AVALIDE^®
(irbesartan-hydrochlorothiazide)
Tablets

When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, AVALIDE should be discontinued as soon as possible. (See WARNINGS: Fetal/Neonatal Morbidity and Mortality.)

AVALIDE^®* (irbesartan-hydrochlorothiazide) Tablets is a combination of an angiotensin II receptor antagonist (AT₁ subtype), irbesartan, and a thiazide diuretic, hydrochlorothiazide (HCTZ).

*Registered trademark of Sanofi-Synthelabo

Irbesartan is a non-peptide compound, chemically described as a 2-butyl-3-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one. Its empirical formula is C₂₅H₂₈N₆O, and its structural formula is:

Irbesartan is a white to off-white crystalline powder with a molecular weight of 428.5. It is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4. Irbesartan is slightly soluble in alcohol and methylene chloride and practically insoluble in water.

Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C₇H₈ClN₃O₄S₂ and its structural formula is:

Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.7. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution.

AVALIDE is available for oral administration in tablets containing either 150 mg or 300 mg of irbesartan combined with 12.5 mg of hydrochlorothiazide or 300 mg of irbesartan combined with 25 mg hydrochlorothiazide. Inactive ingredients include: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, ferric oxide red, ferric oxide yellow, silicon dioxide, and magnesium stearate. In addition, the 300/25 mg pink film-coated tablet contains ferric oxide black, hypromellose-2910, PEG-3350, titanium dioxide, and carnauba wax.

The antihypertensive effects of irbesartan were examined in seven (7) major placebo-controlled, 8–12 week trials in patients with baseline diastolic blood pressures of 95–110 mmHg. Doses of 1–900 mg were included in these trials in order to fully explore the dose-range of irbesartan. These studies allowed a comparison of once- or twice-daily regimens at 150 mg/day, comparisons of peak and trough effects, and comparisons of response by gender, age, and race. Two of the seven placebo-controlled trials identified above and two additional placebo-controlled studies examined the antihypertensive effects of irbesartan and hydrochlorothiazide in combination.

The seven (7) studies of irbesartan monotherapy included a total of 1915 patients randomized to irbesartan (1–900 mg) and 611 patients randomized to placebo. Once-daily doses of 150 to 300 mg provided statistically and clinically significant decreases in systolic and diastolic blood pressure with trough (24 hour post-dose) effects after 6–12 weeks of treatment compared to placebo, of about 8–10/5–6 and 8–12/5–8 mmHg, respectively. No further increase in effect was seen at dosages greater than 300 mg. The dose-response relationships for effects on systolic and diastolic pressure are shown in Figures 1 and 2.

Once-daily administration of therapeutic doses of irbesartan gave peak effects at around 3–6 hours and, in one continuous ambulatory blood pressure monitoring study, again around 14 hours. This was seen with both once-daily and twice-daily dosing. Trough-to-peak ratios for systolic and diastolic response were generally between 60–70%. In a continuous ambulatory blood pressure monitoring study, once-daily dosing with 150 mg gave trough and mean 24-hour responses similar to those observed in patients receiving twice-daily dosing at the same total daily dose.

Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over and under 65 years of age, had generally similar responses. Irbesartan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in blacks (usually a low-renin population). Black patients typically show an improved response with the addition of a low dose diuretic (e.g., 12.5 mg hydrochlorothiazide).

The effect of irbesartan is apparent after the first dose and is close to the full observed effect at 2 weeks. At the end of the 8-week exposure, about 2/3 of the antihypertensive effect was still present 1 week after the last dose. Rebound hypertension was not observed. There was essentially no change in average heart rate in irbesartan-treated patients in controlled trials.

AVALIDE (irbesartan-hydrochlorothiazide) Tablets is indicated for the treatment of hypertension. This fixed dose combination is not indicated for initial therapy (see DOSAGE AND ADMINISTRATION).

AVALIDE is contraindicated in patients who are hypersensitive to any component of this product.

Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, AVALIDE (irbesartan-hydrochlorothiazide) Tablets should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of AVALIDE as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.

If oligohydramnios is observed, AVALIDE (irbesartan-hydrochlorothiazide) Tablets should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (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 ≥50 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD], 300 mg/day, on a body surface area basis). Subcutaneous edema was observed in fetuses at doses ≥180 mg/kg/day (about 4 times the MRHD on a body surface area basis). As these anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was limited to gestation days 6–15, they appear to reflect late gestational effects of the drug. 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) had a slight increase in early resorptions and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in rats and rabbits.

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

Studies in which hydrochlorothiazide was administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.

