Coralan

Coralan

ivabradine

Manufacturer:

Servier

Distributor:

Maxxcare
Full Prescribing Info
Contents
Ivabradine HCl.
Description
Each tablet contains ivabradine 5 and 7.5 mg equivalent to ivabradine HCl 5.39 and 8.085 mg, respectively.
Excipients/Inactive Ingredients: It also contains the following excipients: Lactose monohydrate, magnesium stearate (E470 B), maize starch, maltodextrin, anhydrous colloidal silica (E551), hypromellose (E464), titanium dioxide (E171), macrogol 6000, glycerol (E422), yellow iron oxide (E172) and red iron oxide (E172).
Ivabradine HCl is 3-(3-{[((7S)-3,4-dimethoxybicyclo[4,2,0]octa-1,3,5-trien-7-yl) methyl] methyl amino} propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one, hydrochloride.
Action
Pharmacotherapeutic Group: Cardiac therapy, other cardiac preparations. ATC Code: C01EB17.
Pharmacology: Pharmacodynamics: Mechanism of Action: Ivabradine is a pure heart rate-lowering agent, acting by selective and specific inhibition of the cardiac pacemaker If current that controls the spontaneous diastolic depolarisation in the sinus node and regulates heart rate. The cardiac effects are specific to the sinus node with no effect on intra-atrial, atrioventricular or intraventricular conduction times, nor on myocardial contractility or ventricular repolarisation.
Ivabradine can interact also with the retinal current Ih which closely resembles cardiac If. It participates in the temporal resolution of the visual system, by curtailing the retinal response to bright light stimuli. Under triggering circumstances (eg, rapid changes in luminosity), partial inhibition of Ih by ivabradine underlies the luminous phenomena that may be occasionally experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field (see Adverse Reactions).
Pharmacodynamic Effects: The main pharmacodynamic property of ivabradine in humans is a specific dose-dependent reduction in heart rate. Analysis of heart rate reduction with doses up to 20 mg twice daily indicates a trend towards a plateau effect which is consistent with a reduced risk of severe bradycardia <40 beats/min (bpm) (see Adverse Reactions).
At usual recommended doses (5 or 7.5 mg twice daily), heart rate reduction is approximately 10 bpm at rest and during exercise. This leads to a reduction in cardiac workload and myocardial oxygen consumption. Ivabradine does not influence intracardiac conduction, contractility (no negative inotropic effect) or ventricular repolarisation: In clinical electrophysiology studies, ivabradine had no effect on atrioventricular or intraventricular conduction times or corrected QT intervals; in patients with left ventricular dysfunction [left ventricular ejection fraction (LVEF) between 30% and 45%], ivabradine did not have any deleterious influence on LVEF.
Clinical Efficacy and Safety: The antianginal and anti-ischaemic efficacy of Coralan was studied in 5 double-blind randomised trials (3 vs placebo, and 1 each vs atenolol and amlodipine). These trials included a total of 4111 patients with chronic stable angina pectoris, of whom 2617 received ivabradine. Ivabradine 5 mg twice daily was shown to be effective on exercise test parameters within 3-4 weeks of treatment. Efficacy was confirmed with 7.5 mg twice daily. In particular, the additional benefit over 5 mg twice daily was established in a reference-controlled study versus atenolol: Total exercise duration at trough was increased by about 1 min after 1 month of treatment with 5 mg twice daily and further improved by almost 25 sec after an additional 3-month period with forced titration to 7.5 mg twice daily. In this study, the antianginal and anti-ischaemic benefits of ivabradine were confirmed in patients ≥65 years. The efficacy of 5 and 7.5 mg twice daily was consistent across studies on exercise test parameters (total exercise duration, time to limiting angina, time to angina onset and time to 1 mm ST segment depression) and was associated with a decrease of about 70% in the rate of angina attacks. The twice-daily dosing regimen of ivabradine gave uniform efficacy over 24 hrs.
In 889-patient randomised placebo-controlled study, ivabradine given on top of atenolol 50 mg once daily showed additional efficacy on all ETT parameters at the trough of drug activity (12 hrs after oral intake).
In 725-patient randomised placebo-controlled study, ivabradine did not show additional efficacy on top of amlodipine at the trough of ivabradine activity (12 hrs after oral intake) while an additional efficacy was shown at peak (3-4 hrs after oral intake).
