EASE THE CHALLENGE OF TREATING THE FAILING

SIMDAX® GIVES YOU TIME WHEN IT’S NEEDED MOST1

Reference: 1. Nieminen MS et al. Eur Heart J Suppl. 2017;19(suppl_C);C15-C21. SIMDAX® GIVES WITH THREE YOU TIME WHEN PHARMACOLOGICAL IT’S NEEDED MOST1 EFFECTS…

SIMDAX® is the only inodilator2,3 to provide The clinical effects of SIMDAX® are mediated through:1 The unique triple mechanism sustained hemodynamic benefits3–8 and symptom • Increased cardiac contractility by calcium sensitization of action of levosimendan1 3–5,9,10 control to patients with acute heart failure, of troponin C and in need of inotropic therapy. • through the opening of potassium channels in the vasculature smooth muscle • Cardioprotection, anti-ischemic antistunning effects Cardioprotection through the opening of mitochondrial potassium Mitochondrial K channel opening channels in cardiomyocytes ATP levosimendan

References: 1. Nieminen MS et al. Eur Heart J Suppl. 2017;19(suppl C);C15-C21. 2. Papp Z et al. Int J Cardiol. 2012; 159:82–87. 3. Nieminen Inotropy Vasodilation MS et al. Heart Lung Vessel. 2013;5(4):227–245. 4. Follath et al. Lancet. Cardiac Smooth muscle 2002;360:196–202. 5. Slawsky et al. Circulation. 2000;102:2222–2227. 6. Troponin C KATP channel Nieminen et al. J Am Coll Cardiol. 2000;36:1903–1912. 7. Kivikko et al. sensitization activation Circulation. 2003;107:81–86. 8. Lilleberg et al. Eur J Heart Fail. 2007;9:75– 82. 9. Mebazaa et al. JAMA. 2007;297:1883–1891. 10. Packer et al. JACC Heart Fail. 2013;1(2):103–111. Reference: 1. Papp Z et al. Int J Cardiol. 2012;159:82–87.

3 …SIMDAX® PROVIDES MULTIPLE IMPROVING BENEFITS WITHIN AND BEYOND … THE HEART

® 2 Therapy with SIMDAX , the first-in- L In patients with heart failure, the positive inotropic and Improvement in hemodynamic performance class among the cardio-protective vasodilatory actions of SIMDAX® result in an increased p=0.002 Levosimendan inodilators, brings multiple beneficial contractile force, and a reduction in both 30 Circulation Heart Dobutamine cardiovascular effects.1,2 and .1,2 25 28% Opening of Opening of ++ Ca sensitivity of potassium channels potassium channels SIMDAX® increases , and 20 contractile proteins in smooth muscle in mitochondria , and reduces pulmonary capillary wedge Multiple action of 15 pressure, , and peripheral vascular levosimendan in the 15% Vasodilation + Inotropy + Lusitropy 1,2 cardiovascular system1 resistance. 10

Patients achieving

primary endpoint (%) 5 Improved LV

n

n

n y performance 0 24 hours 24 hours Improved RV n=103 n=100

Reductio of ischemia/ reperfusio injury

Protectio against myocardial stunning

Peripher

Kidney

Gut

Lung Coronary performance References: Proportion of patients with hemodynamic improvement after a 24-hour 1. Pinto BB et al. Curr Opin Anaesthesiol. 2008;21:168–177. References: 1. Nieminen MS et al. J Am Coll Cardiol. 2000;36:1903–1912. infusion, defined as a 30% or greater increase in cardiac output and a 25% or 2: Farmakis D et al. Int J Cardiol. 2016;222:303-12 2. Follath F et al. Lancet. 2002;360:196–202. greater decrease (at least 4 mmHg) in pulmonary capillary wedge pressure.2

4 5 …WITHOUT AN THE HEMODYNAMIC INCREASE IN OXYGEN BENEFITS OF SIMDAX® CONSUMPTION ARE SUSTAINED…

The positive inotropic effects of SIMDAX® are achieved No significant increase in After operation, in a comparative study vs milrinone, Sustained effects of levosimendan 1,2 without an increase in oxygen consumption. oxygen consumption Levosimendan the positive hemodynamic effects of 19 hours when used in cardiac surgery Levosimendan Dobutamine treatment with SIMDAX® lasted much longer than Milrinone

) L/min those from 83 hours treatment with milrinone.1 mono 0.12 p=0.05 40

0.1 )

2

0.08 n.s. 30

0.06 SVI (ml/m

0.04 20 0.02 Base Post End T0 T6 T12 T24 T48 CPB Surgery

Myocardial consumption index (K 0 Stroke volume index (SVI) at the start of surgery (base), 15 min after the end Baseline Treatment (2 hr infusion) of cardiopulmonary bypass (CPB) (post-CPB), at the end of the operation (end References: surgery), at arrival in the intensive care unit (T0), and 6 (T6), 12 (T12), 24 (T24), 1. Nieminen MS et al. J Cardiovasc Pharmacol. 2009;53(4):302–310. A significant increase in the oxygen consumption is induced by dobutamine Reference: and 48 (T48) hours later in both groups. Data are mean±sd. Levosimendan 2. Ukkonen H et al. Clin Pharmacol Ther. 1997;61:596–607. while no difference is noticed during treatment with levosimendan.2 1. De Hert SG et al. Anesth Analg. 2007;104:766–773. (orange) vs Milrinone (blue) *p<0.05.1

