Avalide

Description

AVALIDE (irbesartan and hydrochlorothiazide) tablets are a combination of an angiotensin II receptor antagonist, irbesartan, and a thiazide diuretic, hydrochlorothiazide (HCTZ). Irbesartan is a non-peptide compound, chemically described as 2-butyl-3-p-(o-1H-tetrazol-5-ylphenyl)benzyl-1,3-diazaspiro4.4non-1-en-4-one, with an empirical formula of C25H28N6O and a molecular weight of 428.5. It appears as a white to off-white crystalline powder, is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH 7.4, and is slightly soluble in alcohol and methylene chloride, but 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 a white or practically white crystalline powder, slightly soluble in water, and freely soluble in sodium hydroxide solution. AVALIDE is available for oral administration in film-coated tablets containing either 150 mg or 300 mg of irbesartan combined with 12.5 mg of hydrochlorothiazide. Each dosage strength includes the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, magnesium stearate, silicon dioxide, ferric oxide red, ferric oxide yellow, polyethylene glycol, titanium dioxide, and carnauba wax.

Uses and Indications

AVALIDE is indicated for the management of hypertension in patients who are not adequately controlled with monotherapy. It may also be used as initial therapy 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 AVALIDE mentioned in the provided data.

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; therefore, healthcare professionals should refer to standard practices for administration of similar formulations and adjust based on individual patient needs and clinical judgment.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with hypersensitivity to any component of the product should not use it due to the risk of severe allergic reactions. Additionally, the product is contraindicated in individuals with anuria, as it may exacerbate renal complications.

Patients with a known hypersensitivity to sulfonamide-derived drugs should avoid this product to prevent potential adverse reactions. Furthermore, coadministration of aliskiren with AVALIDE is contraindicated in patients with diabetes, as it may increase the risk of adverse effects.

Warnings and Precautions

The use of AVALIDE necessitates careful consideration of several critical warnings and precautions to ensure patient safety.

Fetal Toxicity It is imperative to recognize the potential for fetal toxicity associated with AVALIDE. Upon confirmation of pregnancy, AVALIDE should be discontinued immediately. Medications that exert effects on the renin-angiotensin system have been linked to serious injury or death in the developing fetus.

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

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

• Impaired Renal Function: Caution is advised in patients with compromised renal function, as AVALIDE may exacerbate renal impairment.

• Systemic Lupus Erythematosus: The use of thiazide diuretics, which are components of AVALIDE, may lead to the exacerbation or activation of systemic lupus erythematosus in susceptible individuals.

• Ocular Conditions: Patients with a history of acute angle-closure glaucoma, acute myopia, or choroidal effusion should be monitored closely, as these conditions may be aggravated by the use of AVALIDE.

While no specific laboratory tests are mandated for monitoring during the use of AVALIDE, healthcare providers should remain alert to the clinical status of their patients and adjust treatment as necessary based on individual responses and any emerging concerns.

Side Effects

Patients receiving AVALIDE may experience a range of adverse reactions. The most common adverse events, occurring in 5% or more of patients treated with AVALIDE and more frequently than with placebo, include dizziness, fatigue, and musculoskeletal pain.

Serious warnings associated with AVALIDE include fetal toxicity, as drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. It is imperative to discontinue AVALIDE as soon as pregnancy is detected.

In clinical trials, additional adverse reactions were observed. Among body-related effects, fatigue was reported in 6% of participants, while chest pain and influenza were noted in 2% and 3%, respectively. Cardiovascular effects included edema (3%) and tachycardia (1%). Gastrointestinal reactions such as abdominal pain, dyspepsia/heartburn, and nausea/vomiting were reported in 2% to 3% of subjects. Immunological reactions included allergy (1%), while musculoskeletal pain was reported in 6% of patients. Nervous system effects included dizziness (8%) and orthostatic dizziness (1%). Renal and genitourinary issues included abnormal urination (2%).

Additional adverse reactions associated with the components of AVALIDE, irbesartan and hydrochlorothiazide, include thrombocytopenia, hepatitis, jaundice, and impaired renal function, including renal failure. Skin reactions such as urticaria and angioedema (which may involve swelling of the face, lips, pharynx, and/or tongue) have also been reported. Other notable reactions include anemia, tinnitus, intestinal angioedema, increased creatine phosphokinase (CPK), hyperkalemia, and hypoglycemia in diabetic patients. Hydrochlorothiazide has been associated with acute angle-closure glaucoma, acute myopia, and choroidal effusion.

Postmarketing experience has corroborated many of these adverse reactions, including thrombocytopenia, hepatitis, jaundice, impaired renal function, urticaria, anemia, tinnitus, intestinal angioedema, angioedema, anaphylactic reactions, increased CPK, hyperkalemia, and hypoglycemia. Furthermore, hydrochlorothiazide has been linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients receiving large cumulative doses.

