AMLODIPINE BESYLATE (Generic for NORVASC)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May administer without regard to meals.
Oral Liquid Formulations
Oral suspension
-Shake well before using.
-Measure with a calibrated oral syringe.
-Storage: Keep in refrigerator (36 to 46 degrees F [2 to 8 degrees C]).

Oral solution
-Measure with a calibrated oral syringe.
-Storage: Store at room temperature in original bottle.

Extemporaneous Compounding-Oral
NOTE: There is an FDA-approved oral solution and suspension of amlodipine (1 mg/mL) commercially available.
Extemporaneous preparation of 1 mg/mL amlodipine oral suspension:
-With a mortar and pestle, grind twenty-four 5 mg amlodipine tablets to a fine powder.
-In a separate container, mix 60 mL of Ora-Sweet with 60 mL of Ora-Plus to make the base solution. Shake well.
-Add a small amount of base solution to amlodipine powder to form a paste. Add geometric amounts of the base solution while mixing well, leaving enough base solution to rinse the mortar after the mixture is transferred to a graduated cylinder.
-Transfer mixture to a graduated cylinder and add the additional base solution to make a total volume of 120 mL. The final concentration is 1 mg/mL.
-Storage: Place in an amber plastic bottle. Shake well before each use. This oral suspension is stable for 90 days refrigerated or up to 56 days when stored at room temperature (approximately 25 degrees C or 77 degrees F).

Most adverse reactions to amlodipine are mild to moderate in severity and related to the drug's peripheral vasodilatory effect. Amlodipine 2.5 or 5 mg/day PO was well tolerated in a randomized, double-blind, placebo-controlled study of 268 hypertensive pediatric patients 6 years and older. In this trial, 6 patients were withdrawn from amlodipine therapy due to drug-related adverse events. Adverse effects are similar to those observed for adults.

Severe headache (3%) and peripheral edema (2% to 4%) were the most commonly reported adverse reactions in a placebo-controlled study of 268 hypertensive pediatric patients. Asthenia, dizziness, and epistaxis were among the most common mild to moderate adverse reactions thought to be treatment-related. In adult clinical trials, edema (2% to 15%), dizziness (1% to 3%), palpitations (1% to 5%), and flushing (1% to 5%) were dose-related adverse reactions. Edema, palpitations, and flushing appear to occur more frequently in adult women. Other adverse reactions reported with amlodipine in adult patients include fatigue (5%) and drowsiness (1% to 2%).

Jaundice and elevated hepatic enzymes (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported with postmarketing experience. Pancreatitis has also been reported rarely (less than 1%).

Leukopenia and thrombocytopenia were reported in less than 1% of amlodipine-treated patients in controlled clinical trials, open trials, or marketing experience. Gynecomastia has been infrequently reported with postmarketing experience; however, a causal relationship is uncertain.

Peripheral neuropathy, paresthesias, tremor, and vertigo have been reported in less than 1% of amlodipine-treated patients in controlled clinical trials, open trials, or marketing experience; a causal relationship has not been established.

Ventricular arrhythmia was reported in 1 patient (0.3%) receiving amlodipine in a placebo-controlled study of 268 hypertensive pediatric patients. Arrhythmia exacerbation (including ventricular tachycardia and atrial fibrillation), bradycardia, syncope, chest pain (unspecified), peripheral ischemia, sinus tachycardia, and vasculitis have been reported in less than 1% of amlodipine-treated patients in controlled clinical trials, open trials, or marketing experience; however, a causal relationship has not been established. Since the peripheral vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, exercise caution when administering amlodipine, as with any other peripheral vasodilator, to patients at risk for hypotension.

Hypoesthesia, insomnia, nervousness or anxiety, depression, abnormal dreams (e.g., nightmares), and depersonalization have been reported in less than 1% of amlodipine-treated patients in controlled clinical trials, open trials, or marketing experience; however, a causal relationship has not been established.

