1016-DIL-01 6.25 /25 Tablets 6.25 mg/25 mg 022071 020452 Carvedilol 1. 1.1 / Alpha (α) beta (β) ATC code: C07AG02 1.2 1.3 1.4 / 1.5 : Carvedilol 6.25 6.25 carvedilol Lactose monohydrate, Sucrose, Povidone K25, Crospovidone type A, Silica (colloidal anhydrous), Magnesium stearate, Yellow iron oxide 25 25 carvedilol Lactose monohydrate, Sucrose, Povidone K25, Crospovidone type A, Silica (colloidal anhydrous), Magnesium stearate 1
2. 2.1 6.25 25 Carvedilol () Carvedilol (CHF) Carvedilol (adjunct) ACE digitalis hydralazine nitrate 2.2 carvedilol 12.5 25 50 () 2
digitalis ACE carvedilol 3.125 2 6.25 12.5 25 85 (187 ) 25 85 50 carvedilol carvedilol carvedilol () carvedilol 3.125 ACE () carvedilol carvedilol 2.2.1 ( )( 3.2.5 ) ( 2.5.5 ) carvedilol Carvedilol ( 2.3 ) Carvedilol (<18 ) ( 2.5.3 3.2.5 ) 3
2.3 Carvedilol - carvedilol - / - β-carvedilol - (Atrioventricular block, AV block) ( ) - (bradycardia)(<50 bpm) - () - ( <85 mmhg) - - 2.4 2.4.1 carvedilol carvedilol carvedilol carvedilol Carvedilol digitalis ( 2.4.3 ) ( <100 mmhg) / carvedilol Carvedilol 55 carvedilol (Prinzmetal s variant angina) 4
Prinzmetal s variant angina β- carvedilol α- Prinzmetal s variant angina carvedilol (COPD) carvedilol carvedilol carvedilol carvedilol carvedilol carvedilol ( 2.4.3 2.5) (Raynaud s phenomenon) Carvedilol ((Raynaud s phenomenon)) β- β-carvedilol α- β- carvedilol α- β- carvedilol carvedilol (negative inotropic) ( 2.4.3 ) (Hypersensitivity) β- carvedilol (Severe cutaneous adverse reactions, SCAR) 5
carvedilol (toxic epidermal necrolysis, TEN) (Stevens- Johnson syndrome, SJS) [ 2.6.2 ()] carvedilol carvedilol β-- carvedilol Carvedilol ( digoxin cyclosporin rifampicin ) 2.4.3 carvedilol ( 2 ) carvedilol 2.4.2 ( ) (work without firm support) 2.4.3 Carvedilol Carvedilol P- P- carvedilol carvedilol P- Digoxin digoxin 20% carvedilol digoxin [ 2.4.1 ( )] Carvedilol digoxin 6
Cyclosporin cyclosporin cyclosporin carvedilol carvedilol cyclosporin 10-20% cyclosporin 10-20% cyclosporin carvedilol P cyclosporin carvedilol cyclosporin cyclosporin cyclosporin carvedilol Carvedilol CYP2D6 CYP2C9 carvedilol (systemic) / (presystemic) R- S-carvedilol ( 3.2.3 ) Amiodarone amiodarone desethylamiodarone R S-carvedilol carvedilol carvedilol amiodarone R S-carvedilol 2.2 S-carvedilol amiodarone desethylamiodarone CYP2C9 carvedilol amiodarone β ECG Rifampicin 12 rifampicin 60% carvedilol carvedilol rifampicin P carvedilol rifampicin β ECG Fluoxetine and Paroxetine 10 CYP2D6 fluoxetine carvedilol R(+) (AUC) 77% 35% 12 paroxetine paroxetine (CYP2D6 ) carvedilol R S-carvedilol 2.5 1.9 7
β- ( ) ( 2.4.1 ( )) Catecholamine- (depleting agent) β- catecholamines ( reserpine ) / Digoxin β- digoxin Non-dihydropyridines calcium channel blockers, amiodarone carvedilol carvedilol diltiazem () β carvedilol (non-dihydropyridines verapamil diltiazem amiodarone ECG Clonidine clonidine β- clonidine β- β- clonidine ( 2.4.1 ( )) carvedilol diltiazem () β- carvedilol verapamil diltiazem ECG β-carvedilol ( α 1 -) carvedilol (negative inotropic) NSAIDs (NSAIDs) β- β- β- β- 2.5 2.5.1 C ( 3.3 ) 8