6 7 Meta-analysis on mortality of ® …WITHOUT COMPROMISE levosimendan clinical trials in SIMDAX DOES ON LONG-TERM cardiology settings1 NOT DISTURB SURVIVAL RELAXATION... S ID RR CI W

Adamopoulos 2006 0.44 (0.10, 1.89) 1.52 Berger 2007 0.79 (0.29, 2.13) 3.04 Bergh 2010 2.14 (0.20, 22.34) 0.60 The use of SIMDAX® was not Duygu 2008 1.54 (0.77, 3.07) 5.58 In a study by Jörgenssen et al. SIMDAX® not only Effects of levosimendan on relaxation time Duygu 2008 0.50 (0.21, 1.20) 3.76 associated with a decrease of Flevai 2006 1.50 (0.17, 13.23) 0.70 improved contractility whilst maintaining constant 90 Levosimendan Follath 2002 0.69 (0.46, 1.04) 11.28 and , but also decreased Placebo survival. Ikonomidis 2007 0.17 (0.01, 3.13) 0.39 85 Kleber 2009 0.28 (0.01, 7.57) 0.31 isovolumic relaxation time.1 Levin 2009 0.32 (0.14, 0.71) 4.33 80 In fact, a meta-analysis of 23 studies Lileberg 2007 1.00 (0.02, 46.05) 0.23 describing the use of SIMDAX® in Mavrogeni 2007 0.25 (0.06, 1.06) 1.52 75 Mebazaa 2007 0.93 (0.78, 1.11) 20.65 cardiology settings show a risk Moiseyev 2002 0.72 (0.51,1.01) 13.68 70 Nieminen 2000 0.59 (0.04, 9.24) 0.44 ® reduction of 0.75 [SIMDAX Packer 2003 0.77 (0.22, 2.70) 1.99 65 441/2207 (20.0%), control 484/1893 Packer 2005 1.10 (0.84, 1.44) 16.62 Parissis 2007 0.50 (0.01, 24.33) 0.22 60 (25.6%), RR=0.75 (95% CI 0.63, Slawsky 2000 0.49 (-.10, 2.34) 1.32 Isovolumic relaxation time (ms) Trikas 2006 0.33 (0.08, 1.42) 1.51 55 0.91), p for effect: 0.003, p for Tziakas 2005 1.00 (0.02, 48.77) 0.22 heterogeneity: 0.131, NNT=18].1 Zairis 2004 0.51 (0.32, 0.81) 9.87 50 Zemljic 2007 1.00 (0.02, 47 97) 0.22 Baseline 0.1 µg/kg/min 0.2 µg/kg/min O . . .1 1. I . .11 Effect of levosimendan vs placebo on Isovolumic relaxation time (IVRT) Reference: Reference: (mean±SEM) at maintained preload and afterload conditions after aortic valve 1. Landoni G et al. Crit Care Med. 2012;40:634–646. 0.00888 1 113 1. Jörgensen K et al. Circulation. 2008;117(8):1075–1081. replacement for aortic stenosis. *p<0.05.1

8 9 ...REDUCES …AND REDUCES MYOCARDIAL INJURY... HOSPITAL STAY

Meta-analysis of the levosimendan effects on length of stay in hospital1

® Current data suggest that SIMDAX also Effects of levosimendan on release of troponin These results are corroborated Study ID WMD (95% CI) Weight % diminishes myocardial injury.1,2 T during cardiac surgery by a meta-analysis of 8 studies Levosimendan ® Bergh CH 2010 -1.40 (-9.00, 6.20) 0.92 1.0 p=0.037 in which SIMDAX Placebo was used in cardiology settings: Duygu H 2008a 0.00 (-1.10, 1.10) 17.48

Duygu H 2008b -2.00 (-2.62, -1.38) 23.69 0.8 Length of stay in hospital was decreased by 1.59 days Follath F 2002 0.80 (-2.59, 4.19) 4.09 0.6 in SIMDAX® treated patients Mebazaa A 2007 -2.50 (-5.51, 0.51) 4.99 in addition to a significant Packer M 2013 -1.60 (-2.56, -0.64) 19.28 0.4 1 reduction in mortality. Parissis JT 2007 -2.60 (-3.63, -1.57) 18.28

Troponin T (µg/l)

0.2 Trikas A 2006 -2.00 (-3.71, -0.29) 11.27

Overall (I2=54.9% p=0.030) -1.59 (-2.33, -0.85) 100.00

0 End of Note: Weights are from random effects analysis Baseline procedure 24 hours 48 hours References: -9 0 9 1. Zangrillo A et al. J Cardiothorac Vasc Anesth. 2009;23:474–478. Troponin T levels up to 48 hours in cardiac surgery patients. Levosimendan 2. Eriksson H et al. Ann Thor Surg. 2009;87:448. (orange) vs placebo (grey). *p=0.032.2 Reference: 1. Landoni G et al. Crit Care Med. 2012;40:634–646 (electronic supplementary material). 10 11 PRODUCT INFORMATION: Simdax 2.5 mg/ml concentrate for solution for infusion.

