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.
Sunday, August 1, 2010
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.
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.
Amlodipine and atorvastatin
SPECIAL ALERTS
HMG-CoA Reductase Inhibitors: Evidence Does Not Suggest Increased Incidence of Amyotrophic Lateral Sclerosis (ALS) - Results of FDA Analysis - September 30, 2008
The U.S. Food and Drug Administration's (FDA) review of 41 long-term controlled clinical trials of HMG-CoA reductase inhibitors finds no evidence of an increased incidence of ALS (also known as Lou Gehrig's disease) related to these medications. This analysis occurred after the FDA had received notice of numerous adverse events of which 109 of these reports mentioned ALS, Lou Gehrig's disease, or motor neuron disease. The clinical trials included in the analysis had a median duration of treatment of 3.3 years (range of duration: 6 months to 5 years) and involved 120,964 patients. The analysis identified a total of 19 cases of ALS " 9 cases per 64,602 patients (0.014%) with statin therapy and 10 cases per 56,362 patients (0.017%) with placebo. The incidence rates, based on approximately 400,000 person-years, were 4.2 per 100,000 person-years in the statin-treated group and 5 per 100,000 person-years in the placebo-treated group.
The FDA recommends that health care providers continue to prescribe, and patients continue to use these products as described within their labeling.
For more information, healthcare professionals may refer to the following:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116957.htm
Colman E, Szarfman A, Wyeth J, et al, "An Evaluation of a Data Mining Signal for Amyotrophic Lateral Sclerosis and Statins Detected in FDA's Spontaneous Adverse Event Reporting System,"Pharmacoepidemiol Drug Saf, 2008, 17(11):1068-76.
U.S. BRAND NAMES — Caduet®
PHARMACOLOGIC CATEGORY
Antilipemic Agent, HMG-CoA Reductase Inhibitor
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS
Amlodipine:
Hypertension: Oral: Initial dose: 5 mg once daily; maximum dose: 10 mg once daily; in general, titrate in 2.5 mg increments over 7-14 days. Usual dosage range (JNC 7): 2.5-10 mg once daily
Angina: Oral: Usual dose: 5-10 mg; lower dose suggested in elderly or hepatic impairment; most patients require 10 mg for adequate effect
Atorvastatin:
Hyperlipidemias: Oral: Initial: 10-20 mg once daily; patients requiring >45% reduction in LDL-C may be started at 40 mg once daily; range: 10-80 mg once daily
Primary prevention of CVD: Oral: 10 mg once daily
DOSING: PEDIATRIC
Hypertension:Amlodipine: Oral: Children >10 years: 2.5-5 mg once daily. Note: Use in ages >10 years because of atorvastatin content.
HeFH:Atorvastatin: Oral: Children 10-17 years (females >1 year postmenarche): 10 mg once daily (maximum: 20 mg/day)
DOSING: ELDERLY — Refer to adult dosing.
Amlodipine: Dosing should start at the lower end of dosing range due to possible increased incidence of hepatic, renal, or cardiac impairment. Elderly patients also show decreased clearance of amlodipine.
Hypertension: 2.5 mg once daily
Angina: 5 mg once daily
DOSING: RENAL IMPAIRMENT — No dosage adjustment is necessary.
DOSING: HEPATIC IMPAIRMENT — Do not use in active liver disease.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Caduet®:
2.5/10: Amlodipine 2.5 mg and atorvastatin 10 mg
2.5/20: Amlodipine 2.5 mg and atorvastatin 20 mg
2.5/40: Amlodipine 2.5 mg and atorvastatin 40 mg
5/10: Amlodipine 5 mg and atorvastatin 10 mg
5/20: Amlodipine 5 mg and atorvastatin 20 mg
5/40: Amlodipine 5 mg and atorvastatin 40 mg
5/80: Amlodipine 5 mg and atorvastatin 80 mg
10/10: Amlodipine 10 mg and atorvastatin 10 mg
10/20: Amlodipine 10 mg and atorvastatin 20 mg
10/40: Amlodipine 10 mg and atorvastatin 40 mg
10/80: Amlodipine 10 mg and atorvastatin 80 mg
DOSAGE FORMS: CONCISE
Tablet:
Caduet®:
2.5/10: Amlodipine 2.5 mg and atorvastatin 10 mg
2.5/20: Amlodipine 2.5 mg and atorvastatin 20 mg
2.5/40: Amlodipine 2.5 mg and atorvastatin 40 mg
5/10: Amlodipine 5 mg and atorvastatin 10 mg
5/20: Amlodipine 5 mg and atorvastatin 20 mg
5/40: Amlodipine 5 mg and atorvastatin 40 mg
5/80: Amlodipine 5 mg and atorvastatin 80 mg
10/10: Amlodipine 10 mg and atorvastatin 10 mg
10/20: Amlodipine 10 mg and atorvastatin 20 mg
10/40: Amlodipine 10 mg and atorvastatin 40 mg
10/80: Amlodipine 10 mg and atorvastatin 80 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — May be administered without regard to meals.
USE — For use when treatment with both amlodipine and atorvastatin is appropriate:
Amlodipine: Treatment of hypertension; treatment of symptomatic chronic stable angina, vasospastic (Prinzmetal's) angina (confirmed or suspected); prevention of hospitalization due to angina with documented CAD (limited to patients without heart failure or ejection fraction <40%)
Atorvastatin: Treatment of dyslipidemias or primary prevention of cardiovascular disease (atherosclerotic) as detailed here:
Primary prevention of cardiovascular disease (high-risk for CVD): To reduce the risk of MI or stroke in patients without evidence of heart disease who have multiple CVD risk factors or type 2 diabetes. Treatment reduces the risk for angina or revascularization procedures in patients with multiple risk factors.
Treatment of dyslipidemias: To reduce elevations in total cholesterol, LDL-C, apolipoprotein B, and triglycerides in patients with elevations of one or more components, and/or to increase HDL-C as present in heterozygous hypercholesterolemia (Fredrickson type IIa hyperlipidemias); treatment of primary dysbetalipoproteinemia (Fredrickson type III), elevated serum TG levels (Fredrickson type IV), and homozygous familial hypercholesterolemia
Treatment of heterozygous familial hypercholesterolemia (HeFH) in adolescent patients (10-17 years of age, females >1 year postmenarche) having LDL-C ≥ 190 mg/dL or LDL-C ≥ 160 mg/dL with positive family history of premature cardiovascular disease (CVD) or with two or more CVD risk factors.
ADVERSE REACTIONS SIGNIFICANT — See individual agents.
CONTRAINDICATIONS — Hypersensitivity to amlodipine, atorvastatin, or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; pregnancy
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of calcium channel blockers. Myopathy/rhabdomyolysis: Patients receiving HMG-CoA reductase inhibitors have developed rhabdomyolysis with acute renal failure and/or myopathy; patients should be monitored closely. This risk is dose-related and is increased with concurrent use of other lipid lowering medications. Temporarily discontinue for elective major surgery, acute medical or surgical conditions, or in any patient experiencing an acute or serious condition predisposing to renal failure (eg, sepsis, hypotension, trauma, uncontrolled seizures). Based upon current evidence, HMG-CoA reductase inhibitor therapy should be continued in the perioperative period unless risk outweighs cardioprotective benefit. Use caution in patients with renal impairment, inadequately treated hypothyroidism, and those taking other drugs associated with myopathy (eg, colchicine); these patients are predisposed to myopathy. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine.
Disease-related concerns: Aortic stenosis: Use amlodipine with caution in patients with severe aortic stenosis. Hepatic impairment and/or ethanol use: Use atorvastatin with caution in patients who consume large amounts of ethanol or have a history of liver disease.
Concurrent drug therapy issues: High potential for interactions: Use atorvastatin with caution in patients taking strong CYP3A4 inhibitors (see drug interactions); consider alternative agents that avoid or lessen potential for CYP-mediated interactions.
Special populations: Elderly: Use atorvastatin with caution in patients with advanced age, these patients are predisposed to myopathy. Pediatrics: Safety and efficacy of the combination of amlodipine/atorvastatin have not been established in children. Safety and efficacy of amlodipine have not been established in patients <6 years of age. Safety and efficacy of atorvastatin have not been established in patients <10 years of age or in premenarcheal girls.
Other warnings/precautions: Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to therapy with atorvastatin. Liver function tests: Must be monitored by periodic laboratory assessment while taking atorvastatin. Titration: Dosage titration of amlodipine should occur after 7-14 days on a given dose.
