AVALIDE (irbesartan 150 mg hydrochlorothiazide 12.5 mg) Dailymed

Warning: Fetal Toxicity

• When pregnancy is detected, discontinue AVALIDE as soon as possible. [See Warnings and Precautions (5.1) .]
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. [See Warnings and Precautions (5.1) .]

WARNING: FETAL TOXICITY

See full prescribing information for complete boxed warning.

• When pregnancy is detected, discontinue AVALIDE as soon as possible. (5.1)
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)

• Hypotension: Correct volume-depletion prior to administration. (5.2)
• Impaired renal function. (5.8)
• Thiazide diuretics may cause an exacerbation or activation of systemic lupus erythematosus. (5.4)
• Acute myopia and secondary angle-closure glaucoma. (5.9)

5.1 Fetal Toxicity

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue AVALIDE as soon as possible [see Use in Specific Populations (8.1) ].

Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

5.2 Hypotension in Volume- or Salt-Depleted Patients

Excessive reduction of blood pressure was rarely seen in patients with uncomplicated hypertension treated with irbesartan alone (<0.1%) or with irbesartan-hydrochlorothiazide (approximately 1%). Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with intravascular volume- or sodium-depletion, e.g., in patients treated vigorously with diuretics or in patients on dialysis. Such volume depletion should be corrected prior to administration of antihypertensive therapy.

If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

5.3 Hypersensitivity Reaction

Hydrochlorothiazide

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

5.4 Systemic Lupus Erythematosus

Hydrochlorothiazide

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

5.5 Lithium Interaction

Hydrochlorothiazide

Lithium generally should not be given with thiazides. [See Drug Interactions (7) .]

5.6 Electrolyte and Metabolic Imbalances

Irbesartan-Hydrochlorothiazide

In double-blind clinical trials of various doses of irbesartan and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 7.5% versus 6.0% for placebo; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was <1.0% versus 1.7% for placebo. No patient discontinued due to increases or decreases in serum potassium. On average, the combination of irbesartan and hydrochlorothiazide had no effect on serum potassium. Higher doses of irbesartan ameliorated the hypokalemic response to hydrochlorothiazide.

Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium. Concurrent therapy with hydrochlorothiazide may reduce the frequency of this effect.

Hydrochlorothiazide

Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

5.7 Hepatic Impairment

Hydrochlorothiazide

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

5.8 Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals [see Drug Interactions (7) ]. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Irbesartan would be expected to behave similarly. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or BUN have been reported. There has been no known use of irbesartan in patients with unilateral or bilateral renal artery stenosis, but a similar effect should be anticipated.

Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

5.9 Acute Myopia and Secondary Angle-Closure Glaucoma

Sulfonamide or sulfonamide derivative drugs, such as hydrochlorothiazide, can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-closure glaucoma. Cases of acute angle-closure glaucoma have been reported with hydrochlorothiazide. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

6 Adverse Reactions

Most common adverse events (≥5% on AVALIDE and more often than on placebo) are dizziness, fatigue, and musculoskeletal pain. (6.1)

  To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Irbesartan-Hydrochlorothiazide

AVALIDE Tablets have been evaluated for safety in 1694 patients treated for essential hypertension in 6 clinical trials. In Studies I through IV with AVALIDE, no adverse events peculiar to this combination drug product have been observed. Adverse events have been limited to those that were reported previously with irbesartan or hydrochlorothiazide (HCTZ). The overall incidence of adverse events was similar with the combination and placebo. In general, treatment with AVALIDE was well tolerated. For the most part, adverse events have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of AVALIDE therapy due to clinical adverse events was required in only 3.6%. This incidence was significantly less (p=0.023) than the 6.8% of patients treated with placebo who discontinued therapy.

