Amlodipine and olmesartan

U.S. BRAND NAMES — Azor™

PHARMACOLOGIC CATEGORY
Angiotensin II Receptor Blocker
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine

DOSING: ADULTS — Dose is individualized; combination product may be substituted for individual components in patients currently maintained on both agents separately or in patients not adequately controlled with monotherapy (using one of the agents or an agent within the same antihypertensive class). May also be used as initial therapy in patients who are likely to need >1 antihypertensive to control blood pressure.

Hypertension: Oral:
Initial therapy (antihypertensive naive): Amlodipine 5 mg/olmesartan 20 mg once daily; dose may be increased after 1-2 weeks of therapy. Maximum recommended dose: Amlodipine 10 mg/day; olmesartan 40 mg/day.
Add-on/replacement therapy: Amlodipine 5-10 mg and olmesartan 20-40 mg once daily depending upon previous doses, current control, and goals of therapy; dose may be titrated after 2 weeks of therapy. Maximum recommended dose: Amlodipine 10 mg/day; olmesartan 40 mg/day.

DOSING: ELDERLY — Initial therapy is not recommended in patients ≥ 75 years of age.

DOSING: RENAL IMPAIRMENT — No specific guidelines for dosage adjustment.

DOSING: HEPATIC IMPAIRMENT — Initial therapy is not recommended.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet:
Azor™ 5/20: Amlodipine besylate 5 mg and olmesartan medoxomil 20 mg
Azor™ 5/40: Amlodipine besylate 5 mg and olmesartan medoxomil 40 mg
Azor™ 10/20: Amlodipine besylate 10 mg and olmesartan medoxomil 20 mg
Azor™ 10/40: Amlodipine besylate 10 mg and olmesartan medoxomil 40 mg

DOSAGE FORMS: CONCISE
Tablet:
Azor™ : 5/20: Amlodipine besylate 5 mg and olmesartan medoxomil 20 mg; 5/40: Amlodipine besylate 5 mg and olmesartan medoxomil 40 mg; 10/20: Amlodipine besylate 10 mg and olmesartan medoxomil 20 mg; 10/40: Amlodipine besylate 10 mg and olmesartan medoxomil 40 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Administer with or without food.

USE — Treatment of hypertension, including initial treatment in patients who will require multiple antihypertensives for adequate control

ADVERSE REACTIONS SIGNIFICANT — Reactions/percentages reported with combination product; also refer to individual agents

>10%: Cardiovascular: Peripheral edema (dose related: 18% to 26%)

Frequency not defined (limited to important or life-threatening): Hypotension, nocturia, orthostatic hypotension, palpitation, pruritus, rash, urinary frequency

CONTRAINDICATIONS — There are no contraindications listed in manufacturer's labeling.

WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: See "Special populations" below.

Concerns related to adverse effects: Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of dihydropyridine calcium channel blockers. Reflex tachycardia may occur resulting in angina and/or MI in patients with obstructive coronary disease, especially in the absence of concurrent beta-blockade. Hyperkalemia: May occur with olmesartan use; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts. Use cautiously, if at all, with these agents and monitor potassium closely. Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; use caution during initiation of therapy, particularly in patients with heart failure, severe aortic stenosis, post-MI patients, volume- or salt-depleted patients, or those undergoing surgery or dialysis. Peripheral edema: The most common side effect of amlodipine is peripheral edema; occurs within 2-3 weeks of starting therapy. Reflex tachycardia: May occur with amlodipine use. Renal function deterioration: Olmesartan may be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.

Disease-related concerns: Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis. Heart failure: Use caution when initiating in heart failure; may need to adjust dose, and/or concurrent diuretic therapy. Hepatic impairment: Use with caution in patients with hepatic impairment; amlodipine and olmesartan exposure increased in hepatic dysfunction. Initial therapy is not recommended; the appropriate combination dosage form is not available. Hypovolemia: Avoid use or use a smaller dose in patients who are volume depleted; correct depletion first. Renal artery stenosis: Use olmesartan with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks. Renal impairment: Use with caution with pre-existing renal insufficiency and severe renal impairment.

