Azor

Amlodipine is a calcium channel blocker. It works by relaxing the muscles of your heart and blood vessels.

Olmesartan is an angiotensin II receptor antagonist. Olmesartan keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.

Amlodipine and olmesartan is a combination medicine used to treat high blood pressure (hypertension). Lowering blood pressure may lower your risk of a stroke or heart attack.

Amlodipine and olmesartan may also be used for purposes not listed in this medication guide.

You should not use this medicine if you are allergic to amlodipine (Norvasc) or olmesartan (Benicar).

If you have diabetes, do not use amlodipine and olmesartan together with any medication that contains aliskiren (such as Amturnide, Tekturna, Tekamlo).

You may also need to avoid taking amlodipine and olmesartan with aliskiren if you have kidney disease.

To make sure amlodipine and olmesartan is safe for you, tell your doctor if you have:

• kidney disease;

• liver disease;

• coronary artery disease;

• angina (chest pain), congestive heart failure;

• high levels of potassium in your blood;

• if you are on a low-salt diet;

• if you are 75 years or older; or

• if you recently had a heart attack.

Do not use if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away. Amlodipine and olmesartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

It is not known whether amlodipine and olmesartan passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Amlodipine and olmesartan is not approved for use by anyone younger than 18 years old.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

In rare cases, when you first start taking this medicine, you may have new or worsening chest pain (angina), or you could have a heart attack. Seek emergency medical attention or call your doctor right away if you have symptoms such as: chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating.

Call your doctor at once if you have:

• new or worsening chest pain;

• severe or ongoing diarrhea with weight loss;

• pounding heartbeats or fluttering in your chest;

• a light-headed feeling, like you might pass out;

• swelling in your hands or feet, rapid weight gain;

• jaundice (yellowing of the skin or eyes); or

• high potassium--nausea, slow or unusual heart rate, weakness, loss of movement.

Common side effects include:

• dizziness, drowsiness;

• swelling;

• skin rash or itching;

• flushing (warmth, redness, or tingly feeling); or

• increased urination (especially at night).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• cyclosporine, lithium, simvastatin, tacrolimus; or

• NSAIDs (nonsteroidal anti-inflammatory drugs)--aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete. Other drugs may interact with amlodipine and olmesartan, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

• If you have an allergy to amlodipine, olmesartan, or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are taking a drug that has aliskiren in it and you also have high blood sugar (diabetes) or kidney problems. Check with your doctor or pharmacist if you are not sure if a drug you take has aliskiren in it.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with Azor.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Azor is 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 Azor.

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.

Azor may also be used as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals.

Patients with 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 should be shaped by considerations such as baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk.

Data from an 8-week, placebo-controlled, parallel-group factorial study [see Clinical Studies (14.1)] provide estimates of the probability of reaching a blood pressure goal with Azor compared to amlodipine or olmesartan medoxomil monotherapy. The figures below provide estimates of the likelihood of achieving the targeted systolic or diastolic blood pressure goals with Azor 10/40 mg compared with amlodipine or olmesartan medoxomil monotherapy, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling from all available data of that treatment group. The right tail of each curve is less reliable because of small numbers of subjects with high baseline blood pressures.

Figure 1: Probability of Achieving Systolic Blood Pressure (SBP) <140 mmHg at Week 8 With LOCF

Figure 2: Probability of Achieving Diastolic Blood Pressure (DBP) <90 mmHg at Week 8 With LOCF

Figure 3: Probability of Achieving Systolic Blood Pressure (SBP) <130 mmHg at Week 8 With LOCF

Figure 4: Probability of Achieving Diastolic Blood Pressure (DBP) <80 mmHg at Week 8 With LOCF

The figures above provide an approximation of the likelihood of reaching a targeted blood pressure goal (e.g., Week 8 SBP <140 mmHg or <130 mmHg or a DBP <90 mmHg or <80 mmHg) for the high-dose treatment groups evaluated in the study. Azor 5/20 mg, the lowest dose combination treatment group, increases the probability of reaching blood pressure goal compared with the highest dose monotherapies, amlodipine 10 mg and olmesartan medoxomil 40 mg.

