Irbesartan/Hydrochlorothiazide

Uses and Indications

This drug is indicated for hypertension in patients not adequately controlled with monotherapy. It may also be used as initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals.

Limitations of Use No specific teratogenic or nonteratogenic effects are mentioned in the provided information.

Dosage and Administration

The recommended initial dosage of Irbesartan and Hydrochlorothiazide is 150 mg/12.5 mg. Based on the patient's response and tolerability, the dosage may be titrated to 300 mg/12.5 mg, and if further control is necessary, to 300 mg/25 mg. This medication may also be used as a replacement therapy for patients who have been titrated on the individual components.

It is important to note that maximum therapeutic effects are typically observed within 2 to 4 weeks following any dose adjustment. Caution is advised in patients with renal impairment, as this medication is not recommended for individuals with severe renal impairment (creatinine clearance <30 mL/min).

Specific details regarding the route, method, and frequency of administration have not been provided in the available data.

Contraindications

Hypersensitivity to any component of this product is a contraindication. The use of this product is also contraindicated in patients with anuria. Additionally, individuals with hypersensitivity to sulfonamide-derived drugs should not use this product.

Coadministration of aliskiren with this product is contraindicated in patients with diabetes due to the associated risks.

Warnings and Precautions

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue irbesartan and hydrochlorothiazide as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

General Precautions

• Hypotension: Correct volume depletion prior to administration.

• Impaired Renal Function: Monitor renal function closely.

• Thiazide Diuretics: May cause an exacerbation or activation of systemic lupus erythematosus.

• Ocular Effects: Risk of acute angle-closure glaucoma, acute myopia, and choroidal effusion.

Laboratory Tests

No specific laboratory tests are recommended.

Emergency Medical Help

No specific instructions for emergency medical help are provided.

Discontinuation Instructions

No specific instructions for discontinuation or when to call a doctor are provided.

Side Effects

Most common adverse events reported in clinical trials (≥5% on irbesartan and hydrochlorothiazide and more often than on placebo) include:

• Dizziness

• Fatigue

• Musculoskeletal pain

Serious Adverse Reactions

• Fetal Toxicity: Drugs that act directly on the renin-angiotensin system, such as irbesartan and hydrochlorothiazide, can cause injury and death to the developing fetus. Discontinuation of the medication is recommended as soon as pregnancy is detected.

• Hypotension: Patients should have volume depletion corrected prior to administration to avoid significant drops in blood pressure.

• Impaired Renal Function: Renal function should be monitored, as the medication may exacerbate existing renal issues.

• Thiazide Diuretics: These may cause an exacerbation or activation of systemic lupus erythematosus.

Additional Adverse Reactions

• Gastrointestinal: Nausea/vomiting (3%), abdominal pain (2%), dyspepsia/heartburn (2%), intestinal angioedema.

• Cardiovascular: Edema (3%), tachycardia (1%).

• Nervous System: Dizziness (8%), orthostatic dizziness (1%).

• Blood and Lymphatic System: Thrombocytopenia, anemia.

• Hepatobiliary: Hepatitis, jaundice.

• Skin and Subcutaneous Tissue: Urticaria, angioedema (including swelling of the face, lips, pharynx, and/or tongue), hypersensitivity reactions.

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

Overdosage

• Irbesartan: Overdose may lead to hypotension and tachycardia; bradycardia may also occur.

• Hydrochlorothiazide: Signs and symptoms of overdose are typically related to electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. If digitalis has been administered, hypokalemia may exacerbate cardiac arrhythmias.

Postmarketing Experience

Adverse reactions reported postmarketing include:

• Blood and Lymphatic System: Thrombocytopenia, anemia.

• Hepatobiliary: Hepatitis, jaundice.

• Renal and Urinary: Impaired renal function, including renal failure.

• Skin and Subcutaneous Tissue: Urticaria, angioedema.

• Metabolism and Nutrition: Hyperkalemia, hypoglycemia in diabetic patients.

• Ear and Labyrinth: Tinnitus.

Patients should be monitored for these adverse reactions, and appropriate management should be initiated as necessary.

Drug Interactions

NSAIDs and selective COX-2 inhibitors may reduce the diuretic effect of thiazides, leading to an increased risk of renal impairment and diminished antihypertensive efficacy. It is recommended to monitor renal function periodically when these agents are co-administered.

