Avalide Information
Avalide (Ibesartan) Warning: Use In Pregnancy
When pregnancy is detected, discontinue Avalide (Ibesartan) as soon as possible. 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. [See.]
Avalide (Ibesartan) Indications And Usage
Avalide (Ibesartan) (irbesartan-hydrochlorothiazide) Tablets is indicated for the treatment of hypertension.
Avalide (Ibesartan) may be used in patients whose blood pressure is not adequately controlled on monotherapy.
Avalide (Ibesartan) may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals.
The choice of Avalide (Ibesartan) as initial therapy for hypertension should be based on an assessment of potential benefits and risks.
Patients with stage 2 (moderate or severe) hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and may be shaped by considerations such as the baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy.
Data from Studies V and VI [see ] provide estimates of the probability of reaching a blood pressure goal with Avalide (Ibesartan) compared to irbesartan or HCTZ monotherapy. The relationship between baseline blood pressure and achievement of a SeSBP
The above graphs provide a rough approximation of the likelihood of reaching a targeted blood pressure goal (eg, Week 8 sitting systolic blood pressure ≤140 mmHg) for the treatment groups. The curve of each treatment group in each study was estimated by logistic regression modeling from all available data of that treatment group. The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures.
For example, a patient with a blood pressure of 180/105 mmHg has about a 25% likelihood of achieving a goal of
The likelihood of achieving these goals on Avalide (Ibesartan) rises to about 40% (systolic) or 70% (diastolic).
Avalide (Ibesartan) Dosage And Administration
The side effects 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 (eg, pancreatitis), the former much more common than the latter. [See .]
Maximum antihypertensive effects are attained within 2 to 4 weeks after a change in dose.
Avalide (Ibesartan) may be administered with or without food.
Avalide (Ibesartan) may be administered with other antihypertensive agents.
Renal impairment.
Hepatic impairment.
Avalide (Ibesartan) Dosage Forms And Strengths
Avalide (Ibesartan) (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 (Ibesartan) Warnings And Precautions
Excessive reduction of blood pressure was rarely seen in patients with uncomplicated hypertension treated with irbesartan alone (
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.
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.
Hydrochlorothiazide
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Hydrochlorothiazide
Lithium generally should not be given with thiazides. [See .]
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.
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 (eg, 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.
Avalide (Ibesartan) Adverse Reactions
The following adverse reactions have been identified during post-approval use of Avalide (Ibesartan) . 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 (Ibesartan) .
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.
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 (Ibesartan) .
Creatinine, Blood Urea Nitrogen:
Liver Function Tests:
Avalide (Ibesartan) Drug Interactions
Irbesartan
No significant drug-drug interactions have been reported with irbesartan. [See .]
Hydrochlorothiazide
When administered concurrently the following drugs may interact with thiazide diuretics:
Alcohol, Barbiturates, or Narcotics:
Antidiabetic Drugs (oral agents and insulin):
Other Antihypertensive Drugs:
Cholestyramine and Colestipol Resins:
Corticosteroids, ACTH:
Pressor Amines (eg, Norepinephrine):
Skeletal Muscle Relaxants, Nondepolarizing (eg, Tubocurarine):
Non-steroidal Anti-inflammatory Drugs:
Avalide (Ibesartan) Use In Specific Populations
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.
Avalide (Ibesartan) Overdosage
Irbesartan
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 listed in the (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 MRHD (300 mg) on a mg/m basis, respectively.
Hydrochlorothiazide
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 LD of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.
Avalide (Ibesartan) Description
Avalide (Ibesartan) (irbesartan-hydrochlorothiazide) Tablets is a combination of an angiotensin II receptor antagonist (AT subtype), irbesartan, and a thiazide diuretic, hydrochlorothiazide (HCTZ).
Irbesartan is a non-peptide compound, chemically described as a 2-butyl-3-[-(-1-tetrazol-5-ylphenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one. Its empirical formula is CHNO, 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-2-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is CHClNOS 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 (Ibesartan) 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.