For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 48% likelihood of achieving a goal of <140 mmHg (systolic) and a 51% likelihood of achieving a goal of <90 mmHg (diastolic) on monotherapy with olmesartan medoxomil 40 mg, and about a 46% likelihood of achieving a goal of <140 mmHg (systolic) and a 60% likelihood of achieving a goal of <90 mmHg (diastolic) on monotherapy with amlodipine 10 mg. The likelihood of achieving these same goals increases to 63% (systolic) and 71% (diastolic) on Azor 5/20 mg, and to 68% (systolic) and 85% (diastolic) on Azor 10/40 mg.

  Azor

An 8-week multicenter, randomized, double-blind, placebo controlled, parallel group factorial study in patients with mild to severe hypertension was conducted to determine if treatment with Azor was associated with clinically significant reduction in blood pressure compared to the respective monotherapies. The study randomized 1940 patients equally to one of the following 12 treatment arms: placebo, monotherapy treatment with amlodipine 5 mg or 10 mg, monotherapy treatment with olmesartan medoxomil 10 mg, 20 mg, or 40 mg, or combination therapy with amlodipine/olmesartan medoxomil at doses of 5/10 mg, 5/20 mg, 5/40 mg, 10/10 mg, 10/20 mg, and 10/40 mg. Patients discontinued their prior antihypertensive treatment. The mean baseline blood pressure of the study population was 164/102 mmHg. Of the total cohort, 970 patients were treated with the combination as initial therapy.

Treatment with Azor resulted in statistically significant greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components. Maximum antihypertensive effects were attained within 2 weeks after a change in dose.

The following table presents the results for mean reduction in seated systolic and diastolic blood pressure following 8 weeks of treatment with Azor. Placebo-adjusted reductions from baseline in blood pressure were progressively greater with increases in dose of both amlodipine and olmesartan medoxomil components of Azor.

The antihypertensive effect of Azor was similar in patients with and without prior antihypertensive medication use, in patients with and without diabetes, in patients ≥65 years of age and <65 years of age, and in women and men. Limited data exist in patients ≥75 years of age.

Azor was effective in treating black patients (usually a low-renin population), and the magnitude of blood pressure reduction in black patients approached that observed for non-Black patients. This effect in black patients has been seen with ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

The blood pressure lowering effect was maintained throughout the 24-hour period with Azor once daily, with trough-to-peak ratios for systolic and diastolic response between 71% and 82%.

Upon completing the 8-week, double-blind, placebo-controlled study, 1684 patients entered a 44-week open-label extension and received combination therapy with amlodipine 5 mg plus olmesartan medoxomil 40 mg. During the open-label extension, patients whose blood pressure was not adequately controlled (i.e., did not achieve a blood pressure goal of <140/90 mmHg, or <130/80 mmHg for those patients with diabetes) on amlodipine/olmesartan medoxomil 5/40 mg were titrated to amlodipine/olmesartan medoxomil 10/40 mg. Patients whose blood pressure was still not adequately controlled were offered additional hydrochlorothiazide 12.5 mg and subsequently 25 mg as required to achieve adequate blood pressure goal.

There are no trials of Azor demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

  Amlodipine

The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect.

  Olmesartan Medoxomil

The antihypertensive effects of olmesartan medoxomil have been demonstrated in seven placebo-controlled studies at doses ranging from 2.5 mg to 80 mg for 6 to 12 weeks, each showing statistically significant reductions in peak and trough blood pressure. A total of 2693 patients (2145 olmesartan medoxomil; 548 placebo) with essential hypertension were studied. The blood pressure lowering effect was maintained throughout the 24-hour period with olmesartan medoxomil once daily, with trough-to-peak ratios for systolic and diastolic response between 60% and 80%.