Ivabradine efficacy was fully maintained throughout the 3- or 4-month treatment periods in the efficacy trials. There was no evidence of pharmacological tolerance (loss of efficacy) developing during treatment nor of rebound phenomena after abrupt treatment discontinuation. The antianginal and anti-ischaemic effects of ivabradine were associated with dose-dependent reductions in heart rate and with a significant decrease in rate pressure product (heart rate x systolic blood pressure) at rest and during exercise. The effects on blood pressure and peripheral vascular resistance were minor and not clinically significant.
A sustained reduction of heart rate was demonstrated in patients treated with ivabradine for at least 1 year (n=713). No influence on glucose or lipid metabolism was observed.
The antianginal and anti-ischaemic efficacy of ivabradine was preserved in diabetic patients (n=457) with a similar safety profile as compared to the overall population.
A large outcome study, BEAUTIFUL, was performed in 10,917 patients with coronary artery disease and left ventricular dysfunction (LVEF <40%) on top of optimal background therapy with 86.9% of patients receiving β-blockers. The main efficacy criterion was the composite of cardiovascular death, hospitalization for acute myocardial infarction (MI) or hospitalization for new onset or worsening heart failure. The study showed no difference in the rate of the primary composite outcome in the ivabradine group by comparison to the placebo group (relative risk ivabradine:placebo 1, p=0.945).
In a post-hoc subgroup of patients with symptomatic angina at randomisation (n=1507), no safety signal was identified regarding cardiovascular death, hospitalization for acute MI or heart failure (ivabradine 12% vs placebo 15.5%, p=0.05).
A large outcome study, SHIFT, was performed in 6505 adult patients with moderate to severe symptoms of chronic heart failure (CHF), with a reduced left ventricular ejection fraction (LVEF ≤35%).
The SHIFT study was a multicentre, international, randomised double-blind placebo controlled trial. The trial population presented a systolic CHF with NYHA class II to IV and in stable condition for ≥4 weeks, with documented hospital admission for worsening HF within 12 months before selection, in sinus rhythm at selection with resting heart rate ≥70 bpm. Patients received standard care including β-blockers (89%), ACE inhibitors and/or angiotensin II antagonists (91%), diuretics (83%) and anti-aldosterone agents (60%). In the ivabradine group, 67% of patients were treated with 7.5 mg twice a day. The median follow-up duration was 22.9 months.
The primary endpoint was a composite of cardiovascular mortality and hospitalisation for worsening heart failure. The study demonstrated a clinically and statistically significant relative risk reduction of 18% in the rate of the primary composite endpoint [hazard ratio ivabradine; placebo: 0.82, 95%CI (0.75;0.9) - p<0.0001]. The absolute risk reduction was 4.2%. The treatment effect was apparent within 3 months of initiation of treatment.
The reduction in the primary endpoint was observed consistently irrespective of age, gender, NYHA class, β-blocker treatment or not, ischaemic or non-ischaemic heart failure aetiology and of background history of diabetes or hypertension.
Treatment of ivabradine for 1 year would prevent 1 cardiovascular death or hospital admission for heart failure for every 26 patients treated. (See Table 1.)

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There was a significant improvement in NYHA class at last recorded value, 887 (28%) of patients on ivabradine improved versus 776 (24%) of patients on placebo (p=0.001).
Treatment with ivabradine was associated with an average reduction in heart rate of 15 bpm from a baseline value of 80 bpm, which was maintained throughout the course of study.
Pharmacokinetics: Under physiological conditions, ivabradine is rapidly released from tablets and is highly water-soluble (>10 mg/mL). Ivabradine is the S-enantiomer with no bioconversion demonstrated in vivo. The N-desmethylated derivative of ivabradine has been identified as the main active metabolite in humans.
Absorption and Bioavailability: Ivabradine is rapidly and almost completely absorbed after oral administration with a peak plasma level reached in about 1 hr under fasting condition. The absolute bioavailability of the film-coated tablets is around 40%, due to first-pass effect in the gut and liver. Food delayed absorption by approximately 1 hr and increased plasma exposure by 20-30%. The intake of the tablet during meals is recommended in order to decrease intraindividual variability in exposure (see Dosage & Administration).
Distribution: Ivabradine is approximately 70% plasma protein bound and the volume of distribution at steady state is close to 100 L in patients. The maximum plasma concentration following chronic administration at the recommended dose of 5 mg twice daily is 22 ng/mL (CV=29%). The average plasma concentration is 10 ng/mL (CV=38%) at steady state.
Biotransformation: Ivabradine is extensively metabolised by the liver and the gut by oxidation through cytochrome P-450 3A4 (CYP3A4) only. The major active metabolite is the N-desmethylated derivative (S 18982) with an exposure about 40% of that of the parent compound. The metabolism of this active metabolite also involves CYP3A4. Ivabradine has low affinity for CYP3A4, shows no clinically relevant CYP3A4 induction or inhibition and is therefore unlikely to modify CYP3A4 substrate metabolism or plasma concentrations. Inversely, potent inhibitors and inducers may substantially affect ivabradine plasma concentrations (see Interactions).