METABOLISM / TRANSPORT EFFECTS
Amlodipine: Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)
Atorvastatin: Substrate of CYP3A4 (major); Inhibits CYP3A4 (weak)
DRUG INTERACTIONS
Aliskiren: Atorvastatin may increase the serum concentration of Aliskiren. 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
Amiodarone: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Management: Dose of HMG-CoA reductase inhibitor may need to be reduced (e.g., simvastatin prescribing information recommends not exceeding 20 mg/day during concurrent therapy). Risk D: Consider therapy modification
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of HMG-CoA Reductase Inhibitors. 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
Bosentan: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
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
Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
CycloSPORINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
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
Dabigatran Etexilate: Atorvastatin may decrease the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy
Danazol: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
DAPTOmycin: HMG-CoA Reductase Inhibitors may enhance the adverse/toxic effect of DAPTOmycin. Specifically, the risk of skeletal muscle toxicity may be increased. Management: Consider temporarily stopping HMG-CoA reductase inhibitor therapy prior to daptomycin. If used together, regular (i.e., at least weekly) monitoring of CPK concentrations is recommended. 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
Digoxin: Atorvastatin may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Diltiazem: Atorvastatin may increase the serum concentration of Diltiazem. Diltiazem may increase the serum concentration of Atorvastatin. Management: Consider using lower atorvastatin doses when used together with diltiazem. Risk D: Consider therapy modification
Dronedarone: May increase the serum concentration of Atorvastatin. 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
Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. This applies to atorvastatin, lovastatin and simvastatin. Conversely, levels of fluvastatin may be increased. Management: Dose adjustment of the HMG-CoA reductase inhibitor may be warranted. No interaction is expected with rosuvastatin or pravastatin. Risk C: Monitor therapy
Fenofibrate: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Fenofibric Acid: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Fluconazole: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Fluconazole: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy
Fusidic Acid: May enhance the adverse/toxic effect of Atorvastatin. Specifically, the risk of rhabdomyolysis may be increased. Fusidic Acid may increase the serum concentration of Atorvastatin. Risk C: Monitor therapy
Gemfibrozil: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Gemfibrozil may increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Grapefruit Juice: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Grapefruit Juice: May increase the serum concentration of AmLODIPine. 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
Macrolide Antibiotics: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. 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 hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic effect of Antihypertensives. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Midazolam: Atorvastatin may increase the serum concentration of Midazolam. Risk C: Monitor therapy
Nafcillin: May increase the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification
Nefazodone: May decrease the metabolism of HMG-CoA Reductase Inhibitors. 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
Niacin: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Niacinamide: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Nitroprusside: Calcium Channel Blockers may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Substrates: P-Glycoprotein Inhibitors may increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phenytoin: Calcium Channel Blockers may decrease the metabolism of Phenytoin. Risk D: Consider therapy modification
Phenytoin: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Limited data suggest pravastatin may slightly decrease protease inhibitor concentrations. Management: Lovastatin and simvastatin are contraindicated with many protease inhibitors; also, avoid rosuvastatin with indinavir. Use lowest possible HMG-CoA reductase inhibitor dose and monitor for signs of toxicity if these agents are used concomitantly. Risk D: Consider therapy modification
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
QuiNINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Consider using a lower starting dose and lower maintenance/maximum doses of atorvastatin, simvastatin, or lovastatin when used together with quinine. Risk D: Consider therapy modification
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
Rifamycin Derivatives: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Rivaroxaban: P-Glycoprotein Inhibitors may increase the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Sildenafil: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
St Johns Wort: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Tacrolimus: Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus. Risk C: Monitor therapy
Topotecan: P-Glycoprotein Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Verapamil: Atorvastatin may increase the serum concentration of Verapamil. Verapamil may increase the serum concentration of Atorvastatin. Management: Consider using lower atorvastatin doses when used together with verapamil. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
ETHANOL / NUTRITION / HERB INTERACTIONS — See individual agents.
PREGNANCY RISK FACTOR — X (show table)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/contraindicated
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — May take with food if desired; may take without regard to time of day. Before initiation of therapy with atorvastatin, patients should be placed on a standard cholesterol-lowering diet for 3-6 months and the diet should be continued during drug therapy. Red yeast rice contains an estimated 2.4 mg lovastatin per 600 mg rice.
PRICING — (data from drugstore.com)
Tablets (Caduet)
2.5-10 mg (30): $121.79
2.5-20 mg (30): $165.54
2.5-40 mg (30): $165.54
5-10 mg (30): $120.74
5-20 mg (30): $160.96
5-40 mg (30): $157.49
5-80 mg (30): $163.78
10-10 mg (30): $121.79
10-20 mg (30): $163.78
10-40 mg (30): $162.74
10-80 mg (30): $174.29
MONITORING PARAMETERS — Blood pressure; lipid levels after 2-4 weeks, CPK, liver function tests (LFTs); it is recommended that LFTs be performed prior to and at 12 weeks following both the initiation of therapy and any elevation in dose of atorvastatin, and periodically (eg, semiannually) thereafter.
CANADIAN BRAND NAMES — Caduet®
INTERNATIONAL BRAND NAMES — Amat (IN); Caduet (AU, BG, CH, CN, CR, CZ, ES, FR, GT, HK, HN, IL, KP, MX, MY, NI, PA, SG, SV, TH, TW, VE); Encavar (PH); Hipertensal Combi (AR); Liparten (PY); Norvastor (PE); Stamcor (IN)
MECHANISM OF ACTION
Amlodipine: Inhibits calcium ion from entering the "slow channels" or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina
Atorvastatin: Inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in cholesterol synthesis (reduces the production of mevalonic acid from HMG-CoA); this then results in a compensatory increase in the expression of LDL receptors on hepatocyte membranes and a stimulation of LDL catabolism
HMG-CoA Reductase Inhibitors: Evidence Does Not Suggest Increased Incidence of Amyotrophic Lateral Sclerosis (ALS) - Results of FDA Analysis - September 30, 2008
The U.S. Food and Drug Administration's (FDA) review of 41 long-term controlled clinical trials of HMG-CoA reductase inhibitors finds no evidence of an increased incidence of ALS (also known as Lou Gehrig's disease) related to these medications. This analysis occurred after the FDA had received notice of numerous adverse events of which 109 of these reports mentioned ALS, Lou Gehrig's disease, or motor neuron disease. The clinical trials included in the analysis had a median duration of treatment of 3.3 years (range of duration: 6 months to 5 years) and involved 120,964 patients. The analysis identified a total of 19 cases of ALS " 9 cases per 64,602 patients (0.014%) with statin therapy and 10 cases per 56,362 patients (0.017%) with placebo. The incidence rates, based on approximately 400,000 person-years, were 4.2 per 100,000 person-years in the statin-treated group and 5 per 100,000 person-years in the placebo-treated group.
The FDA recommends that health care providers continue to prescribe, and patients continue to use these products as described within their labeling.
For more information, healthcare professionals may refer to the following:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116957.htm
Colman E, Szarfman A, Wyeth J, et al, "An Evaluation of a Data Mining Signal for Amyotrophic Lateral Sclerosis and Statins Detected in FDA's Spontaneous Adverse Event Reporting System,"Pharmacoepidemiol Drug Saf, 2008, 17(11):1068-76.
U.S. BRAND NAMES — Caduet®
PHARMACOLOGIC CATEGORY
Antilipemic Agent, HMG-CoA Reductase Inhibitor
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS
Amlodipine:
Hypertension: Oral: Initial dose: 5 mg once daily; maximum dose: 10 mg once daily; in general, titrate in 2.5 mg increments over 7-14 days. Usual dosage range (JNC 7): 2.5-10 mg once daily
Angina: Oral: Usual dose: 5-10 mg; lower dose suggested in elderly or hepatic impairment; most patients require 10 mg for adequate effect
Atorvastatin:
Hyperlipidemias: Oral: Initial: 10-20 mg once daily; patients requiring >45% reduction in LDL-C may be started at 40 mg once daily; range: 10-80 mg once daily
Primary prevention of CVD: Oral: 10 mg once daily
DOSING: PEDIATRIC
Hypertension:Amlodipine: Oral: Children >10 years: 2.5-5 mg once daily. Note: Use in ages >10 years because of atorvastatin content.
HeFH:Atorvastatin: Oral: Children 10-17 years (females >1 year postmenarche): 10 mg once daily (maximum: 20 mg/day)
DOSING: ELDERLY — Refer to adult dosing.
Amlodipine: Dosing should start at the lower end of dosing range due to possible increased incidence of hepatic, renal, or cardiac impairment. Elderly patients also show decreased clearance of amlodipine.
Hypertension: 2.5 mg once daily
Angina: 5 mg once daily
DOSING: RENAL IMPAIRMENT — No dosage adjustment is necessary.
DOSING: HEPATIC IMPAIRMENT — Do not use in active liver disease.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Caduet®:
2.5/10: Amlodipine 2.5 mg and atorvastatin 10 mg
2.5/20: Amlodipine 2.5 mg and atorvastatin 20 mg
2.5/40: Amlodipine 2.5 mg and atorvastatin 40 mg
5/10: Amlodipine 5 mg and atorvastatin 10 mg
5/20: Amlodipine 5 mg and atorvastatin 20 mg
5/40: Amlodipine 5 mg and atorvastatin 40 mg
5/80: Amlodipine 5 mg and atorvastatin 80 mg
10/10: Amlodipine 10 mg and atorvastatin 10 mg
10/20: Amlodipine 10 mg and atorvastatin 20 mg
10/40: Amlodipine 10 mg and atorvastatin 40 mg
10/80: Amlodipine 10 mg and atorvastatin 80 mg
DOSAGE FORMS: CONCISE
Tablet:
Caduet®:
2.5/10: Amlodipine 2.5 mg and atorvastatin 10 mg
2.5/20: Amlodipine 2.5 mg and atorvastatin 20 mg
2.5/40: Amlodipine 2.5 mg and atorvastatin 40 mg
5/10: Amlodipine 5 mg and atorvastatin 10 mg
5/20: Amlodipine 5 mg and atorvastatin 20 mg
5/40: Amlodipine 5 mg and atorvastatin 40 mg
5/80: Amlodipine 5 mg and atorvastatin 80 mg
10/10: Amlodipine 10 mg and atorvastatin 10 mg
10/20: Amlodipine 10 mg and atorvastatin 20 mg
10/40: Amlodipine 10 mg and atorvastatin 40 mg
10/80: Amlodipine 10 mg and atorvastatin 80 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — May be administered without regard to meals.