Muscle cramps were reported in 2% or less of amlodipine-treated patients in clinical trials. Back pain, hot flashes, malaise, pain, rigors (chills), weight gain, weight loss, arthralgia, arthrosis, and myalgia occurred in less than 1% of amlodipine-treated patients in controlled clinical trials, open trials, or marketing experience; a causal relationship has not been established. Based on postmarketing reports, there is a possible association between amlodipine and extrapyramidal disorder.

Dyspnea was reported in 2% or less of amlodipine-treated patients during clinical trials.

Abdominal pain was among the most common mild to moderate adverse reactions reported with amlodipine in a placebo-controlled study of 268 hypertensive pediatric patients. Xerostomia (0.3%) and vomiting (0.3%) were classified as severe adverse reactions. Nausea (3%) was reported with amlodipine in adult clinical trials. Anorexia, constipation, diarrhea, dysphagia, gingival hyperplasia, and flatulence occurred in less than 1% of patients in controlled clinical trials, open trials, or marketing experience; a causal relationship has not been established.

Conjunctivitis, diplopia, visual impairment (abnormal vision), ocular pain, and tinnitus have been reported in less than 1% of amlodipine-treated patients in controlled clinical trials, open trials, or marketing experience; a causal relationship has not been established.

Pruritus and rash were reported in 2% or less of patients during clinical trials. Angioedema, allergic reactions, erythema, erythema multiforme, maculopapular rash, purpura, and diaphoresis occurred in less than 1% of patients in controlled clinical trials, open trials, or marketing experience; a causal relationship has not been established.

Increased urinary frequency, micturition disorder, and nocturia occurred in less than 1% of amlodipine-treated patients in controlled clinical trials, open trials, or marketing experience; a causal relationship has not been established.

Hyperglycemia and thirst (polydipsia) occurred in less than 1% of amlodipine-treated patients in controlled clinical trials, open trials, or marketing experience; a causal relationship has not been established.

Systematic hypotension is possible with amlodipine, particularly in patients with aortic stenosis. Because of the gradual onset of action of amlodipine, acute hypotension is unlikely.

Use amlodipine with caution in patients with hepatic disease; dosage adjustment with slow dose titration is recommended. Amlodipine is extensively metabolized by the liver and elimination half-life is prolonged in patients with hepatic impairment.

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in adult patients with severe obstructive coronary artery disease.

Description: Amlodipine is an oral dihydropyridine calcium-channel blocker used for the treatment of hypertension. It is also used off-label for the treatment of pulmonary hypertension. It is a potent peripheral vasodilator, similar to nifedipine and other members of the dihydropyridine class, although amlodipine has the longest half-life of the group. Although FDA-approved labeling recommends once-daily dosing of amlodipine, younger children may benefit from twice daily dosing due to faster clearance and higher weight-based dosage requirements relative to older children. In adult patients, amlodipine is considered less effective than ACE inhibitors or AII-receptor antagonists in slowing the progression of renal disease in patients with diabetic nephropathy or hypertensive renal disease. Amlodipine is FDA-approved in pediatric patients as young as 6 years of age, but is used off-label in pediatric patients as young as infants.

For the treatment of hypertension:
Oral dosage:
Children 1 to 5 years*: 0.1 mg/kg/dose (range: 0.05 to 0.3 mg/kg/dose) PO once daily, initially. Adjust dose according to blood pressure response, generally no more frequently than every 7 to 14 days, up to a maximum dose of 0.6 mg/kg/day (Max: 5 mg/day). Younger children require higher doses per kg of body weight relative to older children and may benefit from twice daily dosing in some cases.
Children and Adolescents 6 to 17 years: 2.5 to 5 mg PO once daily, initially. Adjust dose according to blood pressure response, generally no more frequently than every 7 to 14 days. Max: 10 mg/day. Alternatively, 0.1 mg/kg/dose (range: 0.05 to 0.3 mg/kg/dose; Max: 5 mg/dose) PO once daily, initially, up to a maximum dose of 0.6 mg/kg/day (Max: 10 mg/day). Younger children require higher doses per kg of body weight relative to older children and may benefit from twice daily dosing in some cases.