Elimination: Ivabradine is eliminated with a main half-life of 2 hrs (70-75% of the AUC) in plasma and an effective half-life of 11 hrs. The total clearance is about 400 mL/min and the renal clearance is about 70 mL/min. Excretion of metabolites occurs to a similar extent via faeces and urine. About 4% of an oral dose is excreted unchanged in urine.
Linearity/Nonlinearity: The kinetics of ivabradine is linear over an oral dose range of 0.5-24 mg.
Special Populations: Elderly: No pharmacokinetic differences (AUC and Cmax) have been observed between elderly (≥65 years) or very elderly patients (≥75 years) and the overall population (see Dosage & Administration).
Renal Insufficiency: The impact of renal impairment (creatinine clearance from 15-60 mL/min) on ivabradine pharmacokinetic is minimal, in relation with the low contribution of renal clearance (about 20%) to total elimination for both ivabradine and its main metabolite S 18982 (see Dosage & Administration).
Hepatic Impairment: In patients with mild hepatic impairment (Child-Pugh score up to 7) unbound AUC of ivabradine and the main active metabolite were about 20% higher than in subjects with normal hepatic function. Data are insufficient to draw conclusions in patients with moderate hepatic impairment. No data are available in patients with severe hepatic impairment (see Dosage & Administration and Contraindications).
Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship: PK/PD relationship analysis has shown that heart rate decreases almost linearly with increasing ivabradine and S 18982 plasma concentrations for doses of up to 15-20 mg twice daily. At higher doses, the decrease in heart rate is no longer proportional to ivabradine plasma concentrations and tends to reach a plateau. High exposures to ivabradine that may occur when ivabradine is given in combination with strong CYP3A4 inhibitors may result in an excessive decrease in heart rate although this risk is reduced with moderate CYP3A4 inhibitors (see Contraindications, Warnings, Precautions and Interactions).
Toxicology: Preclinical Safety Data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. Reproductive toxicity studies showed no effect of ivabradine on fertility in male and female rats. When pregnant animals were treated during organogenesis at exposures close to therapeutic doses, there was a higher incidence of foetuses with cardiac defects in the rat and a small number of foetuses with ectrodactylia in the rabbit.
In dogs given ivabradine (doses of 2, 7 or 24 mg/kg/day) for 1 year, reversible changes in retinal function were observed but were not associated with any damage to ocular structures. These data are consistent with the pharmacological effect of ivabradine related to its interaction with hyperpolarisation-activated Ih currents in the retina, which share extensive homology with the cardiac pacemaker If current.
Other long-term repeat dose and carcinogenicity studies revealed no clinically relevant changes.
Indications/Uses
Symptomatic treatment of chronic stable angina pectoris: Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease in adults with normal sinus rhythm and heart rate ≥70 bpm. Ivabradine is indicated: in adults unable to tolerate or with a contra-indication to the use of beta-blockers; or in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose.
Treatment of chronic heart failure: Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥75 bpm, in combination with standard therapy, including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated.
Dosage/Direction for Use
For the different doses, film-coated tablets containing 5 mg and 7.5 mg ivabradine are available. Symptomatic treatment of chronic stable angina pectoris.
It is recommended that the decision to initiate or titrate treatment takes place with the availability of serial heart rate measurements, ECG or ambulatory 24-hour monitoring.
The starting dose of ivabradine should not exceed 5 mg twice daily in patients aged below 75 years. After three to four weeks of treatment, if the patient is still symptomatic, if the initial dose is well tolerated and if resting heart rate remains above 60 bpm, the dose may be increased to the next higher dose in patients receiving 2.5 mg twice daily or 5 mg twice daily. The maintenance dose should not exceed 7.5 mg twice daily.
If there is no improvement in symptoms of angina within 3 months after start of treatment, treatment of ivabradine should be discontinued.
In addition, discontinuation of treatment should be considered if there is only limited symptomatic response and when there is no clinically relevant reduction in resting heart rate within three months.
If, during treatment, heart rate decreases below 50 beats per minute (bpm) at rest or the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, the dose must be titrated downward including the lowest dose of 2.5 mg twice daily (one half 5 mg tablet twice daily).
After dose reduction, heart rate should be monitored. Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist despite dose reduction.
Treatment of chronic heart failure: The treatment has to be initiated only in patient with stable heart failure. It is recommended that the treating physician should be experienced in the management of chronic heart failure.