Avalide (Ibesartan) Clinical Studies
The antihypertensive effects of irbesartan were examined in 7 major placebo-controlled, 8- to 12-week trials in patients with baseline diastolic blood pressures of 95 to 110 mmHg. Doses of 1 to 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 7 placebo-controlled trials identified above and 2 additional placebo-controlled studies examined the antihypertensive effects of irbesartan and hydrochlorothiazide in combination.
The 7 studies of irbesartan monotherapy included a total of 1915 patients randomized to irbesartan (1 to 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 to 12 weeks of treatment compared to placebo, of about 8 to 10/5 to 6 mmHg and 8 to 12/5 to 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 3 and 4.
Once-daily administration of therapeutic doses of irbesartan gave peak effects at around 3 to 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% to 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 (eg, 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.
The antihypertensive effects of Avalide (Ibesartan) (irbesartan-hydrochlorothiazide) Tablets were examined in 4 placebo-controlled studies in patients with mild-moderate hypertension (mean seated diastolic blood pressure [SeDBP] between 90 and 110 mmHg), one study in patients with moderate hypertension (mean seated systolic blood pressure [SeSBP] 160 to 179 mmHg or SeDBP 100 to 109 mmHg), and one study in patients with severe hypertension (mean SeDBP ≥110 mmHg) of 8 to 12 weeks. These trials included 3149 patients randomized to fixed doses of irbesartan (37.5 to 300 mg) and concomitant hydrochlorothiazide (6.25 to 25 mg).
Study I was a factorial study that compared all combinations of irbesartan (37.5 mg, 100 mg, and 300 mg or placebo) and hydrochlorothiazide (6.25 mg, 12.5 mg, and 25 mg or placebo).
Study II compared the irbesartan-hydrochlorothiazide combinations of 75/12.5 mg and 150/12.5 mg to their individual components and placebo.
Study III investigated the ambulatory blood pressure responses to irbesartan-hydrochlorothiazide (75/12.5 mg and 150/12.5 mg) and placebo after 8 weeks of dosing.
Study IV investigated the effects of the addition of irbesartan (75 or 150 mg) in patients not controlled (SeDBP 93-120 mmHg) on hydrochlorothiazide (25 mg) alone. In Studies I–III, the addition of irbesartan 150 to 300 mg to hydrochlorothiazide doses of 6.25, 12.5, or 25 mg produced further dose-related reductions in blood pressure at trough of 8 to 10 mmHg/3 to 6 mmHg, similar to those achieved with the same monotherapy dose of irbesartan. The addition of hydrochlorothiazide to irbesartan produced further dose-related reductions in blood pressure at trough (24 hours post-dose) of 5 to 6/2 to 3 mmHg (12.5 mg) and 7 to 11/4 to 5 mmHg (25 mg), also similar to effects achieved with hydrochlorothiazide alone. Once-daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide, 300 mg irbesartan and 12.5 mg hydrochlorothiazide, or 300 mg irbesartan and 25 mg hydrochlorothiazide produced mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of about 13 to 15/7 to 9 mmHg, 14/9 to 12 mmHg, and 19 to 21/11 to 12 mmHg, respectively. Peak effects occurred at 3 to 6 hours, with the trough-to-peak ratios >65%.
In Study IV, the addition of irbesartan (75–150 mg) gave an additive effect (systolic/diastolic) at trough (24 hours post-dosing) of 11/7 mmHg.
Avalide (Ibesartan) Patient Counseling Information
Patients using Avalide (Ibesartan) should be told that they may feel lightheaded, especially during the first days of use. Patients should inform their physician if they feel lightheaded or faint. If fainting occurs, the patient should stop using Avalide (Ibesartan) and contact the prescribing doctor.
Patients using Avalide (Ibesartan) should be told that getting dehydrated can lower their blood pressure too much and lead to lightheadedness and possible fainting. Dehydration may occur with excessive sweating, diarrhea, or vomiting and with not drinking enough liquids.
Avalide (Ibesartan)
Avalide (Ibesartan) Principal Display Panel- / . Mg
(irbesartan hydrochlorothiazide) tablets
Each tablet contains 150/12.5 mg of irbesartan hydrochlorothiazide.
Avalide (Ibesartan) Principal Display Panel- / . Mg
(irbesartan hydrochlorothiazide) tablets
Each tablet contains 300/12.5 mg of irbesartan hydrochlorothiazide.