For the treatment of pulmonary hypertension*:
Oral dosage:
Infants, Children, and Adolescents: 0.1 to 0.3 mg/kg/dose PO once daily, initially. Increase dose as tolerated. Usual dose: 2.5 to 7.5 mg/day. Max: 10 mg/day.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 5 years: Safety and efficacy have not been established; however, doses up to 0.6 mg/kg/day PO have been reported off-label.
6 to 12 years: 5 mg/day PO is the maximum dosage per FDA-approved labeling; however, doses up to 0.6 mg/kg/day PO (usually not exceeding adult max: 10 mg/day) have been reported.
-Adolescents
5 mg/day PO is the maximum dosage per FDA-approved labeling; however, doses up to 0.6 mg/kg/day PO (usually not exceeding adult max: 10 mg/day) have been reported.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in pediatric patients with hepatic impairment are not available. FDA-approved product labeling recommends an initial dosage reduction of 50% (2.5 mg PO once daily) in adults with hepatic insufficiency; adjust dosage based on clinical response.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Amlodipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. Amlodipine inhibits this influx, and the resultant decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries. As with other calcium-channel blockers of the dihydropyridine class, amlodipine exerts its effects mainly on arteriolar vasculature. It has no significant effect on sinus node function or cardiac conduction, nor does it possess negative inotropic effects at clinical doses. Because it has a gradual onset, reflex tachycardia does not occur, a side effect that is common with other peripheral vasodilators. Amlodipine therapy usually does not affect hemodynamic parameters in patients with normal ventricular function.

Pharmacokinetics: Amlodipine is administered orally. Amlodipine is approximately 93% bound to plasma proteins. Amlodipine is extensively metabolized to inactive compounds by the liver with 10% of the parent compound and 60% of the inactive metabolites excreted in the urine. The terminal half-life is about 30 to 50 hours. Steady-state plasma concentrations of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
Amlodipine is a CYP3A4 substrate, and its metabolism may be affected by CYP3A4 inhibitors or inducers. Coadministration of erythromycin in healthy volunteers did not significantly change amlodipine systemic exposure; however, strong CYP3A4 inhibitors may increase amlodipine plasma concentrations to a greater extent. Amlodipine is a weak inhibitor of CYP3A4 and may increase exposure of CYP3A substrates.


-Route-Specific Pharmacokinetics
Oral Route
After oral administration, amlodipine peak plasma concentrations are achieved between 6 and 12 hours. Oral bioavailability is estimated to be 64% to 90%; food does not significantly affect absorption. The exposure of amlodipine oral suspension and solution is similar to that of the tablets.


-Special Populations
Pediatrics
Children and Adolescents
Weight-adjusted clearance and volume of distribution were similar to values observed in adults during clinical trials (n= 62; age range: 6 to 17 years). In another pharmacokinetic study, older children and adolescents with body weights similar to that of adults demonstrated similar pharmacokinetic parameters. However, children younger than 6 years demonstrated a weight-normalized clearance of 1 +/- 0.33 L/kg/hour compared to 0.63 +/- 0.36 L/kg/hour for those 6 to 12 years and 0.4 +/- 0.16 L/kg/hour for those 13 to 18 years. Amlodipine serum concentrations were similar whether amlodipine was dosed once or twice daily.

Hepatic Impairment
Amlodipine is extensively metabolized by the liver; clearance is decreased in patients with hepatic impairment. In these patients, the plasma elimination half-life is prolonged (56 hours) and the AUC is increased by 40% to 60%.

Renal Impairment
The pharmacokinetics of amlodipine are not significantly impacted by renal impairment.

Other
Heart Failure
Amlodipine AUC increases approximately 40% to 60% in patients with moderate to severe heart failure.