's creatinine clearance and adjusting the dosage 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 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 exceed 2000 mg/kg, which is approximately 25- and 50-fold the maximum recommended human dose (MRHD) of 300 mg on a mg/m² basis.

Nonclinical Toxicology

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 equal to or greater than 50 mg/kg/day, which is approximately equivalent to the maximum recommended human dose (MRHD) of 300 mg/day on a body surface area basis. Additionally, subcutaneous edema was noted in fetuses at doses equal to or greater than 180 mg/kg/day, approximately four times the MRHD on a body surface area basis. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this dose, about 1.5 times the MRHD on a body surface area basis, exhibited a slight increase in early resorptions and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in both rats and rabbits.

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, the highest dose providing systemic exposure to irbesartan approximately five times that found in humans receiving the MRD of 300 mg/day. Hydrochlorothiazide also showed no adverse effects on the fertility of mice and rats of either sex in studies where these species were exposed, via their diet, to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

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. It was negative in tests for the induction of chromosomal aberrations, both in vitro using a human lymphocyte assay and in vivo in a mouse micronucleus study. No evidence of carcinogenicity was observed when irbesartan was administered at doses of up to 500 mg/kg/day in males and 1000 mg/kg/day in females in rats, and 1000 mg/kg/day in mice for up to two years. Irbesartan was also not mutagenic in a battery of in vitro tests, including the Ames microbial test, rat hepatocyte DNA repair test, and V79 mammalian-cell forward gene-mutation assay, and was negative in several tests for chromosomal aberrations.

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 of various Salmonella typhimurium strains and in the Chinese Hamster Ovary test for chromosomal aberrations, nor in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 μg/mL, and 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

During post-approval use of Irbesartan and Hydrochlorothiazide Tablets, several adverse reactions have been identified. These reactions have been reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to drug exposure. The inclusion of these reactions in labeling is typically based on factors such as the seriousness of the reaction, frequency of reporting, or strength of the causal connection to the medications.

Adverse reactions reported with the combination of Irbesartan and Hydrochlorothiazide include urticaria, jaundice, hepatitis, thrombocytopenia, and impaired renal function, including renal failure.

Additionally, reactions specifically associated with Irbesartan monotherapy include tinnitus, hyperkalemia, angioedema (which may involve swelling of the face, lips, pharynx, and/or tongue), and increased creatine phosphokinase (CPK) levels.

Reactions reported with hydrochlorothiazide monotherapy consist of secondary acute angle closure glaucoma and/or acute myopia.

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 important 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 the event of fainting, patients should discontinue the use of Irbesartan and Hydrochlorothiazide Tablets and contact their prescribing doctor immediately.

Additionally, patients should be cautioned that dehydration 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.

Healthcare providers should also advise patients against using potassium supplements or salt substitutes that contain potassium without prior consultation with their healthcare provider.

Patients must be instructed to discontinue Irbesartan and Hydrochlorothiazide Tablets and seek immediate medical attention if they experience symptoms indicative of Acute Myopia or Secondary Angle-Closure Glaucoma.

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

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) as outlined by 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 Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)