1. INDICATIONS AND USAGE Irbesartan and Hydrochlorothiazide Tablets are indicated for the treatment of hypertension. Irbesartan and Hydrochlorothiazide Tablets may be used in patients whose blood pressure is not adequately controlled on monotherapy. Irbesartan and Hydrochlorothiazide Tablets 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 Irbesartan and Hydrochlorothiazide Tablets 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 mono therapy.
Data from Studies V and VI [see Clinical Studies (14.2)] provide estimates of the probability of reaching a blood pressure goal with Irbesartan and Hydrochlorothiazide Tablets compared to irbesartan or HCTZ monotherapy. The relationship between baseline blood pressure and achievement of a SeSBP <140 or <130 mmHg or SeDBP <90 or <80 mmHg in patients treated with Irbesartan and Hydrochlorothiazide Tablets compared to patients treated with irbesartan or HCTZ monotherapy are shown in Figures 1a through 2b. *For all probability curves, patients without blood pressure measurements at Week 7 (Study VI) and Week 8 (Study V) were counted as not reaching goal (intent-to- treat analysis).
The above graphs provide a rough approximation of the likelihood of reaching a targeted blood pressure goal (e.g., 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 <140 mmHg (systolic) and 50% likelihood of achieving <90 mmHg (diastolic) on irbesartan alone (and lower still likelihoods on HCTZ alone). The likelihood of achieving these goals on Irbesartan and Hydrochlorothiazide Tablets rises to about 40% (systolic) or 70% (diastolic). Irbesartan and Hydrochlorothiazide Tablets USP is a combination of irbesartan, an angiotensin II receptor antagonist, and hydrochlorothiazide, a thiazide diuretic, indicated for hypertension: In patients not adequately controlled with monotherapy.
(1) As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals. (1) Figure 1 and 2
Contraindications
4. CONTRAINDICATIONS Irbesartan and Hydrochlorothiazide Tablets are 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. Do not co-administer aliskiren with Irbesartan and Hydrochlorothiazide Tablets in patients with diabetes [see Drug Interactions (7)] .
Hypersensitivity to any component of this product (4) Anuria (4) Hypersensitivity to sulfonamide-derived drugs (4) Do not co-administer aliskiren with Irbesartan and Hydrochlorothiazide Tablets in patients with diabetes (4)
Warnings and precautions
5. WARNINGS AND PRECAUTIONS Hypotension: Correct volume-depletion prior to administration. (5.2) Impaired renal function. (5.7) Thiazide diuretics may cause an exacerbation or activation of systemic lupus erythematosus. (5.4) Acute myopia and secondary angle-closure glaucoma. (5.8)
5.1Fetal Toxicity 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 Irbesartan and Hydrochlorothiazide Tablets 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.
5.2Hypotension 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.
5.3Hypersensitivity 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.
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
5.5Electrolyte 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% for placebo; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was <1% 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. Coadministration of Irbesartan and Hydrochlorothiazide Tablets with potassium sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that raise serum potassium levels may result in hyperkalemia, sometimes severe. Monitor serum potassium in such patients. 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.
5.6Hepatic 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.
5.7 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.
5.8Acute 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.
Interactions
7. DRUG INTERACTIONS
NSAIDs and selective COX-2 inhibitors: Can reduce diuretic, natriuretic of diuretic, may lead to increased risk of renal impairment and reduced antihypertensive effect. Monitor renal function periodically. (7)
Dual blockade of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia (7)
Antidiabetic drugs: Dosage adjustment of antidiabetic may be required. (7)
Cholestyramine and colestipol: Reduced absorption of thiazides (7)
Lithium: Increases in serum lithium concentrations and lithium toxicity (7)
Carbamazepine: Increased risk of hyponatremia. (7)
7.1Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) Irbesartan
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. The antihypertensive effect of ARBs may be attenuated by NSAIDs.
Therefore, monitor renal function and blood pressure periodically in patients receiving irbesartan and NSAID therapy. Hydrochlorothiazide Administration of a non-steroidal anti-inflammatory agent, including a selective COX-2 inhibitor can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Therefore, when Irbesartan and 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.
