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Amlodipine and atorvastatin

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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.

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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 cautio
n 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

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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. Ri
sk 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

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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

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