USE — For use when treatment with both amlodipine and atorvastatin is appropriate:
Amlodipine: Treatment of hypertension; treatment of symptomatic chronic stable angina, vasospastic (Prinzmetal's) angina (confirmed or suspected); prevention of hospitalization due to angina with documented CAD (limited to patients without heart failure or ejection fraction <40%)
Atorvastatin: Treatment of dyslipidemias or primary prevention of cardiovascular disease (atherosclerotic) as detailed here:
Primary prevention of cardiovascular disease (high-risk for CVD): To reduce the risk of MI or stroke in patients without evidence of heart disease who have multiple CVD risk factors or type 2 diabetes. Treatment reduces the risk for angina or revascularization procedures in patients with multiple risk factors.
Treatment of dyslipidemias: To reduce elevations in total cholesterol, LDL-C, apolipoprotein B, and triglycerides in patients with elevations of one or more components, and/or to increase HDL-C as present in heterozygous hypercholesterolemia (Fredrickson type IIa hyperlipidemias); treatment of primary dysbetalipoproteinemia (Fredrickson type III), elevated serum TG levels (Fredrickson type IV), and homozygous familial hypercholesterolemia
Treatment of heterozygous familial hypercholesterolemia (HeFH) in adolescent patients (10-17 years of age, females >1 year postmenarche) having LDL-C ≥ 190 mg/dL or LDL-C ≥ 160 mg/dL with positive family history of premature cardiovascular disease (CVD) or with two or more CVD risk factors.
ADVERSE REACTIONS SIGNIFICANT — See individual agents.
CONTRAINDICATIONS — Hypersensitivity to amlodipine, atorvastatin, or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; pregnancy
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of calcium channel blockers. Myopathy/rhabdomyolysis: Patients receiving HMG-CoA reductase inhibitors have developed rhabdomyolysis with acute renal failure and/or myopathy; patients should be monitored closely. This risk is dose-related and is increased with concurrent use of other lipid lowering medications. Temporarily discontinue for elective major surgery, acute medical or surgical conditions, or in any patient experiencing an acute or serious condition predisposing to renal failure (eg, sepsis, hypotension, trauma, uncontrolled seizures). Based upon current evidence, HMG-CoA reductase inhibitor therapy should be continued in the perioperative period unless risk outweighs cardioprotective benefit. Use caution in patients with renal impairment, inadequately treated hypothyroidism, and those taking other drugs associated with myopathy (eg, colchicine); these patients are predisposed to myopathy. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine.
Disease-related concerns: Aortic stenosis: Use amlodipine with caution in patients with severe aortic stenosis. Hepatic impairment and/or ethanol use: Use atorvastatin with caution in patients who consume large amounts of ethanol or have a history of liver disease.
Concurrent drug therapy issues: High potential for interactions: Use atorvastatin with caution in patients taking strong CYP3A4 inhibitors (see drug interactions); consider alternative agents that avoid or lessen potential for CYP-mediated interactions.
Special populations: Elderly: Use atorvastatin with caution in patients with advanced age, these patients are predisposed to myopathy. Pediatrics: Safety and efficacy of the combination of amlodipine/atorvastatin have not been established in children. Safety and efficacy of amlodipine have not been established in patients <6 years of age. Safety and efficacy of atorvastatin have not been established in patients <10 years of age or in premenarcheal girls.
Other warnings/precautions: Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to therapy with atorvastatin. Liver function tests: Must be monitored by periodic laboratory assessment while taking atorvastatin. Titration: Dosage titration of amlodipine should occur after 7-14 days on a given dose.
METABOLISM / TRANSPORT EFFECTS
Amlodipine: Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)
Atorvastatin: Substrate of CYP3A4 (major); Inhibits CYP3A4 (weak)
DRUG INTERACTIONS
Aliskiren: Atorvastatin may increase the serum concentration of Aliskiren. 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
Amiodarone: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Management: Dose of HMG-CoA reductase inhibitor may need to be reduced (e.g., simvastatin prescribing information recommends not exceeding 20 mg/day during concurrent therapy). Risk D: Consider therapy modification
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of HMG-CoA Reductase Inhibitors. 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
Bosentan: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
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
Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
CycloSPORINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
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
Dabigatran Etexilate: Atorvastatin may decrease the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy
Danazol: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
DAPTOmycin: HMG-CoA Reductase Inhibitors may enhance the adverse/toxic effect of DAPTOmycin. Specifically, the risk of skeletal muscle toxicity may be increased. Management: Consider temporarily stopping HMG-CoA reductase inhibitor therapy prior to daptomycin. If used together, regular (i.e., at least weekly) monitoring of CPK concentrations is recommended. 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
Digoxin: Atorvastatin may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Diltiazem: Atorvastatin may increase the serum concentration of Diltiazem. Diltiazem may increase the serum concentration of Atorvastatin. Management: Consider using lower atorvastatin doses when used together with diltiazem. Risk D: Consider therapy modification
Dronedarone: May increase the serum concentration of Atorvastatin. 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
Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. This applies to atorvastatin, lovastatin and simvastatin. Conversely, levels of fluvastatin may be increased. Management: Dose adjustment of the HMG-CoA reductase inhibitor may be warranted. No interaction is expected with rosuvastatin or pravastatin. Risk C: Monitor therapy
Fenofibrate: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Fenofibric Acid: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Fluconazole: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Fluconazole: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy
Fusidic Acid: May enhance the adverse/toxic effect of Atorvastatin. Specifically, the risk of rhabdomyolysis may be increased. Fusidic Acid may increase the serum concentration of Atorvastatin. Risk C: Monitor therapy
Gemfibrozil: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Gemfibrozil may increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Grapefruit Juice: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Grapefruit Juice: May increase the serum concentration of AmLODIPine. 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
Macrolide Antibiotics: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. 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 hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic effect of Antihypertensives. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Midazolam: Atorvastatin may increase the serum concentration of Midazolam. Risk C: Monitor therapy
Nafcillin: May increase the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification
Nefazodone: May decrease the metabolism of HMG-CoA Reductase Inhibitors. 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
Niacin: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Niacinamide: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Nitroprusside: Calcium Channel Blockers may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Substrates: P-Glycoprotein Inhibitors may increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phenytoin: Calcium Channel Blockers may decrease the metabolism of Phenytoin. Risk D: Consider therapy modification
Phenytoin: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Limited data suggest pravastatin may slightly decrease protease inhibitor concentrations. Management: Lovastatin and simvastatin are contraindicated with many protease inhibitors; also, avoid rosuvastatin with indinavir. Use lowest possible HMG-CoA reductase inhibitor dose and monitor for signs of toxicity if these agents are used concomitantly. Risk D: Consider therapy modification
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
QuiNINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Consider using a lower starting dose and lower maintenance/maximum doses of atorvastatin, simvastatin, or lovastatin when used together with quinine. Risk D: Consider therapy modification
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
Rifamycin Derivatives: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Rivaroxaban: P-Glycoprotein Inhibitors may increase the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Sildenafil: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
St Johns Wort: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Tacrolimus: Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus. Risk C: Monitor therapy
Topotecan: P-Glycoprotein Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Verapamil: Atorvastatin may increase the serum concentration of Verapamil. Verapamil may increase the serum concentration of Atorvastatin. Management: Consider using lower atorvastatin doses when used together with verapamil. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
ETHANOL / NUTRITION / HERB INTERACTIONS — See individual agents.
PREGNANCY RISK FACTOR — X (show table)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/contraindicated
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — May take with food if desired; may take without regard to time of day. Before initiation of therapy with atorvastatin, patients should be placed on a standard cholesterol-lowering diet for 3-6 months and the diet should be continued during drug therapy. Red yeast rice contains an estimated 2.4 mg lovastatin per 600 mg rice.
PRICING — (data from drugstore.com)
Tablets (Caduet)
2.5-10 mg (30): $121.79
2.5-20 mg (30): $165.54
2.5-40 mg (30): $165.54
5-10 mg (30): $120.74
5-20 mg (30): $160.96
5-40 mg (30): $157.49
5-80 mg (30): $163.78
10-10 mg (30): $121.79
10-20 mg (30): $163.78
10-40 mg (30): $162.74
10-80 mg (30): $174.29
MONITORING PARAMETERS — Blood pressure; lipid levels after 2-4 weeks, CPK, liver function tests (LFTs); it is recommended that LFTs be performed prior to and at 12 weeks following both the initiation of therapy and any elevation in dose of atorvastatin, and periodically (eg, semiannually) thereafter.
