Irbesartan and Hydrochlorothiazide (irbesartan 300 mg / hydrochlorothiazide 12.5 mg) Dailymed

1 Indications And Usage

Irbesartan and hydrochlorothiazide tablets USP are indicated for the treatment of hypertension.

Irbesartan and hydrochlorothiazide tablets USP may be used in patients whose blood pressure is not adequately controlled on monotherapy.

Irbesartan and hydrochlorothiazide tablets USP 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 USP 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 Clinical Studies (14.2)] provide estimates of the probability of reaching a blood pressure goal with irbesartan and hydrochlorothiazide tablets USP 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 USP compared to patients treated with irbesartan or HCTZ monotherapy are shown in Figures 1a through 2b.
Figure 1a: Probability of Achieving SBP < 140 mmHg in Patients From Initial Therapy Studies V (Week 8) and VI (Week 7)^* Figure 1b: Probability of Achieving SBP < 130 mmHg in Patients From Initial Therapy Studies V (Week 8) and VI (Week 7)^* Figure 2a: Probability of Achieving DBP < 90 mmHg in Patients From Initial Therapy Studies V (Week 8) and VI (Week 7)^* Figure 2b: Probability of Achieving DBP < 80 mmHg in Patients From Initial Therapy Studies V (Week 8) and VI (Week 7)^*
* 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 USP rises to about 40% (systolic) or 70% (diastolic).


Irbesartan and hydrochlorothiazide tablets USP are 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)

• 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

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 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 irbesartan and hydrochlorothiazide tablets and more often than on placebo) are dizziness, fatigue, and musculoskeletal pain. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safety@tevapharm.com; 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

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, 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 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 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 occurred in ≥ 1% of patients, and more often on the irbesartan-hydrochlorothiazide combination than on placebo, regardless of drug relationship:

	Irbesartan/HCTZ	Placebo	Irbesartan	HCTZ
	(n = 898)	(n = 236)	(n = 400)	(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 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 treatment group and there was one reported event in the HCTZ treatment group. The incidences of pre-specified adverse events on irbesartan and hydrochlorothiazide, 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 irbesartan and hydrochlorothiazide, 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 as initial therapy and in patients treated with irbesartan as initial therapy. The incidences of the pre-specified adverse events on irbesartan and hydrochlorothiazide 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 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of irbesartan and hydrochlorothiazide. 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.

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 irbesartan and hydrochlorothiazide.

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 irbesartan and hydrochlorothiazide.

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 irbesartan and hydrochlorothiazide alone. No patient discontinued taking irbesartan and hydrochlorothiazide due to increased BUN. One patient discontinued taking irbesartan and hydrochlorothiazide 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 irbesartan and hydrochlorothiazide alone, one patient was discontinued due to elevated liver enzymes.

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