The dual blockade of the renin-angiotensin system can elevate the risk of renal impairment, hypotension, and hyperkalemia.

Antidiabetic drugs may require dosage adjustments when used in conjunction with thiazides, as their effects can be altered.

Cholestyramine and colestipol can reduce the absorption of thiazides, potentially impacting their effectiveness.

Lithium levels may increase when used with diuretics, raising the risk of lithium toxicity. Therefore, caution is advised, and these medications should not be co-administered.

Carbamazepine has been associated with an increased risk of hyponatremia when used alongside thiazides.

Overall, careful monitoring and potential dosage adjustments are necessary when these interactions are anticipated.

Pediatric Use

Safety and effectiveness of Avalide and Irbesartan and Hydrochlorothiazide in pediatric patients have not been established.

In neonates with a history of in utero exposure to Irbesartan and Hydrochlorothiazide, if oliguria or hypotension occurs, it is essential to direct attention toward the support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required to reverse hypotension and/or substitute for disordered renal function.

Geriatric Use

In controlled clinical studies of hypertension involving 1,694 patients receiving irbesartan and hydrochlorothiazide, 264 patients (15.6%) were aged 65 years and older, with 45 patients (2.7%) aged 75 years and older. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients. However, it cannot be ruled out that some older individuals may exhibit greater sensitivity to the medication.

Healthcare professionals should monitor geriatric patients closely for any adverse effects and consider potential dose adjustments based on individual patient response and tolerance.

Pregnancy

Irbesartan and hydrochlorothiazide can cause fetal harm when administered to pregnant patients. 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. When pregnancy is detected, it is recommended to discontinue irbesartan and hydrochlorothiazide 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 increases the maternal risk for preeclampsia, gestational diabetes, premature delivery, and delivery complications, such as the need for cesarean section and postpartum hemorrhage. Additionally, hypertension elevates the fetal risk for intrauterine growth restriction and intrauterine death, necessitating careful monitoring and management of pregnant women with hypertension.

Oligohydramnios, which may occur in pregnant women using drugs affecting the renin-angiotensin system during the second and third trimesters, can result in reduced fetal renal function leading to 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 appropriate based on the gestational week. It is important for patients and healthcare providers to be aware 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, hyperkalemia, and other symptoms of renal impairment. In neonates experiencing oliguria or hypotension, immediate attention should be directed toward supporting blood pressure and renal perfusion, with exchange transfusion or dialysis potentially required to address hypotension and/or substitute for disordered renal function.

Thiazides cross the placenta, and their use during pregnancy is associated with risks of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions observed in adults. Irbesartan has been shown to cross the placenta in animal studies, with pregnant rats exhibiting increased incidences of renal pelvic cavitation and hydroureter when exposed to the drug. Pregnant rabbits have shown high rates of maternal mortality and abortion following exposure to irbesartan. However, when pregnant mice and rats were administered hydrochlorothiazide during their respective periods of major organogenesis, there was no evidence of fetal harm.

In cases where there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, it is crucial to inform the mother of the potential risks to the fetus and to manage maternal hypertension appropriately to optimize outcomes for both mother and fetus.

Lactation

There are no available data on the presence of irbesartan in human milk, nor on its effects on milk production or breastfed infants. However, studies in lactating rats indicate that irbesartan or its metabolites are secreted in breast milk. Thiazides, which are components of the combination product, also appear in human milk.

Due to the potential for adverse effects on nursing infants, the use of irbesartan and hydrochlorothiazide in breastfeeding women is not recommended. Healthcare providers should consider the importance of the medication to the mother when advising on whether to discontinue nursing or the drug. Close monitoring of breastfed infants is advised if exposure occurs, particularly for signs of hypotension, oliguria, or other symptoms of renal impairment.

Renal Impairment

Patients with renal impairment should be closely monitored when considering the use of Irbesartan and Hydrochlorothiazide. It is essential to correct any volume depletion prior to administration to mitigate the risk of hypotension and ensure optimal therapeutic outcomes.

The presence of impaired renal function necessitates careful evaluation, as dosing adjustments may be required based on the severity of the impairment. Specific creatinine clearance thresholds are not provided in the available data; however, clinicians should refer to relevant sections of the prescribing information for detailed guidance on managing patients with varying degrees of renal function.