• High Blood Pressure Treatment

Applies to amlodipine / olmesartan: oral tablet

General

The most common adverse reaction is edema.[Ref]

Other

Very common (10% or more): Edema (up to 13.3%)
Common (1% to 10%): Fatigue, peripheral edema, pitting edema
Uncommon (0.1% to 1%): Asthenia
Rare (less than 0.1%): Face edema

Amlodipine:
Very common (10% or more): Edema (up to 24.5%)
Common (1% to 10%): Fatigue, peripheral edema
Uncommon (0.1% to 1%): Asthenia, chest pain, malaise, pain, pitting edema, gynecomastia

Olmesartan:
Common (1% to 10%): Chest pain, fatigue, influenza-like symptoms, pain, peripheral edema, edema
Uncommon (0.1% to 1%): Asthenia, face edema, malaise, pitting edema[Ref]

There was a greater incidence of edema in women (14.6%) than men (5.6%).[Ref]

Nervous system

There was a greater incidence of somnolence in women (1.6%) than men (1.3%).[Ref]

Common (1% to 10%): Dizziness, headache
Uncommon (0.1% to 1%): Hypoesthesia, lethargy, paresthesia, postural dizziness, vertigo
Rare (less than 0.1%): Syncope

Amlodipine:
Common (1% to 10%): Dizziness, headache, somnolence
Uncommon (0.1% to 1%): Dysgeusia, hypoesthesia, paresthesia, syncope, tremor, tinnitus, postural dizziness, vertigo, peripheral neuropathy
Very rare (less than 0.01%): Hypertonia
Frequency not reported: Extrapyramidal syndrome, ataxia, migraine, amnesia, parosmia

Olmesartan:
Common (1% to 10%): Dizziness, headache
Uncommon (0.1% to 1%): Vertigo
Rare (less than 0.1%): Lethargy[Ref]

Gastrointestinal

Uncommon (0.1% to 1%): Constipation, diarrhea, dry mouth, dyspepsia, nausea, upper abdominal pain, vomiting

Amlodipine:
Common (1% to 10%): Abdominal pain, nausea
Uncommon (0.1% to 1%): Altered bowel habits, dry mouth, dyspepsia, vomiting, constipation, dysphagia, diarrhea, flatulence, pancreatitis, gingival hyperplasia
Very rare (less than 0.01%): Gastritis
Frequency not reported: Loose stools

Olmesartan:
Common (1% to 10%): Abdominal pain, diarrhea, dyspepsia, gastroenteritis, nausea
Uncommon (0.1% to 1%): Vomiting
Very rare (less than 0.01%): Sprue-like enteropathy[Ref]

Cardiovascular

There was a greater incidence of flushing and palpitation in women than men. The incidence of flushing was 4.5% in females and 1.5% in males. The incidence of palpitation was 3.3% in females and 1.4% in males.[Ref]

Uncommon (0.1% to 1%): Palpitations, tachycardia, hypotension, orthostatic hypotension, hypertension
Rare (less than 0.1%): Flushing

Amlodipine:
Common (1% to 10%): Flushing, palpitation
Uncommon (0.1% to 1%): Angina pectoris, hypotension, peripheral ischemia, tachycardia, postural hypotension, hot flushes, vasculitis
Very rare (less than 0.01%): Arrhythmia, myocardial infarction
Frequency not reported: Cardiac failure, pulse irregularity, extrasystoles

Olmesartan:
Uncommon (0.1% to 1%): Angina pectoris, hypertension, tachycardia
Rare (less than 0.1%): Hypotension[Ref]

Musculoskeletal

Uncommon (0.1% to 1%): Back pain, muscle spasm, pain in extremity

Amlodipine:
Common (1% to 10%): Ankle swelling
Uncommon (0.1% to 1%): Arthralgia, back pain, muscle spasm, myalgia, rigors, arthrosis, muscle cramps
Frequency not reported: Muscle weakness, twitching

Olmesartan:
Common (1% to 10%): Arthritis, back pain, skeletal pain, blood creatine phosphokinase increased
Uncommon (0.1% to 1%): Myalgia, arthralgia
Rare (less than 0.1%): Muscle spasm
Frequency not reported: Rhabdomyolysis[Ref]