CANADIAN BRAND NAMES — Caduet®
INTERNATIONAL BRAND NAMES — Amat (IN); Caduet (AU, BG, CH, CN, CR, CZ, ES, FR, GT, HK, HN, IL, KP, MX, MY, NI, PA, SG, SV, TH, TW, VE); Encavar (PH); Hipertensal Combi (AR); Liparten (PY); Norvastor (PE); Stamcor (IN)
MECHANISM OF ACTION
Amlodipine: Inhibits calcium ion from entering the "slow channels" or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina
Atorvastatin: Inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in cholesterol synthesis (reduces the production of mevalonic acid from HMG-CoA); this then results in a compensatory increase in the expression of LDL receptors on hepatocyte membranes and a stimulation of LDL catabolism
Amlodipine and atorvastatin
SPECIAL ALERTS
HMG-CoA Reductase Inhibitors: Evidence Does Not Suggest Increased Incidence of Amyotrophic Lateral Sclerosis (ALS) - Results of FDA Analysis - September 30, 2008
The U.S. Food and Drug Administration's (FDA) review of 41 long-term controlled clinical trials of HMG-CoA reductase inhibitors finds no evidence of an increased incidence of ALS (also known as Lou Gehrig's disease) related to these medications. This analysis occurred after the FDA had received notice of numerous adverse events of which 109 of these reports mentioned ALS, Lou Gehrig's disease, or motor neuron disease. The clinical trials included in the analysis had a median duration of treatment of 3.3 years (range of duration: 6 months to 5 years) and involved 120,964 patients. The analysis identified a total of 19 cases of ALS " 9 cases per 64,602 patients (0.014%) with statin therapy and 10 cases per 56,362 patients (0.017%) with placebo. The incidence rates, based on approximately 400,000 person-years, were 4.2 per 100,000 person-years in the statin-treated group and 5 per 100,000 person-years in the placebo-treated group.
The FDA recommends that health care providers continue to prescribe, and patients continue to use these products as described within their labeling.
For more information, healthcare professionals may refer to the following:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116957.htm
Colman E, Szarfman A, Wyeth J, et al, "An Evaluation of a Data Mining Signal for Amyotrophic Lateral Sclerosis and Statins Detected in FDA's Spontaneous Adverse Event Reporting System,"Pharmacoepidemiol Drug Saf, 2008, 17(11):1068-76.
U.S. BRAND NAMES — Caduet®
PHARMACOLOGIC CATEGORY
Antilipemic Agent, HMG-CoA Reductase Inhibitor
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS
Amlodipine:
Hypertension: Oral: Initial dose: 5 mg once daily; maximum dose: 10 mg once daily; in general, titrate in 2.5 mg increments over 7-14 days. Usual dosage range (JNC 7): 2.5-10 mg once daily
Angina: Oral: Usual dose: 5-10 mg; lower dose suggested in elderly or hepatic impairment; most patients require 10 mg for adequate effect
Atorvastatin:
Hyperlipidemias: Oral: Initial: 10-20 mg once daily; patients requiring >45% reduction in LDL-C may be started at 40 mg once daily; range: 10-80 mg once daily
Primary prevention of CVD: Oral: 10 mg once daily
DOSING: PEDIATRIC
Hypertension:Amlodipine: Oral: Children >10 years: 2.5-5 mg once daily. Note: Use in ages >10 years because of atorvastatin content.
HeFH:Atorvastatin: Oral: Children 10-17 years (females >1 year postmenarche): 10 mg once daily (maximum: 20 mg/day)
DOSING: ELDERLY — Refer to adult dosing.
Amlodipine: Dosing should start at the lower end of dosing range due to possible increased incidence of hepatic, renal, or cardiac impairment. Elderly patients also show decreased clearance of amlodipine.
Hypertension: 2.5 mg once daily
Angina: 5 mg once daily
DOSING: RENAL IMPAIRMENT — No dosage adjustment is necessary.
DOSING: HEPATIC IMPAIRMENT — Do not use in active liver disease.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Caduet®:
2.5/10: Amlodipine 2.5 mg and atorvastatin 10 mg
2.5/20: Amlodipine 2.5 mg and atorvastatin 20 mg
2.5/40: Amlodipine 2.5 mg and atorvastatin 40 mg
5/10: Amlodipine 5 mg and atorvastatin 10 mg
5/20: Amlodipine 5 mg and atorvastatin 20 mg
5/40: Amlodipine 5 mg and atorvastatin 40 mg
5/80: Amlodipine 5 mg and atorvastatin 80 mg
10/10: Amlodipine 10 mg and atorvastatin 10 mg
10/20: Amlodipine 10 mg and atorvastatin 20 mg
10/40: Amlodipine 10 mg and atorvastatin 40 mg
10/80: Amlodipine 10 mg and atorvastatin 80 mg
DOSAGE FORMS: CONCISE
Tablet:
Caduet®:
2.5/10: Amlodipine 2.5 mg and atorvastatin 10 mg
2.5/20: Amlodipine 2.5 mg and atorvastatin 20 mg
2.5/40: Amlodipine 2.5 mg and atorvastatin 40 mg
5/10: Amlodipine 5 mg and atorvastatin 10 mg
5/20: Amlodipine 5 mg and atorvastatin 20 mg
5/40: Amlodipine 5 mg and atorvastatin 40 mg
5/80: Amlodipine 5 mg and atorvastatin 80 mg
10/10: Amlodipine 10 mg and atorvastatin 10 mg
10/20: Amlodipine 10 mg and atorvastatin 20 mg
10/40: Amlodipine 10 mg and atorvastatin 40 mg
10/80: Amlodipine 10 mg and atorvastatin 80 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — May be administered without regard to meals.
USE — For use when treatment with both amlodipine and atorvastatin is appropriate:
Amlodipine: Treatment of hypertension; treatment of symptomatic chronic stable angina, vasospastic (Prinzmetal's) angina (confirmed or suspected); prevention of hospitalization due to angina with documented CAD (limited to patients without heart failure or ejection fraction <40%)
Atorvastatin: Treatment of dyslipidemias or primary prevention of cardiovascular disease (atherosclerotic) as detailed here:
Primary prevention of cardiovascular disease (high-risk for CVD): To reduce the risk of MI or stroke in patients without evidence of heart disease who have multiple CVD risk factors or type 2 diabetes. Treatment reduces the risk for angina or revascularization procedures in patients with multiple risk factors.
Treatment of dyslipidemias: To reduce elevations in total cholesterol, LDL-C, apolipoprotein B, and triglycerides in patients with elevations of one or more components, and/or to increase HDL-C as present in heterozygous hypercholesterolemia (Fredrickson type IIa hyperlipidemias); treatment of primary dysbetalipoproteinemia (Fredrickson type III), elevated serum TG levels (Fredrickson type IV), and homozygous familial hypercholesterolemia
Treatment of heterozygous familial hypercholesterolemia (HeFH) in adolescent patients (10-17 years of age, females >1 year postmenarche) having LDL-C ≥ 190 mg/dL or LDL-C ≥ 160 mg/dL with positive family history of premature cardiovascular disease (CVD) or with two or more CVD risk factors.
ADVERSE REACTIONS SIGNIFICANT — See individual agents.
CONTRAINDICATIONS — Hypersensitivity to amlodipine, atorvastatin, or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; pregnancy
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of calcium channel blockers. Myopathy/rhabdomyolysis: Patients receiving HMG-CoA reductase inhibitors have developed rhabdomyolysis with acute renal failure and/or myopathy; patients should be monitored closely. This risk is dose-related and is increased with concurrent use of other lipid lowering medications. Temporarily discontinue for elective major surgery, acute medical or surgical conditions, or in any patient experiencing an acute or serious condition predisposing to renal failure (eg, sepsis, hypotension, trauma, uncontrolled seizures). Based upon current evidence, HMG-CoA reductase inhibitor therapy should be continued in the perioperative period unless risk outweighs cardioprotective benefit. Use caution in patients with renal impairment, inadequately treated hypothyroidism, and those taking other drugs associated with myopathy (eg, colchicine); these patients are predisposed to myopathy. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine.
Disease-related concerns: Aortic stenosis: Use amlodipine with caution in patients with severe aortic stenosis. Hepatic impairment and/or ethanol use: Use atorvastatin with caution in patients who consume large amounts of ethanol or have a history of liver disease.
Concurrent drug therapy issues: High potential for interactions: Use atorvastatin with caution in patients taking strong CYP3A4 inhibitors (see drug interactions); consider alternative agents that avoid or lessen potential for CYP-mediated interactions.
Special populations: Elderly: Use atorvastatin with caution in patients with advanced age, these patients are predisposed to myopathy. Pediatrics: Safety and efficacy of the combination of amlodipine/atorvastatin have not been established in children. Safety and efficacy of amlodipine have not been established in patients <6 years of age. Safety and efficacy of atorvastatin have not been established in patients <10 years of age or in premenarcheal girls.
Other warnings/precautions: Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to therapy with atorvastatin. Liver function tests: Must be monitored by periodic laboratory assessment while taking atorvastatin. Titration: Dosage titration of amlodipine should occur after 7-14 days on a given dose.