In these double-blind controlled clinical trials, the following adverse events reported with AVALIDE occurred in ≥1% of patients, and more often on the irbesartan-hydrochlorothiazide combination than on placebo, regardless of drug relationship:

	Irbesartan/HCTZ(n=898)(%)	Placebo(n=236)(%)	Irbesartan(n=400)(%)	HCTZ(n=380)(%)
Body as a Whole
Chest Pain	2	1	2	2
Fatigue	6	3	4	3
Influenza	3	1	2	2
Cardiovascular
Edema	3	3	2	2
Tachycardia	1	0	1	1
Gastrointestinal
Abdominal Pain	2	1	2	2
Dyspepsia/heartburn	2	1	0	2
Nausea/vomiting	3	0	2	2
Immunology
Allergy	1	0	1	1
Musculoskeletal
Musculoskeletal Pain	6	5	6	10
Nervous System
Dizziness	8	4	6	5
Dizziness Orthostatic	1	0	1	1
Renal/Genitourinary
Abnormality Urination	2	1	1	2

The following adverse events were also reported at a rate of 1% or greater, but were as, or more, common in the placebo group: headache, sinus abnormality, cough, URI, pharyngitis, diarrhea, rhinitis, urinary tract infection, rash, anxiety/nervousness, and muscle cramp.

Adverse events occurred at about the same rates in men and women, older and younger patients, and black and non-black patients.

Adverse events in Studies V and VI were similar to those described above in Studies I through IV.

Irbesartan

Other adverse events that have been reported with irbesartan, without regard to causality, are uled below:

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 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

Hydrochlorothiazide

Other adverse events that have been reported with hydrochlorothiazide, without regard to causality, are uled below:

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

Initial Therapy

In the moderate hypertension Study V (mean SeDBP between 90 and 110 mmHg), the types and incidences of adverse events reported for patients treated with AVALIDE were similar to the adverse event profile in patients on initial irbesartan or HCTZ monotherapy. There were no reported events of syncope in the AVALIDE treatment group and there was one reported event in the HCTZ treatment group. The incidences of pre-specified adverse events on AVALIDE, irbesartan, and HCTZ, respectively, were: 0.9%, 0%, and 0% for hypotension; 3.0%, 3.8%, and 1.0% for dizziness; 5.5%, 3.8%, and 4.8% for headache; 1.2%, 0%, and 1.0% for hyperkalemia; and 0.9%, 0%, and 0% for hypokalemia. The rates of discontinuation due to adverse events on AVALIDE, irbesartan alone, and HCTZ alone were 6.7%, 3.8%, and 4.8%.

In the severe hypertension (SeDBP ≥110 mmHg) Study VI, the overall pattern of adverse events reported through 7 weeks of follow-up was similar in patients treated with AVALIDE as initial therapy and in patients treated with irbesartan as initial therapy. The incidences of the pre-specified adverse events on AVALIDE and irbesartan, respectively, were: 0% and 0% for syncope; 0.6% and 0% for hypotension; 3.6% and 4.0% for dizziness; 4.3% and 6.6% for headache; 0.2% and 0% for hyperkalemia; and 0.6% and 0.4% for hypokalemia. The rates of discontinuation due to adverse events were 2.1% and 2.2%. [See Clinical Studies (14.2) .]

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of AVALIDE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to AVALIDE.

The following have been very rarely reported: urticaria, angioedema (involving swelling of the face, lips, pharynx, and/or tongue), and hepatitis. Hyperkalemia has been rarely reported.

Very rare cases of jaundice have been reported with irbesartan.

Impaired renal function, including cases of renal failure in patients at risk, has been reported with irbesartan and AVALIDE.

Cases of increased CPK and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

6.3 Laboratory Abnormalities

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of AVALIDE.

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in 2.3% and 1.1%, respectively, of patients with essential hypertension treated with AVALIDE alone. No patient discontinued taking AVALIDE due to increased BUN. One patient discontinued taking AVALIDE due to a minor increase in serum creatinine.

Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with AVALIDE alone, one patient was discontinued due to elevated liver enzymes.

Serum Electrolytes: [See Warnings and Precautions (5.2, 5.6) .]

