Irbesartan and Hydrochlorothiazide

IRBESARTAN AND HYDROCHLOROTHIAZIDE — hydrochlorothiazide and irbesartan tablet, film coated
Lupin Pharmaceuticals, Inc.

WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue irbesartan and hydrochlorothiazide tablets as soon as possible [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

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 compared to irbesartan or hydrochlorothiazide (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 compared to patients treated with irbesartan or HCTZ monotherapy are shown in Figures 1a through 2b.

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

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 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 USP may be administered with or without food.

Irbesartan and hydrochlorothiazide tablets USP may be administered with other antihypertensive agents.

Renal Impairment

The usual regimens of therapy with irbesartan and hydrochlorothiazide tablets USP 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 irbesartan and hydrochlorothiazide 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 USP, in order of increasing mean effect, are (irbesartan and 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 STUDIES (14.2)].

2.3 Replacement Therapy

Irbesartan and hydrochlorothiazide tablets USP may be substituted for the titrated components.

2.4 Initial Therapy

The usual starting dose is irbesartan and hydrochlorothiazide tablets USP, 150/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of 300/25 mg once daily as needed to control blood pressure [see CLINICAL STUDIES (14.2)]. Irbesartan and hydrochlorothiazide tablet USP is 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 film-coated tablets are light peach, biconvex, oval shaped, imprinted with “L058” on one side and plain on the other side; and 300 mg/12.5 mg film-coated tablets are light peach, biconvex, oval shaped, imprinted with “L059” on one side and plain on the other side.

4 CONTRAINDICATIONS

  • Irbesartan and hydrochlorothiazide 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.
  • Do not coadminister aliskiren with irbesartan and hydrochlorothiazide in patients with diabetes [see DRUG INTERACTIONS (7)].

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

Irbesartan and hydrochlorothiazide can cause fetal harm when administered to a pregnant woman. 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 and 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.

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