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

OLMESARTAN MEDOXOMIL, AMLODIPINE AND HYDROCHLOROTHIAZIDE- olmesartan medoxomil, amlodipine besylate and hydrochlorothiazide tablet, film coated
REMEDYREPACK INC.

WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets as soon as possible. ( 5.1 )

  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. ( 5.1 )

1 INDICATIONS AND USAGE

Olmesartan medoxomil, amlodipine and 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 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 40/10/25 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 co-administer 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

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 olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets as soon as possible [ 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 . Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2 ) 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 contains 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.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. 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.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 40/10/25 mg, olmesartan medoxomil/amlodipine 40/10 mg, olmesartan medoxomil/hydrochlorothiazide 40/25 mg, or amlodipine/hydrochlorothiazide 10/25 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 40/10/25 mg compared to 1% of patients treated with olmesartan medoxomil/amlodipine 40/10 mg, 2% of patients treated with olmesartan medoxomil/hydrochlorothiazide 40/25 mg, and 2% of patients treated with amlodipine/hydrochlorothiazide 10/25 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/ AML10/ HCTZ 25 mg (N = 574) n (%) OM 40/ AML10 mg (N = 596) n (%) OM 40/ HCTZ 25mg (N = 580) n (%) AML10/ HCTZ 25 mg (N = 552) n (%)
Edema peripheral 44 (7.7) 42 (7) 6 (1) 46 (8.3)
Headache 37 (6.4) 42 (7) 38 (6.6) 33 (6)
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) 14 (2.4) 13 (2.4)
Nausea 17 (3) 12 (2) 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) 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 tablets 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.

The following adverse reactions occurred in < 1% but > 0.1% of patients in controlled clinical trials under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert physicians to a possible relationship:

Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis

Central and Peripheral Nervous System : hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo

Gastrointestinal : anorexia, constipation, dyspepsia*, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia

General : allergic reaction, asthenia*, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease

Musculoskeletal System : arthralgia, arthrosis, muscle cramps*, myalgia

Psychiatric : sexual dysfunction (male* and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization

Respiratory : dyspnea*, epistaxis

Skin and Appendages : angioedema, erythema multiforme, pruritus*, rash*, rash erythematous, rash maculopapular

Special Senses : abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus

Urinary System : micturition frequency, micturition disorder, nocturia

Autonomic Nervous System: dry mouth, sweating increased

Metabolic and Nutritional: hyperglycemia, thirst

Hemopoietic: leukopenia, purpura, thrombocytopenia

* = events that occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

The following adverse reactions occurred in < 0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.

Hydrochlorothiazide

Other adverse reactions 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

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