METABOLISM / TRANSPORT EFFECTS
Amlodipine: Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)
Atorvastatin: Substrate of CYP3A4 (major); Inhibits CYP3A4 (weak)
DRUG INTERACTIONS
Aliskiren: Atorvastatin may increase the serum concentration of Aliskiren. 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
Amiodarone: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Management: Dose of HMG-CoA reductase inhibitor may need to be reduced (e.g., simvastatin prescribing information recommends not exceeding 20 mg/day during concurrent therapy). Risk D: Consider therapy modification
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of HMG-CoA Reductase Inhibitors. 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
Bosentan: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
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
Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
CycloSPORINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
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
Dabigatran Etexilate: Atorvastatin may decrease the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy
Danazol: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
DAPTOmycin: HMG-CoA Reductase Inhibitors may enhance the adverse/toxic effect of DAPTOmycin. Specifically, the risk of skeletal muscle toxicity may be increased. Management: Consider temporarily stopping HMG-CoA reductase inhibitor therapy prior to daptomycin. If used together, regular (i.e., at least weekly) monitoring of CPK concentrations is recommended. 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
Digoxin: Atorvastatin may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Diltiazem: Atorvastatin may increase the serum concentration of Diltiazem. Diltiazem may increase the serum concentration of Atorvastatin. Management: Consider using lower atorvastatin doses when used together with diltiazem. Risk D: Consider therapy modification
Dronedarone: May increase the serum concentration of Atorvastatin. 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
Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. This applies to atorvastatin, lovastatin and simvastatin. Conversely, levels of fluvastatin may be increased. Management: Dose adjustment of the HMG-CoA reductase inhibitor may be warranted. No interaction is expected with rosuvastatin or pravastatin. Risk C: Monitor therapy
Fenofibrate: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Fenofibric Acid: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Fluconazole: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Fluconazole: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy
Fusidic Acid: May enhance the adverse/toxic effect of Atorvastatin. Specifically, the risk of rhabdomyolysis may be increased. Fusidic Acid may increase the serum concentration of Atorvastatin. Risk C: Monitor therapy
Gemfibrozil: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Gemfibrozil may increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Grapefruit Juice: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Grapefruit Juice: May increase the serum concentration of AmLODIPine. 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
Macrolide Antibiotics: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. 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 hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic effect of Antihypertensives. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Midazolam: Atorvastatin may increase the serum concentration of Midazolam. Risk C: Monitor therapy
Nafcillin: May increase the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification
Nefazodone: May decrease the metabolism of HMG-CoA Reductase Inhibitors. 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
Niacin: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Niacinamide: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Nitroprusside: Calcium Channel Blockers may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Substrates: P-Glycoprotein Inhibitors may increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phenytoin: Calcium Channel Blockers may decrease the metabolism of Phenytoin. Risk D: Consider therapy modification
Phenytoin: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Limited data suggest pravastatin may slightly decrease protease inhibitor concentrations. Management: Lovastatin and simvastatin are contraindicated with many protease inhibitors; also, avoid rosuvastatin with indinavir. Use lowest possible HMG-CoA reductase inhibitor dose and monitor for signs of toxicity if these agents are used concomitantly. Risk D: Consider therapy modification
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
QuiNINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Consider using a lower starting dose and lower maintenance/maximum doses of atorvastatin, simvastatin, or lovastatin when used together with quinine. Risk D: Consider therapy modification
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
Rifamycin Derivatives: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Rivaroxaban: P-Glycoprotein Inhibitors may increase the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Sildenafil: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
St Johns Wort: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Tacrolimus: Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus. Risk C: Monitor therapy
Topotecan: P-Glycoprotein Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Verapamil: Atorvastatin may increase the serum concentration of Verapamil. Verapamil may increase the serum concentration of Atorvastatin. Management: Consider using lower atorvastatin doses when used together with verapamil. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
ETHANOL / NUTRITION / HERB INTERACTIONS — See individual agents.
PREGNANCY RISK FACTOR — X (show table)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/contraindicated
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — May take with food if desired; may take without regard to time of day. Before initiation of therapy with atorvastatin, patients should be placed on a standard cholesterol-lowering diet for 3-6 months and the diet should be continued during drug therapy. Red yeast rice contains an estimated 2.4 mg lovastatin per 600 mg rice.
PRICING — (data from drugstore.com)
Tablets (Caduet)
2.5-10 mg (30): $121.79
2.5-20 mg (30): $165.54
2.5-40 mg (30): $165.54
5-10 mg (30): $120.74
5-20 mg (30): $160.96
5-40 mg (30): $157.49
5-80 mg (30): $163.78
10-10 mg (30): $121.79
10-20 mg (30): $163.78
10-40 mg (30): $162.74
10-80 mg (30): $174.29
MONITORING PARAMETERS — Blood pressure; lipid levels after 2-4 weeks, CPK, liver function tests (LFTs); it is recommended that LFTs be performed prior to and at 12 weeks following both the initiation of therapy and any elevation in dose of atorvastatin, and periodically (eg, semiannually) thereafter.
CANADIAN BRAND NAMES — Caduet®
INTERNATIONAL BRAND NAMES — Amat (IN); Caduet (AU, BG, CH, CN, CR, CZ, ES, FR, GT, HK, HN, IL, KP, MX, MY, NI, PA, SG, SV, TH, TW, VE); Encavar (PH); Hipertensal Combi (AR); Liparten (PY); Norvastor (PE); Stamcor (IN)
MECHANISM OF ACTION
Amlodipine: Inhibits calcium ion from entering the "slow channels" or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina
Atorvastatin: Inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in cholesterol synthesis (reduces the production of mevalonic acid from HMG-CoA); this then results in a compensatory increase in the expression of LDL receptors on hepatocyte membranes and a stimulation of LDL catabolism
HMG-CoA Reductase Inhibitors: Evidence Does Not Suggest Increased Incidence of Amyotrophic Lateral Sclerosis (ALS) - Results of FDA Analysis - September 30, 2008
The U.S. Food and Drug Administration's (FDA) review of 41 long-term controlled clinical trials of HMG-CoA reductase inhibitors finds no evidence of an increased incidence of ALS (also known as Lou Gehrig's disease) related to these medications. This analysis occurred after the FDA had received notice of numerous adverse events of which 109 of these reports mentioned ALS, Lou Gehrig's disease, or motor neuron disease. The clinical trials included in the analysis had a median duration of treatment of 3.3 years (range of duration: 6 months to 5 years) and involved 120,964 patients. The analysis identified a total of 19 cases of ALS " 9 cases per 64,602 patients (0.014%) with statin therapy and 10 cases per 56,362 patients (0.017%) with placebo. The incidence rates, based on approximately 400,000 person-years, were 4.2 per 100,000 person-years in the statin-treated group and 5 per 100,000 person-years in the placebo-treated group.
The FDA recommends that health care providers continue to prescribe, and patients continue to use these products as described within their labeling.
For more information, healthcare professionals may refer to the following:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116957.htm
Colman E, Szarfman A, Wyeth J, et al, "An Evaluation of a Data Mining Signal for Amyotrophic Lateral Sclerosis and Statins Detected in FDA's Spontaneous Adverse Event Reporting System,"Pharmacoepidemiol Drug Saf, 2008, 17(11):1068-76.
U.S. BRAND NAMES — Caduet®
PHARMACOLOGIC CATEGORY
Antilipemic Agent, HMG-CoA Reductase Inhibitor
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS
Amlodipine:
Hypertension: Oral: Initial dose: 5 mg once daily; maximum dose: 10 mg once daily; in general, titrate in 2.5 mg increments over 7-14 days. Usual dosage range (JNC 7): 2.5-10 mg once daily
Angina: Oral: Usual dose: 5-10 mg; lower dose suggested in elderly or hepatic impairment; most patients require 10 mg for adequate effect
Atorvastatin:
Hyperlipidemias: Oral: Initial: 10-20 mg once daily; patients requiring >45% reduction in LDL-C may be started at 40 mg once daily; range: 10-80 mg once daily
Primary prevention of CVD: Oral: 10 mg once daily
DOSING: PEDIATRIC
Hypertension:Amlodipine: Oral: Children >10 years: 2.5-5 mg once daily. Note: Use in ages >10 years because of atorvastatin content.
HeFH:Atorvastatin: Oral: Children 10-17 years (females >1 year postmenarche): 10 mg once daily (maximum: 20 mg/day)
DOSING: ELDERLY — Refer to adult dosing.
Amlodipine: Dosing should start at the lower end of dosing range due to possible increased incidence of hepatic, renal, or cardiac impairment. Elderly patients also show decreased clearance of amlodipine.
Hypertension: 2.5 mg once daily
Angina: 5 mg once daily
DOSING: RENAL IMPAIRMENT — No dosage adjustment is necessary.
DOSING: HEPATIC IMPAIRMENT — Do not use in active liver disease.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Caduet®:
2.5/10: Amlodipine 2.5 mg and atorvastatin 10 mg
2.5/20: Amlodipine 2.5 mg and atorvastatin 20 mg
2.5/40: Amlodipine 2.5 mg and atorvastatin 40 mg
5/10: Amlodipine 5 mg and atorvastatin 10 mg
5/20: Amlodipine 5 mg and atorvastatin 20 mg
5/40: Amlodipine 5 mg and atorvastatin 40 mg
5/80: Amlodipine 5 mg and atorvastatin 80 mg
10/10: Amlodipine 10 mg and atorvastatin 10 mg
10/20: Amlodipine 10 mg and atorvastatin 20 mg
10/40: Amlodipine 10 mg and atorvastatin 40 mg
10/80: Amlodipine 10 mg and atorvastatin 80 mg
DOSAGE FORMS: CONCISE
Tablet:
Caduet®:
2.5/10: Amlodipine 2.5 mg and atorvastatin 10 mg
2.5/20: Amlodipine 2.5 mg and atorvastatin 20 mg
2.5/40: Amlodipine 2.5 mg and atorvastatin 40 mg
5/10: Amlodipine 5 mg and atorvastatin 10 mg
5/20: Amlodipine 5 mg and atorvastatin 20 mg
5/40: Amlodipine 5 mg and atorvastatin 40 mg
5/80: Amlodipine 5 mg and atorvastatin 80 mg
10/10: Amlodipine 10 mg and atorvastatin 10 mg
10/20: Amlodipine 10 mg and atorvastatin 20 mg
10/40: Amlodipine 10 mg and atorvastatin 40 mg
10/80: Amlodipine 10 mg and atorvastatin 80 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — May be administered without regard to meals.
