Prescription Drug Information: Irbesartan and Hydrochlorothiazide

IRBESARTAN AND HYDROCHLOROTHIAZIDE — irbesartan and hydrochlorothiazide tablet
Alembic Pharmaceuticals Limited

WARNING: FETAL TOXICITY

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

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.

Figure 1 and 2
(click image for full-size original)

*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).

2. DOSAGE AND ADMINISTRATION

2.1 General Considerations

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 (e.g., pancreatitis), the former much more common than the latter [see Adverse Reactions (6)].
Maximum antihypertensive effects are attained within 2 to 4 weeks after a change in dose.
Irbesartan and Hydrochlorothiazide Tablets may be administered with or without food.
Irbesartan and Hydrochlorothiazide Tablets may be administered with other antihypertensive agents.
Renal impairment: The usual regimens of therapy with Irbesartan and Hydrochlorothiazide Tablets may be followed as long as the patient’s creatinine clearance is >30mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so Irbesartan and Hydrochlorothiazide Tablets is not recommended.
Hepatic impairment: No dosage adjustment is necessary in patients with hepatic impairment.

2.2 Add-On Therapy

In patients not controlled on monotherapy with irbesartan or hydrochlorothiazide, the recommended doses of Irbesartan and Hydrochlorothiazide Tablets, in order of increasing mean effect, are (irbesartan-hydrochlorothiazide) 150 mg/12.5 mg, 300 mg/12.5 mg, and 300 mg/25 mg. The largest incremental effect will likely be in the transition from monotherapy to 150 mg/12.5 mg [see Clinical Studies (14.2)].

2.3 Replacement Therapy

Irbesartan and Hydrochlorothiazide Tablets may be substituted for the titrated components.

2.4 Initial Therapy

The usual starting dose is Irbesartan and Hydrochlorothiazide Tablets 150 mg/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 300 mg/25 mg tablet once daily as needed to control blood pressure [see Clinical Studies (14.2)]. Irbesartan and Hydrochlorothiazide Tablets are not recommended as initial therapy in patients with intravascular volume depletion [see Warnings and Precautions (5.2)].

3. DOSAGE FORMS AND STRENGTHS

Irbesartan and Hydrochlorothiazide Tablets USP 150 mg/12.5 mg and 300 mg/12.5 mg are Peach coloured mottled, oval shaped, biconvex, uncoated tablets. 150 mg/12.5 mg debossed with “L180” on one side and plain on other side and 300 mg/12.5 mg debossed with “L181” on one side and plain on other side. Irbesartan and Hydrochlorothiazide Tablets USP 300 mg/25 mg is Pinkish brown, oval shaped, biconvex, film coated tablets, debossed with “L182” on one side and plain on other side.

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)].

5. WARNINGS AND PRECAUTIONS

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 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.

5.2 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 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% 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.

5.6 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.

5.7 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.

5.8 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.

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