Genitourinary

Uncommon (0.1% to 1%): Pollakiuria, erectile dysfunction/impotence

Amlodipine:
Uncommon (0.1% to 1%): Increased urinary frequency, micturition disorder, nocturia, erectile dysfunction/impotence, gynecomastia, sexual dysfunction
Frequency not reported: Dysuria, polyuria

Olmesartan:
Common (1% to 10%): Hematuria, urinary tract infection[Ref]

Metabolic

Uncommon (0.1% to 1%): Hyperkalemia, blood potassium decreased

Amlodipine:
Uncommon (0.1% to 1%): Weight decreased, weight increased, anorexia, thirst, hyperglycemia
Frequency not reported: Increased appetite

Olmesartan:
Common (1% to 10%): Hypertriglyceridemia, hyperuricemia, hyperglycemia
Rare (less than 0.1%): Hyperkalemia[Ref]

Respiratory

Uncommon (0.1% to 1%): Cough, dyspnea

Amlodipine:
Uncommon (0.1% to 1%): Dyspnea, rhinitis, epistaxis
Very rare (less than 0.01%): Cough

Olmesartan:
Common (1% to 10%): Bronchitis, cough, pharyngitis, rhinitis, sinusitis[Ref]

Renal

Uncommon (0.1% to 1%): Blood creatinine increased, blood uric acid increased

Olmesartan:
Common (1% to 10%): Blood urea increased
Rare (less than 0.1%): Acute renal failure, renal insufficiency, blood creatinine increased[Ref]

Dermatologic

Uncommon (0.1% to 1%): Rash
Rare (less than 0.1%): Urticaria

Amlodipine:
Uncommon (0.1% to 1%): Alopecia, exanthema, hyperhidrosis, pruritus, purpura, rash, skin discoloration, sweating increased, angioedema, rash erythematous, rash maculopapular
Very rare (less than 0.01%): Angioneurotic edema, erythema multiforme, exfoliative dermatitis, photosensitivity, Quincke edema, Stevens-Johnson syndrome, urticaria
Frequency not reported: Skin dryness, dermatitis, cold and clammy skin

Olmesartan:
Uncommon (0.1% to 1%): Allergic dermatitis, exanthema, pruritus, rash, urticaria
Rare (less than 0.1%): Angioneurotic edema
Postmarketing reports: Angioedema, alopecia[Ref]

Psychiatric

Uncommon (0.1% to 1%): Libido decreased

Amlodipine:
Uncommon (0.1% to 1%): Depression, insomnia, irritability, mood changes, sleep disorder, nervousness, abnormal dreams, anxiety, depersonalization
Rare (less than 0.1%): Confusion
Frequency not reported: Apathy, agitation[Ref]

Hepatic

Uncommon (0.1% to 1%): GGT increased

Amlodipine:
Very rare (less than 0.01%): Hepatic enzymes increased, hepatitis, jaundice

Olmesartan:
Common (1% to 10%): Hepatic enzymes increased[Ref]

Immunologic

Rare (less than 0.1%): Allergic reaction/drug hypersensitivity

Amlodipine:
Uncommon (0.1% to 1%): Allergic reactions
Very rare (less than 0.01%): Allergic reaction/drug hypersensitivity

Olmesartan:
Uncommon (0.1% to 1%): Anaphylactic reaction[Ref]

Ocular

Amlodipine:
Uncommon (0.1% to 1%): Visual disturbance, abnormal vision, conjunctivitis, diplopia, eye pain
Frequency not reported: Xerophthalmia[Ref]

Hematologic

Frequency not reported: Hemoglobin decreased, hematocrit decreased

Amlodipine:
Uncommon (0.1% to 1%): Leukopenia, thrombocytopenia

Olmesartan:
Uncommon (0.1% to 1%): Thrombocytopenia[Ref]

Some side effects of Azor may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.