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Product Name
:
NORVEK
Chemical Name
:
Amlodipine (besylate)
Therapeutic Category
:
Cardiovascular drugs
Pharmacologic Category
:
Calcium Channel Blocker - Calcium Channel Blocker, Dihydropyridine
Pharmaceutical Form
:
Tablets
Composition
:
Amlodipine (besylate) 5mg / 10mg
Dosing
 
Dosing: Adult
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; most patients require 10 mg for adequate effect.

Dosing: Pediatric

Hypertension: Oral: Children 6-17 years: 2.5-5 mg once daily

Dosing: Geriatric

Dosing should start at the lower end of dosing range and titrated to response 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
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%)
Adverse Reactions
 
>10%: Cardiovascular: Peripheral edema (2% to 15% dose related; HF patients: 27% [Packer, 1996])
1% to 10%:
Cardiovascular: Flushing (1% to 5% dose related), palpitation (1% to 5% dose related)
Central nervous system: Dizziness (1% to 3% dose related), fatigue (5%), 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%)
Neuromuscular & skeletal: Muscle cramps (1% to 2%), weakness (1% to 2%)
Respiratory: Dyspnea (1% to 2%), pulmonary edema (HF patients: 27% [Packer, 1996])
<1% (Limited to important or life-threatening): Abnormal dreams, abnormal vision, abnormal visual accommodation, acute interstitial nephritis, allergic reactions, agitation, alopecia, amnesia, angioedema, anorexia, anxiety, apathy, appetite increased, arrhythmia, arthralgia, arthrosis, ataxia, atrial fibrillation, back pain, bradycardia, cardiac failure, chest pain, cholestasis, cold and clammy skin, conjunctivitis, constipation, cough, depersonalization, depression, dermatitis, diaphoresis increased, diarrhea, diplopia, dysphagia, dysuria, epistaxis, erythema multiforme, exfoliative dermatitis, extrasystoles, eye pain, female sexual dysfunction, flatulence, gastritis, gingival hyperplasia, gynecomastia, hepatitis, hot flushes, hyperglycemia, hypertonia, hypoesthesia, hypotension, insomnia, jaundice, leukocytoclastic vasculitis, leukopenia, loose stools, malaise, micturition disorder, micturition frequency, migraine, muscle weakness, myalgia, nervousness, nocturia, nonthrombocytopenic purpura, pain, pancreatitis, paresthesia, parosmia, peripheral ischemia, peripheral neuropathy, phototoxicity, polyuria, postural dizziness, postural hypotension, pulse irregularity, purpura, rash erythematous, rash maculopapular, rhinitis, rigors, skin discoloration, skin dryness, Stevens-Johnson syndrome, syncope, tachycardia, taste perversion, thirst, thrombocytopenia, tinnitus, transaminases increased, tremor, twitching, urticaria, vasculitis, ventricular tachycardia, vertigo, vomiting, weight gain/loss, xerophthalmia, xerostomia
Contraindications
 
Hypersensitivity to amlodipine or any component of the formulation
Warnings / Precautions Drug
 
Concerns related to adverse effects:
• Angina/MI: Increased angina and/or MI have 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.
• Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; blood pressure must be lowered at a rate appropriate for the patient's clinical condition.
• Peripheral edema: The most common side effect is peripheral edema; occurs within 2-3 weeks of starting therapy.
Disease-related concerns:
• Aortic stenosis: Use amlodipine with extreme caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.
• Hepatic impairment: Use with caution in patients with hepatic impairment; may require lower starting dose; titrate slowly in patients with severe hepatic impairment.
• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Use amlodipine with caution in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition.
Special populations:
• Elderly: Initiate at a lower dose in the elderly.
Other warnings/precautions:
• Titration: Peak antihypertensive effect is delayed; dosage titration should occur after 7-14 days on a given dose.
Metabolism/Transport Effects
Substrate of CYP3A4 (major); Inhibits CYP1A2 (moderate), 2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 2D6 (weak), 3A4 (weak)
Interactions
 
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. Management: Monitor for decreased therapeutic effects of calcium channel blockers with concomitant barbiturate therapy. Calcium channel blocker dose adjustments may be necessary. Nimodipine Canadian labeling contraindicates concomitant use with phenobarbital. Risk C: Monitor therapy
Beta-Blockers: Calcium Channel Blockers (Dihydropyridine) may enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy
Calcium Channel Blockers (Nondihydropyridine): Calcium Channel Blockers (Dihydropyridine) may enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration 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). Management: Consider calcium channel blocker (CCB) dose adjustments or alternative therapy in patients receiving concomitant carbamazepine. Nimodipine Canadian labeling contraindicates concurrent use with carbamazepine. Risk D: Consider therapy modification
Clopidogrel: Calcium Channel Blockers may diminish the therapeutic effect of Clopidogrel. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
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
CycloSPORINE (Systemic): May decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). 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
Fluconazole: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy
Fosphenytoin: Calcium Channel Blockers may increase the serum concentration of Fosphenytoin. Management: Monitor for phenytoin toxicity with concomitant use of a calcium channel blocker (CCB) or decreased phenytoin effects with CCB discontinuation. Monitor for decreased CCB therapeutic effects. Nimodipine Canadian labeling contraindicates use with phenytoin. Risk D: Consider therapy modification
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
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Macrolide Antibiotics: May decrease the metabolism of Calcium Channel Blockers. Management: Consider using a noninteracting macrolide. Monitor for increased therapeutic effects of calcium channel blockers if an interacting macrolide antibiotic is initiated, or decreased effects if a macrolide is discontinued. Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin (Systemic); 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 hypotensive effect of Antihypertensives. 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
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phenytoin: Calcium Channel Blockers may increase the serum concentration of Phenytoin. Management: Monitor for phenytoin toxicity with concomitant use of a calcium channel blocker (CCB) or decreased phenytoin effects with CCB discontinuation. Monitor for decreased CCB therapeutic effects. Nimodipine Canadian labeling contraindicates use with phenytoin. 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 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. Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of QuiNIDine. QuiNIDine may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Risk C: Monitor therapy
Rifamycin Derivatives: May increase the metabolism of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers. Management: The labeling for some U.S. and Canadian calcium channel blockers contraindicate use with rifampin however recommendations vary. Consult appropriate labeling. Risk D: Consider therapy modification
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Simvastatin: AmLODIPine may increase the serum concentration of Simvastatin. Management: Avoid the concurrent use of amlodipine with simvastatin when possible. If used together, avoid doses of simvastatin greater than 20 mg/day (for adults). Risk D: Consider therapy modification
Tacrolimus: Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus. Risk C: Monitor therapy
Tacrolimus (Systemic): Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Pregnancy
 
C
Pregnancy Implications
Embryotoxic effects have been demonstrated in animal studies. No well-controlled studies have been conducted in pregnant women. Use in pregnancy only when clearly needed and when the benefits outweigh the potential hazard to the fetus.
Lactation
 
Excretion in breast milk unknown/not recommended
Monitoring Parameters
 
Heart rate, blood pressure, peripheral edema
Mechanism of Action
 
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. Amlodipine directly acts on vascular smooth muscle to produce peripheral arterial vasodilation reducing peripheral vascular resistance and blood pressure.
Pharmacodynamics / Kinetics
 
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. Amlodipine directly acts on vascular smooth muscle to produce peripheral arterial vasodilation reducing peripheral vascular resistance and blood pressure.
 
   
 
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