A development toxicity study was performed in rats with doses of 50/50 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.

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

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.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. 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 angiotensin converting enzyme 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.

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. 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.

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.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of AVALIDE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

AVALIDE (irbesartan-hydrochlorothiazide) Tablets has been evaluated for safety in 898 patients treated for essential hypertension. In clinical trials with AVALIDE, no adverse experiences peculiar to this combination drug product have been observed. Adverse experiences have been limited to those that were reported previously with irbesartan and/or hydrochlorothiazide (HCTZ). The overall incidence of adverse experiences reported with the combination was comparable to placebo. In general, treatment with AVALIDE was well tolerated. For the most part, adverse experiences 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 experiences 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 experiences reported with AVALIDE occurred in ≥1% of patients, and more often on the irbesartan-hydrochlorothiazide combination than on placebo, regardless of drug relationship:

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.

Other adverse experiences 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, cardio-respiratory arrest, heart failure, hypertensive crisis

Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria

Endocrine/Metabolic/Electrolyte Imbalances: sexualdysfunction, 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

Other adverse experiences 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

The following have been very rarely reported in post-marketing experience: 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.

Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of AVALIDE (irbesartan-hydrochlorothiazide) Tablets.

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.

Hemoglobin: Mean decreases of approximately 0.2 g/dL occurred in patients treated with AVALIDE alone, but were rarely of clinical importance. This compared to a mean of 0.4 g/dL in patients receiving placebo. No patients were discontinued due to anemia.

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 PRECAUTIONS.)

No data are available in regard to overdosage in humans. However, daily doses of 900 mg for 8 weeks were well tolerated. The most likely manifestations of overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. Irbesartan is not removed by hemodialysis.

To obtain up-to-date information about the treatment of overdosage, a good resource is a certified regional Poison Control Center. Telephone numbers of certified Poison Control Centers are uled in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of 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 such determinations have, in any event, no established role in the management of irbesartan overdose.

Acute oral toxicity studies with irbesartan in mice and rats indicated acute lethal doses were in excess of 2000 mg/kg, about 25- and 50-fold the maximum recommended human dose (300 mg) on a mg/m² basis, respectively.

The most common signs and symptoms of overdose observed in humans are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD₅₀ of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

The recommended initial dose of irbesartan is 150 mg once daily. Patients requiring further reduction in blood pressure should be titrated to 300 mg once daily.

A lower initial dose of irbesartan (75 mg) is recommended in patients with depletion of intravascular volume (e.g., patients treated vigorously with diuretics or on hemodialysis) (see WARNINGS: Hypotension in Volume- or Salt-depleted Patients). Patients not adequately treated by the maximum dose of 300 mg once daily are unlikely to derive additional benefit from a higher dose or twice-daily dosing.

Hydrochlorothiazide is effective in doses of 12.5 to 50 mg once daily.

To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.

The side effects (see WARNINGS) of irbesartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of irbesartan and hydrochlorothiazide will be associated with both sets of dose-independent side effects.

AVALIDE may be administered with other antihypertensive agents.

AVALIDE may be administered with or without food.

The combination may be substituted for the titrated components.

A patient whose blood pressure is inadequately controlled by irbesartan or hydrochlorothiazide alone may be switched to once daily AVALIDE. Recommended doses of AVALIDE, in order of increasing mean effect, are (irbesartan-hydrochlorothiazide) 150/12.5 mg, 300/12.5 mg, and 300/25 mg. The largest incremental effect will likely be in the transition from monotherapy to 150/12.5 mg. (See CLINICAL PHARMACOLOGY: Clinical Studies.) It takes 2–4 weeks for the blood pressure to stabilize after a change in the dose of AVALIDE.

The usual dose of AVALIDE is one tablet once daily. The maximal antihypertensive effect is attained about 2–4 weeks after initiation of therapy.

The usual regimens of therapy with AVALIDE may be followed as long as the patient's creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so AVALIDE is not recommended.

No dosage adjustment is necessary in patients with hepatic impairment.

AVALIDE^® (irbesartan-hydrochlorothiazide) 150/12.5 mg and 300/12.5 mg tablets are peach, biconvex, and oval with a heart debossed on one side and “2775” or “2776” on the reverse side. The 300/25 mg film-coated tablet is pink, biconvex, and oval with a heart debossed on one side and “2788” on the reverse side. AVALIDE^® Tablets are supplied as follows:

Store at 25° C (77° F); excursions permitted to 15° C - 30° C (59° F - 86° F) [see USP Controlled Room Temperature].