Drug Interactions

The concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors may diminish the diuretic effect of certain medications, potentially resulting in an increased risk of renal impairment and a reduction in antihypertensive efficacy. It is advisable to monitor renal function periodically in patients receiving these combinations.

When considering the dual blockade of the renin-angiotensin system, there is an elevated risk of renal impairment, hypotension, and hyperkalemia. Clinicians should exercise caution and consider appropriate monitoring of renal function and electrolyte levels in patients on such regimens.

Antidiabetic medications may necessitate dosage adjustments to maintain glycemic control, particularly when used in conjunction with other agents that affect glucose metabolism.

The use of cholestyramine and colestipol has been shown to reduce the absorption of thiazide diuretics, which may necessitate adjustments in therapy or monitoring of blood pressure and fluid status.

Lithium therapy can be affected by other medications, leading to increased serum lithium concentrations and a heightened risk of lithium toxicity. Regular monitoring of serum lithium levels is recommended to avoid adverse effects.

Carbamazepine has been associated with an increased risk of hyponatremia, and clinicians should monitor sodium levels in patients receiving this medication, particularly in those at higher risk for electrolyte imbalances.

Packaging & NDC

The table below lists all NDC Code configurations of Avalide (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 AVALIDE, 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 drug may be present in some older individuals.

Healthcare providers should exercise caution when prescribing AVALIDE to elderly patients, considering the potential for increased sensitivity. Monitoring for adverse effects and therapeutic response is recommended to ensure optimal management in this population. Additionally, while no specific dosage adjustments are mandated based on age alone, careful assessment of each geriatric patient's overall health status and concurrent medications is advisable to mitigate any risks associated with treatment.

Pregnancy

AVALIDE 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, AVALIDE should be discontinued 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, necessitating careful monitoring and management of pregnant women with hypertension.

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 for patients and healthcare providers to recognize that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. Infants with a history of in utero exposure to AVALIDE should be closely monitored for hypotension, oliguria, hyperkalemia, and other signs of renal impairment. In neonates presenting with oliguria or hypotension, immediate attention should be directed toward supporting blood pressure and renal perfusion, with exchange transfusion or dialysis considered as potential interventions for reversing hypotension and/or addressing disordered renal function.

Additionally, thiazides, which cross the placenta, are associated with risks of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have been observed in adults.

Lactation

There are no available data on the presence of irbesartan in human milk, effects on milk production, or the breastfed infant. However, studies in lactating rats indicate that irbesartan or some metabolite of irbesartan is secreted in milk. Additionally, thiazides are known to appear in human milk.

Due to the potential for adverse effects on the nursing infant, the use of AVALIDE in breastfeeding women is not recommended.

Renal Impairment

Patients with renal impairment may experience altered pharmacokinetics, necessitating careful consideration of dosing adjustments. It is essential to correct any volume depletion prior to administration to ensure optimal therapeutic outcomes. Monitoring of renal function is recommended to assess the need for further adjustments in dosing or to implement additional precautions as necessary.

Hepatic Impairment

There is no information available regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise clinical judgment when considering the use of this medication in patients with liver problems, as the absence of data does not preclude the need for careful evaluation and monitoring in this population.

Overdosage

In the event of an overdosage, it is important to note that no specific data are available regarding human overdosage. However, clinical experience indicates that daily doses of 900 mg for 8 weeks have been well tolerated.

Potential Symptoms The most likely manifestations of overdosage include hypotension and tachycardia, with the possibility of bradycardia also occurring. In cases of hydrochlorothiazide overdose, the predominant signs and symptoms are typically related to electrolyte depletion, which may manifest as hypokalemia, hypochloremia, and hyponatremia, alongside dehydration resulting from excessive diuresis. If digitalis has been co-administered, hypokalemia may further exacerbate cardiac arrhythmias.

Toxicity Data Acute oral toxicity studies have shown that the acute 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. For hydrochlorothiazide, the oral LD50 is greater than 10 g/kg in both mice and rats.

Management Procedures It is critical to note that irbesartan is not removed by hemodialysis, and the extent to which hydrochlorothiazide is removed by this method has not been established. In cases of suspected overdosage, healthcare professionals are advised to contact a certified regional Poison Control Center for the most current information regarding treatment options and management strategies.

Nonclinical Toxicology

Irbesartan demonstrated no adverse effects on fertility or mating in male or female rats at oral doses up to 650 mg/kg/day, which corresponds to a systemic exposure approximately five times that observed in humans receiving the maximum recommended human dose (MRHD) of 300 mg/day. Similarly, hydrochlorothiazide did not adversely affect fertility in 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 with 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. Additionally, irbesartan and hydrochlorothiazide were negative in tests for the induction of chromosomal aberrations, both in vitro using human lymphocytes and in vivo in a mouse micronucleus study.