Therapeutic indications Hepatic impairment: Simdax must be used with caution Simdax infusion should be used cautiously in patients with Simdax is indicated for the short-term treatment of acu- in patients with mild to moderate hepatic impairment alt- tachycardia atrial fibrillation with rapid ventricular respon- tely decompensated severe chronic heart failure (ADHF) hough no dose adjustment appears necessary for these se or potentially life-threatening arrhythmias. in situations where conventional therapy is not sufficient, patients. Simdax should not be used in patients with seve- Interaction with other medicinal products and and in cases where inotropic support is considered app- re hepatic impairment. other forms of interaction ropriate. Children: Simdax should not be administered to children Consistent with current medical practice, levosimendan Dosage and administration and adolescents under 18 years of age. should be used with caution when used with other intra- Simdax is for in-hospital use only. It should be adminis- venous vasoactive medicinal products due to a potentially Contraindications tered in a hospital setting where adequate monitoring increased risk of hypotension. Hypersensitivity to levosimendan or to any of the exci- facilities and expertise with the use of inotropic agents pients. Severe hypotension and tachycardia. Signi­ficant No pharmacokinetic interactions have been observed in are available. mechanical obstructions affecting ventricular filling or a population analysis of patients receiving digoxin and Simdax is to be diluted prior to administration. The infusi- outflow or both. Severe renal impairment (creatinine clea- Simdax infusion. Simdax infusion can be used in patients on is for intravenous use only and can be administered by rance <30 ml/min) and severe hepatic impairment. History receiving beta-blocking agents without loss of efficacy. the peripheral or central route. of Torsades de Pointes. Co-administration of isosorbide mononit­rate and levosi- Dosage: The dose and duration of treatment should be mendan in healthy volunteers resulted in significant po- Special warnings and special precautions for u­s­e tentiation of the orthostatic hypotensive response. individualised according to the patient’s clinical condition An initial haemodynamic effect of levosimendan may be a and response. decrease in systolic and diastolic blood pressure, therefo- Undesirable effects The recommended duration of infusion in patients with re, levosimendan should be used with caution in patients The most commonly (>1/10) reported adverse reactions acute decompensation of severe chronic heart failure is 24 with low baseline systolic or diastolic blood pressure or include headache, hypotension and ventricular tachycar- hours. No signs of development of tolerance or rebound those at risk for a hypotensive episode. More conservati- dia. phenomena have been observed following discontinua- ve dosing regimens are recommen­ded for these patients. Overdose tion of Simdax infusion. Haemo­dynamic effects persist Physicians should tailor the dose and duration of therapy Overdose of Simdax may induce hypotension and tachy- for at least 24 hours and may be seen up to 9 days after to the condition and response of the patient. cardia. High doses (at or above 0.4 microgram/kg/min) discontinuation of a 24-hour infusion. Severe hypovolaemia should be corrected prior to levosi- and infusions over 24 hours increase the heart rate and Experience of repeated administration of Simdax is li- mendan infusion. If excessive changes in blood pressure are sometimes associated with prolongation of the QTc mited. Experience with concomitant use of vaso­active or heart rate are observed, the rate of infusion should be interval. Simdax overdose leads to increased plasma con- agents, including inotropic agents (except di­goxin) is li- reduced or the infusion discontinued. centrations of the active metabolite, which may lead to mited. a more pronounced and prolonged effect on heart rate The exact duration of all haemodynamic effects has not requiring a corresponding extension of the observation Monitoring of treatment: Consistent with current med- been determined, however, the haemodynamic effects, period. ical practice, ECG, blood pressure and heart rate must be generally last for 7-10 days. This is partly due to the pre- monitored during treatment and the urine output mea- Storage sence of active metabolites, which reach their maximum Store at 2°C-8°C (in a refrigerator). Do not freeze. sured. Monitoring of these parameters for at least 3 days plasma concentrations about 48 hours after the infusion after the end of infusion or until the patient is clinically has been stopped. Non-invasive monitoring for at least stable is recommended. In patients with mild to moderate 4-5 days after the end of infusion is recommended. Moni- renal or mild to moderate hepatic impairment monitoring toring is recommended to continue until the blood pres- is recommended for at least 5 days. sure reduction has reached its maximum and the blood Elderly: No dose adjustment is required for elderly pa- pressure starts to increase again, and may need to be tients. longer than 5 days if there are any signs of continuing Renal impairment: Simdax must be used with caution in blood pressure decrease, but can be shorter than 5 days patients with mild to moderate renal impairment. Simdax if the patient is clinically stable. In patients with mild to should not be used in patients with severe renal impair- moderate renal or mild to moderate hepatic impairment ment (creatinine clearance <30 ml/min). an extended period of monitoring maybe needed.

CONTACT INFORMATION: Orion Corporation, Orion Pharma, PO Box 65, FI-02101 ESPOO, FINLAND. Tel. +358 10 4261 sim1217