USE — For use when treatment with both amlodipine and atorvastatin is appropriate:
Amlodipine: Treatment of hypertension; treatment of symptomatic chronic stable angina, vasospastic (Prinzmetal's) angina (confirmed or suspected); prevention of hospitalization due to angina with documented CAD (limited to patients without heart failure or ejection fraction <40%)
Atorvastatin: Treatment of dyslipidemias or primary prevention of cardiovascular disease (atherosclerotic) as detailed here:
Primary prevention of cardiovascular disease (high-risk for CVD): To reduce the risk of MI or stroke in patients without evidence of heart disease who have multiple CVD risk factors or type 2 diabetes. Treatment reduces the risk for angina or revascularization procedures in patients with multiple risk factors.
Treatment of dyslipidemias: To reduce elevations in total cholesterol, LDL-C, apolipoprotein B, and triglycerides in patients with elevations of one or more components, and/or to increase HDL-C as present in heterozygous hypercholesterolemia (Fredrickson type IIa hyperlipidemias); treatment of primary dysbetalipoproteinemia (Fredrickson type III), elevated serum TG levels (Fredrickson type IV), and homozygous familial hypercholesterolemia
Treatment of heterozygous familial hypercholesterolemia (HeFH) in adolescent patients (10-17 years of age, females >1 year postmenarche) having LDL-C ≥ 190 mg/dL or LDL-C ≥ 160 mg/dL with positive family history of premature cardiovascular disease (CVD) or with two or more CVD risk factors.
ADVERSE REACTIONS SIGNIFICANT — See individual agents.
CONTRAINDICATIONS — Hypersensitivity to amlodipine, atorvastatin, or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; pregnancy
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of calcium channel blockers. Myopathy/rhabdomyolysis: Patients receiving HMG-CoA reductase inhibitors have developed rhabdomyolysis with acute renal failure and/or myopathy; patients should be monitored closely. This risk is dose-related and is increased with concurrent use of other lipid lowering medications. Temporarily discontinue for elective major surgery, acute medical or surgical conditions, or in any patient experiencing an acute or serious condition predisposing to renal failure (eg, sepsis, hypotension, trauma, uncontrolled seizures). Based upon current evidence, HMG-CoA reductase inhibitor therapy should be continued in the perioperative period unless risk outweighs cardioprotective benefit. Use caution in patients with renal impairment, inadequately treated hypothyroidism, and those taking other drugs associated with myopathy (eg, colchicine); these patients are predisposed to myopathy. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine.
Disease-related concerns: Aortic stenosis: Use amlodipine with caution in patients with severe aortic stenosis. Hepatic impairment and/or ethanol use: Use atorvastatin with caution in patients who consume large amounts of ethanol or have a history of liver disease.
Concurrent drug therapy issues: High potential for interactions: Use atorvastatin with caution in patients taking strong CYP3A4 inhibitors (see drug interactions); consider alternative agents that avoid or lessen potential for CYP-mediated interactions.
Special populations: Elderly: Use atorvastatin with caution in patients with advanced age, these patients are predisposed to myopathy. Pediatrics: Safety and efficacy of the combination of amlodipine/atorvastatin have not been established in children. Safety and efficacy of amlodipine have not been established in patients <6 years of age. Safety and efficacy of atorvastatin have not been established in patients <10 years of age or in premenarcheal girls.
Other warnings/precautions: Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to therapy with atorvastatin. Liver function tests: Must be monitored by periodic laboratory assessment while taking atorvastatin. Titration: Dosage titration of amlodipine should occur after 7-14 days on a given dose.
METABOLISM / TRANSPORT EFFECTS
Amlodipine: Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)
Atorvastatin: Substrate of CYP3A4 (major); Inhibits CYP3A4 (weak)
DRUG INTERACTIONS
Aliskiren: Atorvastatin may increase the serum concentration of Aliskiren. 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
Amiodarone: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Management: Dose of HMG-CoA reductase inhibitor may need to be reduced (e.g., simvastatin prescribing information recommends not exceeding 20 mg/day during concurrent therapy). Risk D: Consider therapy modification
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of HMG-CoA Reductase Inhibitors. 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
Bosentan: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
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
Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
CycloSPORINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
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
Dabigatran Etexilate: Atorvastatin may decrease the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy
Danazol: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
DAPTOmycin: HMG-CoA Reductase Inhibitors may enhance the adverse/toxic effect of DAPTOmycin. Specifically, the risk of skeletal muscle toxicity may be increased. Management: Consider temporarily stopping HMG-CoA reductase inhibitor therapy prior to daptomycin. If used together, regular (i.e., at least weekly) monitoring of CPK concentrations is recommended. 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
Digoxin: Atorvastatin may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Diltiazem: Atorvastatin may increase the serum concentration of Diltiazem. Diltiazem may increase the serum concentration of Atorvastatin. Management: Consider using lower atorvastatin doses when used together with diltiazem. Risk D: Consider therapy modification
Dronedarone: May increase the serum concentration of Atorvastatin. 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
Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. This applies to atorvastatin, lovastatin and simvastatin. Conversely, levels of fluvastatin may be increased. Management: Dose adjustment of the HMG-CoA reductase inhibitor may be warranted. No interaction is expected with rosuvastatin or pravastatin. Risk C: Monitor therapy
Fenofibrate: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Fenofibric Acid: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Fluconazole: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Fluconazole: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy
Fusidic Acid: May enhance the adverse/toxic effect of Atorvastatin. Specifically, the risk of rhabdomyolysis may be increased. Fusidic Acid may increase the serum concentration of Atorvastatin. Risk C: Monitor therapy
Gemfibrozil: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Gemfibrozil may increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Grapefruit Juice: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Grapefruit Juice: May increase the serum concentration of AmLODIPine. 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
Macrolide Antibiotics: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. 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 hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic effect of Antihypertensives. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Midazolam: Atorvastatin may increase the serum concentration of Midazolam. Risk C: Monitor therapy
Nafcillin: May increase the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification
Nefazodone: May decrease the metabolism of HMG-CoA Reductase Inhibitors. 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
Niacin: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Niacinamide: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Nitroprusside: Calcium Channel Blockers may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Substrates: P-Glycoprotein Inhibitors may increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phenytoin: Calcium Channel Blockers may decrease the metabolism of Phenytoin. Risk D: Consider therapy modification
Phenytoin: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Limited data suggest pravastatin may slightly decrease protease inhibitor concentrations. Management: Lovastatin and simvastatin are contraindicated with many protease inhibitors; also, avoid rosuvastatin with indinavir. Use lowest possible HMG-CoA reductase inhibitor dose and monitor for signs of toxicity if these agents are used concomitantly. Risk D: Consider therapy modification
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
QuiNINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Consider using a lower starting dose and lower maintenance/maximum doses of atorvastatin, simvastatin, or lovastatin when used together with quinine. Risk D: Consider therapy modification
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
Rifamycin Derivatives: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Rivaroxaban: P-Glycoprotein Inhibitors may increase the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Sildenafil: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
St Johns Wort: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Tacrolimus: Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus. Risk C: Monitor therapy
Topotecan: P-Glycoprotein Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Verapamil: Atorvastatin may increase the serum concentration of Verapamil. Verapamil may increase the serum concentration of Atorvastatin. Management: Consider using lower atorvastatin doses when used together with verapamil. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
ETHANOL / NUTRITION / HERB INTERACTIONS — See individual agents.
PREGNANCY RISK FACTOR — X (show table)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/contraindicated
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — May take with food if desired; may take without regard to time of day. Before initiation of therapy with atorvastatin, patients should be placed on a standard cholesterol-lowering diet for 3-6 months and the diet should be continued during drug therapy. Red yeast rice contains an estimated 2.4 mg lovastatin per 600 mg rice.
PRICING — (data from drugstore.com)
Tablets (Caduet)
2.5-10 mg (30): $121.79
2.5-20 mg (30): $165.54
2.5-40 mg (30): $165.54
5-10 mg (30): $120.74
5-20 mg (30): $160.96
5-40 mg (30): $157.49
5-80 mg (30): $163.78
10-10 mg (30): $121.79
10-20 mg (30): $163.78
10-40 mg (30): $162.74
10-80 mg (30): $174.29
MONITORING PARAMETERS — Blood pressure; lipid levels after 2-4 weeks, CPK, liver function tests (LFTs); it is recommended that LFTs be performed prior to and at 12 weeks following both the initiation of therapy and any elevation in dose of atorvastatin, and periodically (eg, semiannually) thereafter.