7.2Dual 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 Irbesartan and Hydrochlorothiazide Tablets and other agents that affect the RAS. In most patients no benefit has been associated with using two RAS inhibitors concomitantly.
In general, avoid combined use of RAS inhibitors. Do not coadminister aliskiren with Irbesartan and Hydrochlorothiazide Tablets in patients with diabetes. Avoid use of aliskiren with Irbesartan and Hydrochlorothiazide Tablets in patients with renal impairment (GFR <60 mL/min).
7.3Agents Increasing Serum Potassium Coadministration of Irbesartan and Hydrochlorothiazide
Tabletswith other drugs that raise serum potassium levels may result in hyperkalemia, sometimes severe. Monitor serum potassium in such patients.
7.4Antidiabetic Drugs
(oral agents and insulin) Dosage adjustment of the antidiabetic drug may be required when coadministered with hydrochlorothiazide.
7.5Cholestyramine and Colestipol Resins Absorption
of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Stagger the dosage of hydrochlorothiazide and the resin such that Irbesartan and Hydrochlorothiazide Tablets are administered at least 4 hours before or 4 to 6 hours after the administration of the resin.
7.6Lithium Increases
in serum lithium concentrations and lithium toxicity have been reported with concomitant use of irbesartan or thiazide diuretics. Monitor lithium levels in patients receiving Irbesartan and Hydrochlorothiazide Tablets and lithium.
7.7Carbamazepine
Concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic hyponatremia. Monitor electrolytes during concomitant use.
Pregnancy and breastfeeding
8.1Pregnancy 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 Irbesartan and Hydrochlorothiazide Tablets 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 Irbesartan and Hydrochlorothiazide Tablets, 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 Irbesartan and Hydrochlorothiazide Tabletsfor 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.
Adverse reactions
6. ADVERSE REACTIONS Most common adverse events (≥5% on Irbesartan and Hydrochlorothiazide Tablets and more often than on placebo) are dizziness, fatigue, and musculoskeletal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical 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 Irbesartan and Hydrochlorothiazide Tablets have been evaluated for safety in 1694 patients treated for essential hypertension in 6 clinical trials. In Studies I through IV with Irbesartan and Hydrochlorothiazide Tablets, 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 Irbesartan and Hydrochlorothiazide Tablets 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 Irbesartan and Hydrochlorothiazide Tablets 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 Irbesartan and Hydrochlorothiazide Tablets 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 listed 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 listed 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 Irbesartan and Hydrochlorothiazide Tablets were similar to the adverse event profile in patients on initial irbesartan or HCTZ monotherapy.
There were no reported events of syncope in the Irbesartan and Hydrochlorothiazide Tablets treatment group and there was one reported event in the HCTZ treatment group. The incidences of pre-specified adverse events on Irbesartan and Hydrochlorothiazide Tablets, irbesartan, and HCTZ, respectively, were: 0.9%, 0%, and 0% for hypotension; 3%, 3.8%, and 1% for dizziness; 5.5%, 3.8%, and 4.8% for headache; 1.2%, 0%, and 1% for hyperkalemia; and 0.9%, 0%, and 0% for hypokalemia.
The rates of discontinuation due to adverse events on Irbesartan and Hydrochlorothiazide Tablets, 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 Irbesartan and Hydrochlorothiazide Tablets as initial therapy and in patients treated with irbesartan as initial therapy.
The incidences of the pre-specified adverse events on Irbesartan and Hydrochlorothiazide Tablets and irbesartan, respectively, were: 0% and 0% for syncope; 0.6% and 0% for hypotension; 3.6% and 4% 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)].
6.2Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of Irbesartan and Hydrochlorothiazide Tablets. 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 Irbesartan and Hydrochlorothiazide Tablets.
The following have been reported with irbesartan and with hydrochlorothiazide monotherapies: urticaria, jaundice, hepatitis, thrombocytopenia, impaired renal function including renal failure. The following have been reported with irbesartan monotherapy: tinnitus, hyperkalemia, angioedema (involving swelling of the face, lips, pharynx, and/or tongue), increased CPK The following have been reported with hydrochlorothiazide monothe
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Composition
Active ingredients
HYDROCHLOROTHIAZIDE 25MG; IRBESARTAN 300MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