Special populations: Elderly: Initial therapy is not recommended in patients ≥ 75 years of age; the appropriate combination dosage form is not available. Pediatrics: Safety and efficacy of this combination have not been established in children. Pregnancy: [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Angiotensin receptor blockers should be discontinued as soon as possible once pregnancy is detected.

Other warnings/precautions: Titration: Dosage titration may occur after 1-2 weeks in antihypertensive naive patients and 2-4 weeks in add-on or replacement therapy if blood pressure control inadequate. This may be done by increasing one component at a time or by increasing both components to achieve more rapid control of blood pressure.

METABOLISM / TRANSPORT EFFECTS — Amlodipine: Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)

DRUG INTERACTIONS
ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy

Alpha1-Blockers: May enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy

Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification

Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification

Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Calcium Channel Blockers (Dihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Risk C: Monitor therapy

Calcium Salts: May diminish the therapeutic effect of Calcium Channel Blockers. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Calcium Channel Blockers (Dihydropyridine). Risk C: Monitor therapy

Clopidogrel: Calcium Channel Blockers may diminish the therapeutic effect of Clopidogrel. Risk C: Monitor therapy

CycloSPORINE: May decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Nicardipine may likewise inhibit the metabolism of cyclosporine. Cyclosporine dosage adjustments might be needed. Risk C: Monitor therapy

CYP1A2 Substrates: CYP1A2 Inhibitors (Moderate) may decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Management: According to eltrombopag prescribing information, consideration of a preventative dose reduction may be warranted. Risk D: Consider therapy modification

Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Fluconazole: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy

Grapefruit Juice: May increase the serum concentration of AmLODIPine. Risk C: Monitor therapy

Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an angiotensin II receptor antagonist. Risk D: Consider therapy modification

Macrolide Antibiotics: May decrease the metabolism of Calcium Channel Blockers. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. Risk D: Consider therapy modification

Magnesium Salts: Calcium Channel Blockers may enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Nafcillin: May increase the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification

Neuromuscular-Blocking Agents (Nondepolarizing): Calcium Channel Blockers may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: Monitor therapy

Nitroprusside: Calcium Channel Blockers may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Phenytoin: Calcium Channel Blockers may decrease the metabolism of Phenytoin. Risk D: Consider therapy modification

Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Potassium Salts: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Potassium-Sparing Diuretics: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Protease Inhibitors: May decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Risk D: Consider therapy modification

QuiNIDine: Calcium Channel Blockers (Dihydropyridine) may decrease the serum concentration of QuiNIDine. Risk C: Monitor therapy

Quinupristin: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers. Risk D: Consider therapy modification

RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification

Tacrolimus: Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus. Risk C: Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/Nutraceutical: Avoid bayberry, blue cohosh, cayenne, ephedra, ginger, ginseng (American), kola, licorice (may worsen hypertension). Avoid black cohosh, California poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, shepherd's purse (may enhance antihypertensive effects).

PREGNANCY RISK FACTOR — C/D (show table) (2nd and 3rd trimesters)

PREGNANCY IMPLICATIONS — See individual agents.

LACTATION — Excretion in breast milk unknown/not recommended

BREAST-FEEDING CONSIDERATIONS — See individual agents.

DIETARY CONSIDERATIONS — Avoid salt substitutes which contain potassium. May be taken with or without food.

PRICING — (data from drugstore.com)
Tablets (Azor)
5-20 mg (30): $89.36
5-40 mg (30): $107.30
10-20 mg (30): $96.25
10-40 mg (90): $337.74

MONITORING PARAMETERS — Baseline and periodic electrolyte panels, renal and liver function, urinalysis; BP, heart rate, peripheral edema; in CHF, serum potassium during dose escalation and periodically thereafter

MECHANISM OF ACTION — See individual agents.

PHARMACODYNAMICS / KINETICS — See individual agents.