β- (placental perfusion) () carvedilol carvedilol Carvedilol 2.5.2 carvedilol / carvedilol β carvedilol 2.5.3 2.2.1 2.5.4 ( 2.2.1 ) 2.5.5 carvedilol carvedilol ( 2.2.1 ) 2.5.6 Carvedilol ( 2.3 ) carvedilol (AUC) 6.8 2.6 2.6.1 (ADRs MedDRA MedDRA system organ class CIOMS (CIOMS frequency category 9
1/10 1/100 <1/10 1/1,000 <1/100 1/10,000 <1/1,000 <1/10,000 1 carvedilol 1 (Hypervolemia) ( ) 10
() (ALT) (AST) γ (GGT) () ( ) (presyncope) 11
/ ( ) (alopecia) ( ) 12
carvedilol ( 2.4 ) (14.5%) carvedilol (15.4%) carvedilol / ( 2.4 ) 2.6.2 Carvedilol / β- [ (TEN)- (SJS) ( 2.4 )] 2.7 Atropine 0.5 2 () Glucagon 1 10 2 5 /( ) 13
dobutamine isoprenaline orciprenaline adrenaline phosphodiesterase(pde) milrinone norfenephrine noradrenaline β- ( ) aminophylline diazepam clonazepam carvedilol carvedilol / 3. 3.1 3.1.1 Carvedilol α 1 β 1 β 2 - Carvedilol Carvedilol (reactive oxygen radicals) Carvedilol R(+) S(-) α- Carvedilol carvedilol (marker) (oxidative stress) Carvedilol β- β 1 - β 2 - S(-) Carvedilol (intrinsic sympathomimetic activity) ( propanolol) Carvedilol β- - 14
-(renin-angiotensin-aldosterone system) Carvedilol α - Carvedilol phenylephrine (α -(agonist)) II Carvedilol (HDL/LDL) 3.1.2 / Carvedilol Carvedilol β α 1 β- Carvedilol (vascular bed) carvedilol carvedilol (Renal impairment) carvedilol Carvedilol ( ) carvedilol carvedilol ( 1mm ST ) carvedilol ( wedge pressure) ( ) carvedilol Carvedilol 15
(Renal impairment) (Meta-Analysis)(> 4000 ) 60.8% carvedilol ( ) 3.2 3.2.1 25 mg carvedilol 1.5 (t max ) 21 mg/l (C max ) C max carvedilol carvedilol 25% Carvedilol S-(-)- R-(+)- S-(-)- 15% R-(+)- 31% R-carvedilol S-carvedilol 2 carvedilol P P carvedilol 3.2.2 Carvedilol 95% 1.5 2 / 3.2.3 carvedilol (parent substance) phenol 3 β- 4 -hydroxyphenol β- carvedilol 13 carvedilol 3 3 10 carvedilol hydroxy-carbazole carvedilol 30-80 carvedilol P450 carvedilol CYP2D6 CYP3A4 CYP2E1 CYP2C9 CYP1A2 R CYP2D6 S CYP2D6 CYP2C9 (Genetic polymorphism) 16
R S-carvedilol CYP2D6 R S-carvedilol CYP2D6 CYP2D6 R S-carvedilol CYP2D6 3.2.4 50 mg carvedilol 11 60% carvedilol carvedilol 16% carvedilol 2% 12.5 mg carvedilol carvedilol 600 ml/min 2.5 50 mg 6.5 carvedilol S-carvedilol R-carvedilol 2 3.2.5 Carvedilol 2.3 2.5.6 / 24 R- S-carvedilol R- S-carvedilol carvedilol 17
carvedilol glycolated hemoglobin A 1 carvedilol (X ) carvedilol 3.3 3.3.1 75 // 200 // (38 100 [MRHD]) carvedilol 3.3.2 Carvedilol 3.3.3 carvedilol ( 200 / 100 MRHD) ( ) 3.3.4 carvedilol 60 /(>30 MRHD) 200 / 75 /(38 100 MRHD)( ) 4. 4.1 (EXP) 30 C () 4.2 / 18
4.2 6.25 25 4-1000 2-1000 2014 3 CDS 6.0 04.14-DIL-3B01 6.25 022071 Roche S.p.A Via Morelli 2, Segrate (MI), Italy F. Hoffmann-La Roche Ltd. Wurmisweg, CH-4303 Kaiseraugst, Switzerland 25 020452 Roche S.p.A Via Morelli 2, Segrate (MI), Italy F. Hoffmann-La Roche Ltd. Wurmisweg, CH-4303 Kaiseraugst, Switzerland ( ): 191 3 134 9 02-27153111 19