The usual recommended starting dose of ivabradine is 5 mg twice daily. After two weeks of treatment, the dose can be increased to 7.5 mg twice daily if resting heart rate is persistently above 60 bpm or decreased to 2.5 mg twice daily (one half 5 mg tablet twice daily) if resting heart rate is persistently below 50 bpm or in case of symptoms related to bradycardia such as dizziness, fatigue or hypotension. If heart rate is between 50 and 60 bpm, the dose of 5 mg twice daily should be maintained.
If during treatment, heart rate decreases persistently below 50 beats per minute (bpm) at rest or the patient experiences symptoms related to bradycardia, the dose must be titrated downward to the next lower dose in patients receiving 7.5 mg twice daily or 5 mg twice daily. If heart rate increases persistently above 60 beats per minute at rest, the dose can be up titrated to the next upper dose in patients receiving 2.5 mg twice daily or 5 mg twice daily.
Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist.
Elderly: In patients ≥75 years, a lower starting dose should be considered for these patients (2.5 mg twice daily ie, one-half 5-mg tab twice daily) before up-titration if necessary.
Renal Insufficiency: No dose adjustment is required in patients with renal insufficiency and creatinine clearance >15 mL/min (see Pharmacology: Pharmacokinetics under Actions).
No data are available in patients with creatinine clearance <15 mL/min. Ivabradine should therefore be used with caution in this population.
Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. Caution should be exercised when using ivabradine in patients with moderate hepatic impairment. Ivabradine is contraindicated for use in patients with severe hepatic insufficiency, since it has not been studied in this population and a large increase in systemic exposure is anticipated (see Contraindications and Pharmacology: Pharmacokinetics under Actions).
Administration: Tablets must be taken orally twice daily ie, once in the morning and once in the evening during meals (see Pharmacology: Pharmacokinetics under Actions).
Overdosage
Overdose may lead to severe and prolonged bradycardia (see Adverse Reactions). Severe bradycardia should be treated symptomatically in a specialised environment. In the event of bradycardia with poor haemodynamic tolerance, symptomatic treatment including IV β-stimulating agents eg, isoprenaline may be considered. Temporary cardiac electrical pacing may be instituted if required.
Contraindications
Hypersensitivity to ivabradine or to any excipients of Coralan (see Description); resting heart rate <60 bpm prior to treatment; cardiogenic shock; acute MI; severe hypotension (<90/50 mmHg); severe hepatic insufficiency; sick sinus syndrome; sino-atrial block; unstable or acute heart failure; pacemaker dependent (heart rate imposed exclusively by the pacemaker); unstable angina; AV-block of 3rd degree.
Combination with strong cytochrome P-450 3A4 inhibitors eg, azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see Pharmacology: Pharmacokinetics under Actions, and Interactions).
Use in Pregnancy: There are no or limited amount of data from the use of ivabradine in pregnant women. Studies in animals have shown reproductive toxicity. These studies have shown embryotoxic and teratogenic effects (see Toxicology under Actions). The potential risk for humans is unknown. Therefore, ivabradine is contraindicated during pregnancy.
Use in Lactation: Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contraindicated during breastfeeding.
Use In Pregnancy & Lactation
Use in Pregnancy: There are no or limited amount of data from the use of ivabradine in pregnant women. Studies in animals have shown reproductive toxicity. These studies have shown embryotoxic and teratogenic effects (see Toxicology under Actions). The potential risk for humans is unknown. Therefore, ivabradine is contraindicated during pregnancy.
Use in Lactation: Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contraindicated during breastfeeding.
Side Effects
Coralan has been studied in clinical trials involving nearly 14,000 participants.
The most common adverse reactions with ivabradine, luminous phenomena (phosphenes) and bradycardia, are dose-dependent and related to the pharmacological effect of the medicinal product.
The following adverse reactions have been reported during clinical trials and are ranked using the following frequency: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data). (See Table 2.)

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Luminous phenomena (phosphenes) were reported by 14.5% of patients, described as a transient enhanced brightness in a limited area of the visual field. They are usually triggered by sudden variations in light intensity. The onset of phosphenes is generally within the first 2 months of treatment after which they may occur repeatedly. Phosphenes were generally reported to be of mild to moderate intensity. All phosphenes resolved during or after treatment, of which a majority (77.5%) resolved during treatment.
Fewer than 1% of patients changed their daily routine or discontinued the treatment in relation with phosphenes.
Bradycardia was reported by 3.3% of patients particularly within the first 2-3 months of treatment initiation. 0.5% of patients experienced a severe bradycardia ≤40 bpm.
