,intravenous administration of 10 mg did not significantly alter A-H and H-V conduction andsinus node recovery time after pacing. Similar results were obtained in patients receivingamlodipine and concomitant beta-blockers. In clinical studies in which amlodipine wasadministered in combination with beta-blockers to patients with either hypertension or angina, noadverse effects on electrocardiographic parameters were observed. In clinical trials with anginapatients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higherdegrees of AV blocks.
12.3 Pharmacokinetics
The exposure (Cmax and AUC) of KATERZIA oral suspension is similar to that of Norvasc®tablet.
Absorption
After oral administration of therapeutic doses of amlodipine, absorption produces peak plasmaconcentrations between 6 and 12 hours. Absolute bioavailability has been estimated to bebetween 64 and 90%.
Effect of Food
Compared to fasted state administration, standard high-fat, high-calorie breakfast did not have asignificant effect on the absorption of KATERZIA.
Distribution
Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasmaproteins in hypertensive patients.
Metabolism
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolismwith 10% of the parent compound and 60% of the metabolites excreted in the urine.
Excretion
Elimination from the plasma is biphasic with a terminal elimination half-life of about 30–50hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutivedaily dosing.
Specific Populations
Pediatric Patients
Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar tovalues in adults.
Renal Impairment
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.
Patients with renal failure may therefore receive the usual initial dose.
Hepatic Impairment
Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipinewith a resulting increase in AUC of approximately 40–60%, and a lower initial dose may berequired. A similar increase in AUC was observed in patients with moderate to severe heartfailure.
Drug Interactions
In vitro data indicate that amlodipine has no effect on the human plasma protein binding ofdigoxin, phenytoin, warfarin, and indomethacin.
Impact of Other Drugs on AmlodipineCo-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, andgrapefruit juice have no impact on the exposure to amlodipine.
CYP3A inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipinein elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure.
Erythromycin co-administration in healthy volunteers did not significantly change amlodipinesystemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see Drug Interactions(7.1)].
Impact of Amlodipine on Other Drugs
Amlodipine is a weak inhibitor of CYP3A and may increase exposure to CYP3A substrates.
Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol, andthe warfarin prothrombin response ti |