7 Drug Interactions

Irbesartan (7):

• NSAIDs and selective COX-2 inhibitors: May lead to increased risk of renal impairment and loss of antihypertensive effect. Monitor renal function periodically.
• Dual blockade of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia.

Hydrochlorothiazide (7):

• Antidiabetic drugs: Dosage adjustment of antidiabetic may be required
• Cholestyramine and colestipol: Reduced absorption of thiazides
• Lithium: Reduced renal clearance and high risk of lithium toxicity when used with diuretics. Should not be given with diuretics.
• NSAIDs: Can reduce diuretic, natriuretic, and antihypertensive effects of diuretics and increase risk for renal impairment.
• Carbamazepine: Increased risk of hyponatremia.

Irbesartan

No significant drug-drug interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, and nifedipine. [See Clinical Pharmacology (12.3) .]

Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including irbesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving irbesartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.

DRUG INTERACTIONS SECTION

Dual Blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin-receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on AVALIDE and other agents that affect the RAS.

Do not coadminister aliskiren with AVALIDE in patients with diabetes. Avoid use of aliskiren with AVALIDE in patients with renal impairment (GFR <60 mL/min).

Hydrochlorothiazide

When administered concurrently the following drugs may interact with thiazide diuretics:

Alcohol, Barbiturates, or Narcotics: potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs (oral agents and insulin): dosage adjustment of the antidiabetic drug may be required.

Other Antihypertensive Drugs: additive effect or potentiation.

Cholestyramine and Colestipol Resins: absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. AVALIDE should be taken at least one hour before or four hours after these medications.

Corticosteroids, ACTH: intensified electrolyte depletion, particularly hypokalemia.

Pressor Amines (e.g., Norepinephrine): possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal Muscle Relaxants, Nondepolarizing (e.g., Tubocurarine): possible increased responsiveness to the muscle relaxant.

Lithium: should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with AVALIDE. [See Warnings and Precautions (5.5) .]

Non-steroidal Anti-inflammatory Drugs: in some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Therefore, when AVALIDE (irbesartan-hydrochlorothiazide) Tablets and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic hyponatremia. Electrolytes should be monitored during concomitant use.

8 Use In Specific Populations

• Nursing Mothers: Potential for adverse effects in infant. (8.3)

8.1 Pregnancy

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue AVALIDE as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue AVALIDE, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to AVALIDE for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4) ].

Irbesartan crosses the placenta in rats and rabbits. In pregnant rats given irbesartan at doses greater than the maximum recommended human dose (MRHD), fetuses showed increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla. Subcutaneous edema also occurred in fetuses at doses about 4 times the MRHD (based on body surface area). These anomalies occurred when pregnant rats received irbesartan through Day 20 of gestation but not when drug was stopped on gestation Day 15. The observed effects are believed to be late gestational effects of the drug. Pregnant rabbits given oral doses of irbesartan equivalent to 1.5 times the MRHD experienced a high rate of maternal mortality and abortion. Surviving females had a slight increase in early resorptions and a corresponding decrease in live fetuses [see Nonclinical Toxicology (13.2) ].

Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan.

When pregnant mice and rats were given hydrochlorothiazide at doses up to 3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the MRHD) during their respective periods of major organogenesis, there was no evidence of fetal harm.

A development toxicity study was performed in rats with doses of 50/50 mg/kg/day and 150/150 mg/kg/day irbesartan-hydrochlorothiazide. Although the high dose combination appeared to be more toxic to the dams than either drug alone, there did not appear to be an increase in toxicity to the developing embryos.

8.3 Nursing Mothers

It is not known whether irbesartan is excreted in human milk, but irbesartan or some metabolite of irbesartan is secreted at low concentration in the milk of lactating rats.

Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Neonates with a history of in utero exposure to AVALIDE:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of 1694 patients receiving AVALIDE in controlled clinical studies of hypertension, 264 (15.6%) were 65 years and over, while 45 (2.7%) were 75 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. [See Clinical Pharmacology (12.3) and Clinical Studies (14) .]