Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide: Package Insert and Label Information

OLMESARTAN MEDOXOMIL, AMLODIPINE AND HYDROCHLOROTHIAZIDE- olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide tablet, film coated
Teva Pharmaceuticals USA, Inc.

WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets as soon as possible. (5.1, 8.1)
  • Drugs that act directly on the renin-angiotensin system (RAS) can cause injury and death to the developing fetus. (5.1, 8.1)

1 INDICATIONS AND USAGE

Olmesartan medoxomil, amlodipine, hydrochlorothiazide tablets are indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Limitations of Use

This fixed combination drug is not indicated for the initial therapy of hypertension.

2 DOSAGE AND ADMINISTRATION

Dose once daily. Dosage may be increased in 2-week intervals, as needed. The maximum recommended dose of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets is 40 mg/10 mg/25 mg.

Dose selection should be individualized based on previous therapy.

3 DOSAGE FORMS AND STRENGTHS

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are available in the following strength combinations:

20/5/12.5

40/5/12.5

40/5/25

40/10/12.5

40/10/25

Olmesartan medoxomil (mg)

20

40

40

40

40

Amlodipine equivalent (mg)

5

5

5

10

10

Hydrochlorothiazide (mg)

12.5

12.5

25

12.5

25

4 CONTRAINDICATIONS

Because of the hydrochlorothiazide component, olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are contraindicated in patients with anuria, hypersensitivity to any component, or hypersensitivity to other sulfonamide-derived drugs.

Do not coadminister aliskiren with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in patients with diabetes [see Drug Interactions (7.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

Olmesartan medoxomil. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets 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 olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets as soon as possible [see Use in Specific Populations (8.1)].

Hydrochlorothiazide. Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice and thrombocytopenia [see Use in Specific Populations (8.1)].

5.2 Hypotension in Volume- or Salt-Depleted Patients

Olmesartan medoxomil. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Initiate treatment with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give 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.

Amlodipine. Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.

5.3 Increased Angina and/or Myocardial Infarction

Amlodipine. Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction upon starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

5.4 Impaired Renal Function

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. Impaired renal function was reported in 2.1% of subjects receiving olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets compared to 0.2% to 1.3% of subjects receiving dual combination therapy of olmesartan medoxomil and amlodipine, olmesartan medoxomil and hydrochlorothiazide or amlodipine and hydrochlorothiazide.

If progressive renal impairment becomes evident consider withholding or discontinuing olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets.

Olmesartan medoxomil. Changes in renal function occur in some individuals treated with olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in patients treated with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets due to the olmesartan medoxomil component [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets because of the olmesartan medoxomil component.

Hydrochlorothiazide. Thiazides may precipitate azotemia in patients with renal disease. Cumulative effects of the drug may develop in patients with impaired renal function.

5.5 Patients with Hepatic Impairment

Amlodipine. Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2 ) is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment.

5.6 Electrolyte and Metabolic Imbalances

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets contain hydrochlorothiazide which can cause hypokalemia, hyponatremia and hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets also contain olmesartan, a drug that affects the RAS. Drugs that inhibit the RAS can also cause hyperkalemia.

Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

Hyperuricemia may occur or frank gout may be precipitated in patients receiving thiazide therapy.

Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.

5.7 Postsympathectomy Patients

The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.

5.8 Systemic Lupus Erythematosus

Hydrochlorothiazide. Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

5.9 Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. 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 hydrochlorothiazide 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.

5.10 Sprue-like Enteropathy

Olmesartan medoxomil. Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in cases where no other etiology is identified.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide Tablets

In the controlled trial of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets, patients were randomized to olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets 40 mg/10 mg/25 mg, olmesartan medoxomil/amlodipine 40 mg/10 mg, olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg, or amlodipine/hydrochlorothiazide 10 mg/25 mg. Subjects who received triple combination therapy were treated between two and four weeks with one of the three dual combination therapies. Safety data from this study were obtained in 574 patients with hypertension who received olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets for 8 weeks.

The frequency of adverse reactions was similar between men and women, patients <65 years of age and patients ≥65 years of age, patients with and without diabetes, and Black and non-Black patients. Discontinuations because of adverse events occurred in 4% of patients treated with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets, 40 mg/10 mg/25 mg compared to 1% of patients treated with olmesartan medoxomil/amlodipine 40 mg/10 mg, 2% of patients treated with olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg, and 2% of patients treated with amlodipine/hydrochlorothiazide 10 mg/25 mg. The most common reason for discontinuation with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets was dizziness (1%).

Dizziness was one of the most frequently reported adverse reactions with incidence of 1.4% to 3.6% in subjects continuing on dual combination therapy compared to 5.8% to 8.9% in subjects who switched to olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets.

The other most frequent adverse reactions that occurred in at least 2% of subjects are presented in the table below:

Table 1

Adverse Reaction

OM 40 mg/AML 10 mg/

HCTZ 25 mg

(N = 574)

n (%)

OM 40 mg/

AML 10 mg

(N = 596)

n (%)

OM 40 mg/

HCTZ 25 mg

(N = 580)

n (%)

AML10 mg/

HCTZ 25 mg

(N = 552)

n (%)

Edema peripheral

44 (7.7)

42 (7.0)

6 (1.0)

46 (8.3)

Headache

37 (6.4)

42 (7.0)

38 (6.6)

33 (6.0)

Fatigue

24 (4.2)

34 (5.7)

31 (5.3)

36 (6.5)

Nasopharyngitis

20 (3.5)

11 (1.8)

20 (3.4)

16 (2.9)

Muscle spasms

18 (3.1)

12 (2.0)

14 (2.4)

13 (2.4)

Nausea

17 (3.0)

12 (2.0)

22 (3.8)

12 (2.2)

Upper respiratory tract infection

16 (2.8)

26 (4.4)

18 (3.1)

14 (2.5)

Diarrhea

15 (2.6)

14 (2.3)

12 (2.1)

9 (1.6)

Urinary tract infection

14 (2.4)

8 (1.3)

6 (1.0)

7 (1.3)

Joint swelling

12 (2.1)

17 (2.9)

2 (0.3)

16 (2.9)


Syncope was reported by 1% of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablet subjects compared to 0.5% or less for the other treatment groups.

Olmesartan medoxomil

Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 treated for at least 1 year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse reactions similar to that seen with placebo. Adverse reactions were generally mild, transient, and without relationship to the dose of olmesartan medoxomil.

Amlodipine

Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials.

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