CANADIAN BRAND NAMES — Caduet®
INTERNATIONAL BRAND NAMES — Amat (IN); Caduet (AU, BG, CH, CN, CR, CZ, ES, FR, GT, HK, HN, IL, KP, MX, MY, NI, PA, SG, SV, TH, TW, VE); Encavar (PH); Hipertensal Combi (AR); Liparten (PY); Norvastor (PE); Stamcor (IN)
MECHANISM OF ACTION
Amlodipine: Inhibits calcium ion from entering the "slow channels" or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina
Atorvastatin: Inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in cholesterol synthesis (reduces the production of mevalonic acid from HMG-CoA); this then results in a compensatory increase in the expression of LDL receptors on hepatocyte membranes and a stimulation of LDL catabolism
Amlodipine
MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
AmLODIPine may be confused with aMILoride
Norvasc® may be confused with Navane®, Norvir®, Vascor®
U.S. BRAND NAMES — Norvasc®
PHARMACOLOGIC CATEGORY
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS
Hypertension: Oral: Initial dose: 5 mg once daily; maximum dose: 10 mg once daily. In general, titrate in 2.5 mg increments over 7-14 days. Usual dosage range (JNC 7): 2.5-10 mg once daily.
Angina: Oral: Usual dose: 5-10 mg; lower dose suggested in elderly or hepatic impairment; most patients require 10 mg for adequate effect.
DOSING: PEDIATRIC — Hypertension: Oral: Children 6-17 years: 2.5-5 mg once daily
(For additional information see "Amlodipine: Pediatric drug information")
DOSING: ELDERLY — Dosing should start at the lower end of dosing range due to possible increased incidence of hepatic, renal, or cardiac impairment. Elderly patients also show decreased clearance of amlodipine.
Hypertension: Oral: 2.5 mg once daily
Angina: Oral: 5 mg once daily
DOSING: RENAL IMPAIRMENT — Dialysis: Hemodialysis and peritoneal dialysis do not enhance elimination. Supplemental dose is not necessary.
DOSING: HEPATIC IMPAIRMENT
Hypertension: Administer 2.5 mg once daily
Angina: Administer 5 mg once daily
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 2.5 mg, 5 mg, 10 mg
Norvasc®: 2.5 mg, 5 mg, 10 mg
DOSAGE FORMS: CONCISE
Tablet: 2.5 mg, 5 mg, 10 mg
Norvasc®: 2.5 mg, 5 mg, 10 mg
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — May be administered without regard to meals.
USE — Treatment of hypertension; treatment of symptomatic chronic stable angina, vasospastic (Prinzmetal's) angina (confirmed or suspected); prevention of hospitalization due to angina with documented CAD (limited to patients without heart failure or ejection fraction <40%)>10%: Cardiovascular: Peripheral edema (2% to 15% dose related)
1% to 10%:
Cardiovascular: Flushing (1% to 3%), palpitation (1% to 4%)
Central nervous system: Headache (7%; similar to placebo 8%), dizziness (1% to 3%), fatigue (4%), somnolence (1% to 2%)
Dermatologic: Rash (1% to 2%), pruritus (1% to 2%)
Endocrine & metabolic: Male sexual dysfunction (1% to 2%)
Gastrointestinal: Nausea (3%), abdominal pain (1% to 2%), dyspepsia (1% to 2%), gingival hyperplasia
Neuromuscular & skeletal: Muscle cramps (1% to 2%), weakness (1% to 2%)
Respiratory: Dyspnea (1% to 2%), pulmonary edema (15% from PRAISE trial, CHF population)
<1%>90%) to inactive metabolite
Bioavailability: 64% to 90%
Half-life elimination: 30-50 hours; increased with hepatic dysfunction
Time to peak, plasma: 6-12 hours
Excretion: Urine (10% as parent, 60% as metabolite)
PATIENT INFORMATION — Take as prescribed; do not stop abruptly without consulting prescriber. You may experience headache (if unrelieved, consult prescriber), nausea or vomiting (frequent small meals may help), or constipation (increased dietary bulk and fluids may help). May cause drowsiness; use caution when driving or engaging in tasks that require alertness until response to drug is known. Report unrelieved headache, vomiting, constipation, palpitations, peripheral or facial swelling, weight gain >5 lb/week, or respiratory changes.
Sound-alike/look-alike issues:
AmLODIPine may be confused with aMILoride
Norvasc® may be confused with Navane®, Norvir®, Vascor®
U.S. BRAND NAMES — Norvasc®
PHARMACOLOGIC CATEGORY
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS
Hypertension: Oral: Initial dose: 5 mg once daily; maximum dose: 10 mg once daily. In general, titrate in 2.5 mg increments over 7-14 days. Usual dosage range (JNC 7): 2.5-10 mg once daily.
Angina: Oral: Usual dose: 5-10 mg; lower dose suggested in elderly or hepatic impairment; most patients require 10 mg for adequate effect.
DOSING: PEDIATRIC — Hypertension: Oral: Children 6-17 years: 2.5-5 mg once daily
(For additional information see "Amlodipine: Pediatric drug information")
DOSING: ELDERLY — Dosing should start at the lower end of dosing range due to possible increased incidence of hepatic, renal, or cardiac impairment. Elderly patients also show decreased clearance of amlodipine.
Hypertension: Oral: 2.5 mg once daily
Angina: Oral: 5 mg once daily
DOSING: RENAL IMPAIRMENT — Dialysis: Hemodialysis and peritoneal dialysis do not enhance elimination. Supplemental dose is not necessary.
DOSING: HEPATIC IMPAIRMENT
Hypertension: Administer 2.5 mg once daily
Angina: Administer 5 mg once daily
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 2.5 mg, 5 mg, 10 mg
Norvasc®: 2.5 mg, 5 mg, 10 mg
DOSAGE FORMS: CONCISE
Tablet: 2.5 mg, 5 mg, 10 mg
Norvasc®: 2.5 mg, 5 mg, 10 mg
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — May be administered without regard to meals.
USE — Treatment of hypertension; treatment of symptomatic chronic stable angina, vasospastic (Prinzmetal's) angina (confirmed or suspected); prevention of hospitalization due to angina with documented CAD (limited to patients without heart failure or ejection fraction <40%)>10%: Cardiovascular: Peripheral edema (2% to 15% dose related)
1% to 10%:
Cardiovascular: Flushing (1% to 3%), palpitation (1% to 4%)
Central nervous system: Headache (7%; similar to placebo 8%), dizziness (1% to 3%), fatigue (4%), somnolence (1% to 2%)
Dermatologic: Rash (1% to 2%), pruritus (1% to 2%)
Endocrine & metabolic: Male sexual dysfunction (1% to 2%)
Gastrointestinal: Nausea (3%), abdominal pain (1% to 2%), dyspepsia (1% to 2%), gingival hyperplasia
Neuromuscular & skeletal: Muscle cramps (1% to 2%), weakness (1% to 2%)
Respiratory: Dyspnea (1% to 2%), pulmonary edema (15% from PRAISE trial, CHF population)
<1%>90%) to inactive metabolite
Bioavailability: 64% to 90%
Half-life elimination: 30-50 hours; increased with hepatic dysfunction
Time to peak, plasma: 6-12 hours
Excretion: Urine (10% as parent, 60% as metabolite)
PATIENT INFORMATION — Take as prescribed; do not stop abruptly without consulting prescriber. You may experience headache (if unrelieved, consult prescriber), nausea or vomiting (frequent small meals may help), or constipation (increased dietary bulk and fluids may help). May cause drowsiness; use caution when driving or engaging in tasks that require alertness until response to drug is known. Report unrelieved headache, vomiting, constipation, palpitations, peripheral or facial swelling, weight gain >5 lb/week, or respiratory changes.
Amlodipine
MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
AmLODIPine may be confused with aMILoride
Norvasc® may be confused with Navane®, Norvir®, Vascor®
U.S. BRAND NAMES — Norvasc®
PHARMACOLOGIC CATEGORY
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS
Hypertension: Oral: Initial dose: 5 mg once daily; maximum dose: 10 mg once daily. In general, titrate in 2.5 mg increments over 7-14 days. Usual dosage range (JNC 7): 2.5-10 mg once daily.
Angina: Oral: Usual dose: 5-10 mg; lower dose suggested in elderly or hepatic impairment; most patients require 10 mg for adequate effect.
DOSING: PEDIATRIC — Hypertension: Oral: Children 6-17 years: 2.5-5 mg once daily
(For additional information see "Amlodipine: Pediatric drug information")
DOSING: ELDERLY — Dosing should start at the lower end of dosing range due to possible increased incidence of hepatic, renal, or cardiac impairment. Elderly patients also show decreased clearance of amlodipine.
Hypertension: Oral: 2.5 mg once daily
Angina: Oral: 5 mg once daily
DOSING: RENAL IMPAIRMENT — Dialysis: Hemodialysis and peritoneal dialysis do not enhance elimination. Supplemental dose is not necessary.
DOSING: HEPATIC IMPAIRMENT
Hypertension: Administer 2.5 mg once daily
Angina: Administer 5 mg once daily
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 2.5 mg, 5 mg, 10 mg
Norvasc®: 2.5 mg, 5 mg, 10 mg
DOSAGE FORMS: CONCISE
Tablet: 2.5 mg, 5 mg, 10 mg
Norvasc®: 2.5 mg, 5 mg, 10 mg
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — May be administered without regard to meals.