Irbesartan was administered at doses of up to 500 mg/kg/day for males and 1000 mg/kg/day for females in rats, and up to 1000 mg/kg/day in mice for a duration of up to two years, with no evidence of carcinogenicity observed. In two-year feeding studies conducted by the National Toxicology Program (NTP), hydrochlorothiazide also showed no evidence of carcinogenic potential 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, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay using various strains of Salmonella typhimurium 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 also yielded negative results. Positive test results were noted only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays at specific concentrations, 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

During postapproval use of AVALIDE, several adverse reactions have been reported voluntarily from a population of uncertain size. Due to the nature of these reports, it is not always possible 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 AVALIDE.

Adverse reactions associated with the combination of irbesartan and hydrochlorothiazide include:

• Blood and lymphatic system: Thrombocytopenia

• Hepatobiliary: Hepatitis, Jaundice

• Renal and urinary: Impaired renal function, including renal failure

• Skin and subcutaneous tissue: Urticaria

Reactions specifically linked to irbesartan include:

• Blood and lymphatic system: Anemia

• Ear and labyrinth: Tinnitus

• Gastrointestinal: Intestinal angioedema

• Skin and subcutaneous tissue: Angioedema (involving swelling of the face, lips, pharynx, and/or tongue)

• Immune system: Anaphylactic reaction, including anaphylactic shock

• Investigations: Increased CPK (Creatine Phosphokinase)

• Metabolism and nutrition: Hyperkalemia, Hypoglycemia in diabetic patients

Reactions associated with hydrochlorothiazide include:

• Eye: Acute angle-closure glaucoma, Acute myopia, and Choroidal effusion

Additionally, hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. A study conducted in the Sentinel System indicated that the increased risk was predominantly for squamous cell carcinoma (SCC) and was observed in white patients taking large cumulative doses. The overall increased risk for SCC was approximately 1 additional case per 16,000 patients per year, while for white patients taking a cumulative dose of ≥50,000 mg, the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

Patient Counseling

Healthcare providers should inform female patients of childbearing age about the potential consequences of exposure to AVALIDE during pregnancy. It is essential 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 AVALIDE should be made aware that they may experience lightheadedness, particularly during the initial days of treatment. They should be advised to inform their physician if they feel lightheaded or faint. In cases of fainting, patients must discontinue the use of AVALIDE and contact their prescribing doctor immediately.

It is important to educate patients about the risks of dehydration, which can lead to excessively low blood pressure, resulting in lightheadedness and potential fainting. Patients should be informed that dehydration may occur due to excessive sweating, diarrhea, vomiting, or inadequate fluid intake.

Patients should be cautioned against using potassium supplements or salt substitutes that contain potassium without first consulting their healthcare provider.

Healthcare providers must instruct patients to discontinue AVALIDE and seek immediate medical attention if they experience symptoms indicative of acute angle-closure glaucoma, acute myopia, or choroidal effusion.

For patients taking hydrochlorothiazide, it is crucial to advise them to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Storage and Handling

The product is supplied in accordance with the following specifications. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C and 30°C (59°F and 86°F) as defined by USP guidelines.

Proper storage conditions are essential to maintain the integrity of the product. It is recommended that the product be kept in its original container to protect it from environmental factors. Special handling requirements should be observed to ensure the product remains within the specified temperature range throughout its storage period.

Additional Clinical Information

Postmarketing experience has revealed several adverse reactions associated with AVALIDE, which includes irbesartan and hydrochlorothiazide. These reactions are reported voluntarily and may not reliably indicate their frequency or establish a causal relationship to the drug. The decision to include these reactions in labeling is based on factors such as the seriousness of the reaction, frequency of reporting, and strength of the causal connection to AVALIDE.

Adverse reactions identified include thrombocytopenia, hepatitis, jaundice, impaired renal function, and urticaria. Specific to irbesartan, additional reactions include anemia, tinnitus, intestinal angioedema, angioedema affecting the face and throat, anaphylactic reactions, increased CPK levels, hyperkalemia, and hypoglycemia in diabetic patients. Hydrochlorothiazide is associated with acute angle-closure glaucoma, acute myopia, and choroidal effusion. Furthermore, hydrochlorothiazide has been linked to an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), with a notable risk increase in white patients receiving high cumulative doses. The overall risk for SCC is approximately one additional case per 16,000 patients per year, escalating to one additional case per 6,700 patients per year for those taking ≥50,000 mg cumulatively.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Avalide as submitted by Sanofi-Aventis U. S. LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)