Drug Interactions
Pharmacodynamic Interactions: Concomitant Use Not Recommended: QT-Prolonging Medicinal Products: Cardiovascular QT-prolonging medicinal products (eg, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone); noncardiovascular QT-prolonging medicinal products (eg, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin IV).
The concomitant use of cardiovascular and noncardiovascular QT-prolonging medicinal products with ivabradine should be avoided since QT prolongation may be exacerbated by heart rate reduction. If the combination appears necessary, close cardiac monitoring is needed.
Concomitant Use with Precaution: Potassium-depleting diuretics (thiazide and loop diuretics): Hypokalemia can increase the risk of arrhythmia. As ivabradine may cause bradycardia, the resulting combination of hypokalemia and bradycardia is a predisposing factor to the onset of severe arrhythmias, especially in patients with long QT syndrome, whether congenital or substance-induced.
Pharmacokinetic Interactions: Cytochrome P-450 3A4 (CYP3A4): Ivabradine is metabolised by CYP3A4 only and it is a very weak inhibitor of this cytochrome. Ivabradine was shown not to influence the metabolism and plasma concentrations of other CYP3A4 substrates (mild, moderate and strong inhibitors). CYP3A4 inhibitors and inducers are liable to interact with ivabradine and influence its metabolism and pharmacokinetics to a clinically significant extent. Drug-drug interaction studies have established that CYP3A4 inhibitors increase ivabradine plasma concentrations, while inducers decrease them. Increased plasma concentrations of ivabradine may be associated with the risk of excessive bradycardia.
Contraindication of Concomitant Use: The concomitant use of potent CYP3A4 inhibitors eg, azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone is contraindicated (see Contraindications). The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and josamycin (1 g twice daily) increased ivabradine mean plasma exposure by 7- to 8-fold.
Concomitant Use Not Recommended: Moderate CYP3A4 Inhibitors: Specific interaction studies in healthy volunteers and patients have shown that the combination of ivabradine with the heart rate-reducing agents diltiazem or verapamil resulted in an increase in ivabradine exposure (2- to 3-fold increase in AUC) and an additional heart rate reduction of 5 bpm. The concomitant use of ivabradine with these medicinal products is not recommended.
Concomitant Use With Precautions: Moderate CYP3A4 Inhibitors: The concomitant use of ivabradine with other moderate CYP3A4 inhibitors (eg, fluconazole) may be considered at the starting dose of 2.5 mg twice daily and if resting heart rate is >60 bpm, with monitoring of heart rate.
Grapefruit Juice: Ivabradine exposure was increased by 2-fold following the co-administration with grapefruit juice. Therefore, the intake of grapefruit juice should be restricted during the treatment with ivabradine.
CYP3A4 Inducers: CYP3A4 inducers [eg, rifampicin, barbiturates, phenytoin, Hypericum perforatum (St. John's wort)] may decrease ivabradine exposure and activity. The concomitant use of CYP3A4-inducing medicinal products may require an adjustment of the dose of ivabradine. The combination of ivabradine 10 mg twice daily with St. John's wort was shown to reduce ivabradine AUC by half. The intake of St. John's wort should be restricted during the treatment with ivabradine.
Other Concomitant Use: Specific drug-drug interaction studies have shown no clinically significant effect of the following medicinal products on pharmacokinetics and pharmacodynamics of ivabradine: Proton-pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG-CoA reductase inhibitors (simvastatin), dihydropyridine calcium channel blockers (amlodipine, lacidipine), digoxin and warfarin. In addition, there was no clinically significant effect of ivabradine on the pharmacokinetics of simvastatin, amlodipine, lacidipine, on the pharmacokinetics and pharmacodynamics of digoxin, warfarin and on the pharmacodynamics of aspirin.
In pivotal phase III clinical trials, the following medicinal products were routinely combined with ivabradine with no evidence of safety concerns: Angiotensin-converting enzyme inhibitors, angiotensin II antagonists, β-blockers, diuretics, anti-aldosterone, short- and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton-pump inhibitors, oral antidiabetics, aspirin and other antiplatelet medicinal products.
Paediatric Population: Interaction studies have only been performed in adults.
Storage
Store below 30°C.
MIMS Class
ATC Classification
C01EB17 - ivabradine ; Belongs to the class of other cardiac preparations.
Presentation/Packing
FC tab 5 mg (salmon-coloured, oblong, scored on both sides, engraved with "5" on one face and
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on the other face) x 4 x 14's. 7.5 mg (salmon-coloured, triangular, engraved with "7.5" on one face and
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on the other face) x 4 x 14's.
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