USE — Treatment of hypertension; treatment of symptomatic chronic stable angina, vasospastic (Prinzmetal's) angina (confirmed or suspected); prevention of hospitalization due to angina with documented CAD (limited to patients without heart failure or ejection fraction <40%)>10%: Cardiovascular: Peripheral edema (2% to 15% dose related)
1% to 10%:
Cardiovascular: Flushing (1% to 3%), palpitation (1% to 4%)
Central nervous system: Headache (7%; similar to placebo 8%), dizziness (1% to 3%), fatigue (4%), somnolence (1% to 2%)
Dermatologic: Rash (1% to 2%), pruritus (1% to 2%)
Endocrine & metabolic: Male sexual dysfunction (1% to 2%)
Gastrointestinal: Nausea (3%), abdominal pain (1% to 2%), dyspepsia (1% to 2%), gingival hyperplasia
Neuromuscular & skeletal: Muscle cramps (1% to 2%), weakness (1% to 2%)
Respiratory: Dyspnea (1% to 2%), pulmonary edema (15% from PRAISE trial, CHF population)
<1%>90%) to inactive metabolite
Bioavailability: 64% to 90%
Half-life elimination: 30-50 hours; increased with hepatic dysfunction
Time to peak, plasma: 6-12 hours
Excretion: Urine (10% as parent, 60% as metabolite)
PATIENT INFORMATION — Take as prescribed; do not stop abruptly without consulting prescriber. You may experience headache (if unrelieved, consult prescriber), nausea or vomiting (frequent small meals may help), or constipation (increased dietary bulk and fluids may help). May cause drowsiness; use caution when driving or engaging in tasks that require alertness until response to drug is known. Report unrelieved headache, vomiting, constipation, palpitations, peripheral or facial swelling, weight gain >5 lb/week, or respiratory changes.
Sound-alike/look-alike issues:
AmLODIPine may be confused with aMILoride
Norvasc® may be confused with Navane®, Norvir®, Vascor®
U.S. BRAND NAMES — Norvasc®
PHARMACOLOGIC CATEGORY
Calcium Channel Blocker
Calcium Channel Blocker, Dihydropyridine
DOSING: ADULTS
Hypertension: Oral: Initial dose: 5 mg once daily; maximum dose: 10 mg once daily. In general, titrate in 2.5 mg increments over 7-14 days. Usual dosage range (JNC 7): 2.5-10 mg once daily.
Angina: Oral: Usual dose: 5-10 mg; lower dose suggested in elderly or hepatic impairment; most patients require 10 mg for adequate effect.
DOSING: PEDIATRIC — Hypertension: Oral: Children 6-17 years: 2.5-5 mg once daily
(For additional information see "Amlodipine: Pediatric drug information")
DOSING: ELDERLY — Dosing should start at the lower end of dosing range due to possible increased incidence of hepatic, renal, or cardiac impairment. Elderly patients also show decreased clearance of amlodipine.
Hypertension: Oral: 2.5 mg once daily
Angina: Oral: 5 mg once daily
DOSING: RENAL IMPAIRMENT — Dialysis: Hemodialysis and peritoneal dialysis do not enhance elimination. Supplemental dose is not necessary.
DOSING: HEPATIC IMPAIRMENT
Hypertension: Administer 2.5 mg once daily
Angina: Administer 5 mg once daily
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 2.5 mg, 5 mg, 10 mg
Norvasc®: 2.5 mg, 5 mg, 10 mg
DOSAGE FORMS: CONCISE
Tablet: 2.5 mg, 5 mg, 10 mg
Norvasc®: 2.5 mg, 5 mg, 10 mg
GENERIC EQUIVALENT AVAILABLE — Yes
ADMINISTRATION — May be administered without regard to meals.
USE — Treatment of hypertension; treatment of symptomatic chronic stable angina, vasospastic (Prinzmetal's) angina (confirmed or suspected); prevention of hospitalization due to angina with documented CAD (limited to patients without heart failure or ejection fraction <40%)>10%: Cardiovascular: Peripheral edema (2% to 15% dose related)
1% to 10%:
Cardiovascular: Flushing (1% to 3%), palpitation (1% to 4%)
Central nervous system: Headache (7%; similar to placebo 8%), dizziness (1% to 3%), fatigue (4%), somnolence (1% to 2%)
Dermatologic: Rash (1% to 2%), pruritus (1% to 2%)
Endocrine & metabolic: Male sexual dysfunction (1% to 2%)
Gastrointestinal: Nausea (3%), abdominal pain (1% to 2%), dyspepsia (1% to 2%), gingival hyperplasia
Neuromuscular & skeletal: Muscle cramps (1% to 2%), weakness (1% to 2%)
Respiratory: Dyspnea (1% to 2%), pulmonary edema (15% from PRAISE trial, CHF population)
<1%>90%) to inactive metabolite
Bioavailability: 64% to 90%
Half-life elimination: 30-50 hours; increased with hepatic dysfunction
Time to peak, plasma: 6-12 hours
Excretion: Urine (10% as parent, 60% as metabolite)
PATIENT INFORMATION — Take as prescribed; do not stop abruptly without consulting prescriber. You may experience headache (if unrelieved, consult prescriber), nausea or vomiting (frequent small meals may help), or constipation (increased dietary bulk and fluids may help). May cause drowsiness; use caution when driving or engaging in tasks that require alertness until response to drug is known. Report unrelieved headache, vomiting, constipation, palpitations, peripheral or facial swelling, weight gain >5 lb/week, or respiratory changes.
Amlexanox
U.S. BRAND NAMES — Aphthasol®
PHARMACOLOGIC CATEGORY
Anti-inflammatory, Locally Applied
DOSING: ADULTS — Aphthous ulcers: Topical: Administer ~1/4 inch (0.5 cm) directly on ulcers 4 times/day following oral hygiene, after meals, and at bedtime.
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Paste, oral:
Aphthasol®: 5% (3 g) [contains benzyl alcohol]
DOSAGE FORMS: CONCISE
Paste, oral:
Aphthasol®: 5% (3 g)
GENERIC EQUIVALENT AVAILABLE — No
USE — Treatment of aphthous ulcers (ie, canker sores)
USE - UNLABELED / INVESTIGATIONAL — Allergic disorders
ADVERSE REACTIONS SIGNIFICANT
1% to 2%:
Dermatologic: Allergic contact dermatitis
Gastrointestinal: Oral irritation
<1% (Limited to important or life-threatening): Contact mucositis
CONTRAINDICATIONS — Hypersensitivity to amlexanox or any component of the formulation
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Mucositis: Discontinue therapy if contact mucositis develops. Rash: Discontinue therapy if rash develops.
Special populations: Pediatrics: Safety and efficacy have not been established in children.
DRUG INTERACTIONS — There are no known significant interactions.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Due to lack of data, avoid use in pregnancy, if possible.
LACTATION — Excretion in breast milk unknown/use caution
PRICING — (data from drugstore.com)
Paste (Aphthasol)
5% (3): $29.99
INTERNATIONAL BRAND NAMES — Elics (JP); Solfa (JP)
MECHANISM OF ACTION — As a benzopyrano-bipyridine carboxylic acid derivative, amlexanox has anti-inflammatory and antiallergic properties; it inhibits chemical mediatory release of the slow-reacting substance of anaphylaxis (SRS-A) and may have antagonistic effects on interleukin-3
PHARMACODYNAMICS / KINETICS
Absorption: Some from swallowed paste
Metabolism: Hydroxylated and conjugated metabolites
Half-life elimination: 3.5 hours
Time to peak, serum: 2 hours
Excretion: Urine (17% as unchanged drug)
PHARMACOLOGIC CATEGORY
Anti-inflammatory, Locally Applied
DOSING: ADULTS — Aphthous ulcers: Topical: Administer ~1/4 inch (0.5 cm) directly on ulcers 4 times/day following oral hygiene, after meals, and at bedtime.
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Paste, oral:
Aphthasol®: 5% (3 g) [contains benzyl alcohol]
DOSAGE FORMS: CONCISE
Paste, oral:
Aphthasol®: 5% (3 g)
GENERIC EQUIVALENT AVAILABLE — No
USE — Treatment of aphthous ulcers (ie, canker sores)
USE - UNLABELED / INVESTIGATIONAL — Allergic disorders
ADVERSE REACTIONS SIGNIFICANT
1% to 2%:
Dermatologic: Allergic contact dermatitis
Gastrointestinal: Oral irritation
<1% (Limited to important or life-threatening): Contact mucositis
CONTRAINDICATIONS — Hypersensitivity to amlexanox or any component of the formulation
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Mucositis: Discontinue therapy if contact mucositis develops. Rash: Discontinue therapy if rash develops.
Special populations: Pediatrics: Safety and efficacy have not been established in children.
DRUG INTERACTIONS — There are no known significant interactions.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Due to lack of data, avoid use in pregnancy, if possible.
LACTATION — Excretion in breast milk unknown/use caution
PRICING — (data from drugstore.com)
Paste (Aphthasol)
5% (3): $29.99
INTERNATIONAL BRAND NAMES — Elics (JP); Solfa (JP)
MECHANISM OF ACTION — As a benzopyrano-bipyridine carboxylic acid derivative, amlexanox has anti-inflammatory and antiallergic properties; it inhibits chemical mediatory release of the slow-reacting substance of anaphylaxis (SRS-A) and may have antagonistic effects on interleukin-3
PHARMACODYNAMICS / KINETICS
Absorption: Some from swallowed paste
Metabolism: Hydroxylated and conjugated metabolites
Half-life elimination: 3.5 hours
Time to peak, serum: 2 hours
Excretion: Urine (17% as unchanged drug)
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