In summary, prior to initiating treatment, it is crucial to assess and address any volume depletion in patients with renal impairment to prevent adverse effects and ensure the safe use of this medication.

Hepatic Impairment

Patients with hepatic impairment have no specific dosage adjustments, special monitoring requirements, or precautions outlined for the use of Avalide or Irbesartan and Hydrochlorothiazide. The available information does not provide guidance on the management of these medications in individuals with liver problems. Therefore, healthcare providers should exercise caution and consider individual patient factors when prescribing these medications to patients with hepatic impairment.

Overdosage

No data are available regarding overdosage in humans; however, daily doses of 900 mg for 8 weeks have been well tolerated. The most likely manifestations of overdosage are expected to include hypotension and tachycardia, with bradycardia also being a potential outcome. Acute oral toxicity studies indicate 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.

The most common signs and symptoms associated with hydrochlorothiazide overdose are primarily due to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

Irbesartan is not removed by hemodialysis, and the extent to which hydrochlorothiazide is removed by hemodialysis has not been established. In managing overdose, it is crucial to consider the potential for multiple-drug interactions, drug-drug interactions, and unusual drug kinetics in the patient. Laboratory determinations of serum levels of irbesartan are not widely available and do not have an established role in the management of irbesartan overdose.

For up-to-date information regarding the treatment of overdosage, it is recommended to contact a certified regional Poison Control Center.

Nonclinical Toxicology

Teratogenic Effects

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, leading to increased fetal and neonatal morbidity and mortality. Oligohydramnios resulting from such use can be linked to fetal lung hypoplasia and skeletal deformations. Potential adverse neonatal outcomes include skull hypoplasia, anuria, hypotension, renal failure, and death. It is recommended to discontinue irbesartan and hydrochlorothiazide as soon as pregnancy is detected. In cases where alternative therapies are not available, patients 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 observed, discontinuation of the medication should be considered unless it is deemed lifesaving for the mother.

Irbesartan has been shown to cross the placenta in animal studies. 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 on Day 15. Pregnant rabbits receiving oral doses of irbesartan equivalent to 1.5 times the MRHD experienced high rates of maternal mortality and abortion, with surviving females showing increased early resorptions and decreased live fetuses. Conversely, administration of hydrochlorothiazide to pregnant mice and rats at high doses during major organogenesis did not result in fetal harm.

Non-Teratogenic Effects

Irbesartan and hydrochlorothiazide have not demonstrated adverse effects on fertility or mating in male or female rats at oral doses up to 650 mg/kg/day and 100 mg/kg/day, respectively. Hydrochlorothiazide also showed no adverse effects on 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted with the combination of irbesartan and hydrochlorothiazide. However, irbesartan has been administered to rats and mice at doses of up to 500/1000 mg/kg/day (males/females) and 1000 mg/kg/day, respectively, for up to two years without evidence of carcinogenicity. Two-year feeding studies conducted by the National Toxicology Program (NTP) found no evidence of carcinogenic potential for hydrochlorothiazide in female mice or in male and female rats at doses of up to approximately 600 mg/kg/day and 100 mg/kg/day, respectively. The NTP did find equivocal evidence for hepatocarcinogenicity in male mice.

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. Both compounds were negative in tests for induction of chromosomal aberrations in vitro (human lymphocyte assay) and in vivo (mouse micronucleus study). The combination has not been evaluated in definitive studies of fertility.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Positive results were observed only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays at specific concentrations, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Storage and Handling

Avalide is supplied as film-coated tablets. It should be stored at 25°C (77°F), with permissible excursions between 15°C and 30°C (59°F and 86°F) in accordance with USP Controlled Room Temperature guidelines.

Irbesartan and Hydrochlorothiazide is available in both tablet and film-coated tablet forms. The recommended storage temperature is between 20°C and 25°C (68°F and 77°F), with excursions allowed from 15°C to 30°C (59°F to 86°F) as per USP Controlled Room Temperature standards.

For the tablet form of Irbesartan and Hydrochlorothiazide, it is essential to dispense the product in a tight, light-resistant container as defined by the USP, equipped with a child-resistant closure when required. The packaging typically consists of 90 tablets in a plastic bottle.