LANDIOLOL: 63 Adverse Event Reports & Safety Profile

RAPIBLYK (landiolol) for injection is a beta-1 adrenergic receptor blocker with a very short duration of action (elimination half-life is approximately 4 minutes). Landiolol is: [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 3-[4-[(2S)-2-hydroxy-3-[2-(morpholine-4-carbonylamino)ethylamino]propoxy]phenyl]propionate and has the following structure: The active pharmaceutical ingredient is the hydrochloride salt of landiolol, which has the empirical formula C 25 H 39 N 3 O 8 ∙ HCl and a molecular weight of 546.06 g/mol. It has two chiral centers and is used as pure S,S-enantiomer. Landiolol HCl is a white crystalline powder. It is a relatively hydrophilic compound, which is very soluble in water. RAPIBLYK is supplied as a single presentation of 280 mg landiolol (equivalent to 300 mg landiolol HCl) as a white to almost white sterile lyophilized powder for intravenous injection in a 50 mL vial. Inactive ingredients include 300 mg of mannitol and sodium hydroxide as needed to adjust pH. StructuralFormula

AND USAGE RAPIBLYK is indicated for the short-term reduction of ventricular rate in adults with supraventricular tachycardia including atrial fibrillation and atrial flutter. RAPIBLYK is a beta adrenergic blocker indicated for the short-term reduction of ventricular rate in adults with supraventricular tachycardia including atrial fibrillation and atrial flutter. ( 1 )

AND ADMINISTRATION Administer as an intravenous infusion in a monitored setting. ( 2.1 ) Titrate according to ventricular rate. ( 2.1 ) If normal cardiac function, start at 9 mcg/kg/min; adjust dose in 10-minute intervals as needed in increments of 9 mcg/kg/min to a maximum of 36 mcg/kg/min. ( 2.1 ) If impaired cardiac function, start at 1 mcg/kg/min; adjust dose in 15-minute intervals as needed in increments of 1 mcg/kg/min to a maximum of 36 mcg/kg/min. ( 2.1 ).

2.1 Recommended Dosage Administer RAPIBLYK as a continuous intravenous infusion, titrating as needed for heart rate control. There are limited data beyond 24 hours of use.

Table

1: Dosing Normal cardiac function Impaired cardiac function Starting dose 9 mcg/kg/min 1 mcg/kg/min Titration interval 10 min 15 min Titration step 9 mcg/kg/min 1 mcg/kg/min Maximum dose 36 mcg/kg/min 36 mcg/kg/min 9 mcg/kg/min landiolol is equivalent to 9.6 mcg/kg/min landiolol hydrochloride.

2.2 Transitioning from RAPIBLYK Injection Therapy to Alternative Medications When transitioning to alternative medications consider the pharmacodynamics of the medication to which the patient is being transitioned and monitor clinical response. If switched to an oral beta-blocker, the dosage of RAPIBLYK can be reduced as follows: Ten minutes after administration of the oral beta-blocker, reduce the infusion rate of RAPIBLYK by 50%. If satisfactory control is maintained for at least one hour, discontinue RAPIBLYK.

2.3 Instructions for Preparation Use appropriate aseptic technique for reconstitution. Reconstitute each 280 mg vial of RAPIBLYK with 50 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Gently swirl to dissolve contents. Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be a clear, colorless solution. Use immediately. The reconstituted RAPIBLYK solution storage conditions are described in Table 2. Discard unused portion.

Table

2: Reconstituted RAPIBLYK Solution Storage and Use Conditions Diluent used to Prepare Solution Reconstituted RAPIBLYK Solution Storage and Use Conditions 50 mL of 0.9% Sodium Chloride Injection, USP Use within 4 hours at room temperature (25°C, 77°F) 50 mL of 5% Dextrose Injection, USP Use within 48 hours at room temperature (25°C, 77°F)

2.4 Administration Following reconstitution, the product contains 280 mg landiolol/50 mL = 5.6 mg/mL. The infusion rate can be calculated as: Infusion rate (mL/hour) = target dose (mcg/kg/min) × body weight (kg) / 93

RAPIBLYK is contraindicated in patients with: Severe sinus bradycardia, sick sinus syndrome, heart block greater than first degree [see Warnings and Precautions ( 5.2 )] . Decompensated heart failure [see Warnings and Precautions ( 5.3 )] . Cardiogenic shock: May precipitate further cardiovascular collapse and cause cardiac arrest. Pulmonary hypertension: May precipitate cardiorespiratory decompensation. Hypersensitivity reactions, including anaphylaxis, to landiolol or any of the inactive ingredients

5.3 Severe sinus bradycardia ( 4 ) Sick sinus syndrome ( 4 ) Heart block greater than first degree ( 4 ) Decompensated heart failure ( 4 ) Cardiogenic shock ( 4 ) Pulmonary hypertension ( 4 ) Known hypersensitivity to landiolol ( 4 )

REACTIONS The most common adverse reaction (9.9%) is hypotension ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact AOP Orphan Pharmaceuticals at [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Landiolol injection was studied in 19 placebo-controlled clinical trials involving 1,761 patients (in a variety of clinical in-patient settings) with supraventricular tachycardia or at high risk for supraventricular tachycardia. The most important and common adverse reaction is hypotension, which occurred in 9.9% of patients receiving RAPIBLYK vs. 1% in those receiving placebo <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> .

AND PRECAUTIONS Risk of hypotension, bradycardia, and cardiac failure: Monitor for signs and symptoms of cardiovascular adverse effects. Reduce or discontinue use ( 5.1 , 5.2 , 5.3 ) Risk of exacerbating reactive airway disease ( 5.5 ) Diabetes mellitus: May mask symptoms of hypoglycemia and alter glucose levels; monitor ( 5.6 ) Monitor for signs of myocardial ischemia when abruptly discontinuing in patients with coronary artery disease ( 5.10 )

5.1 Hypotension Patients with hemodynamic compromise, hypovolemia, or on interacting medications are at increased risk of hypotension. Monitor blood pressure closely, especially if pretreatment blood pressure is low. Reduce or stop RAPIBLYK injection for hypotension then expect the blood pressure effect to wane within 30 minutes.

5.2 Bradycardia Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction disorders are at increased risk of bradycardia, including sinus pause, heart block, severe bradycardia, and cardiac arrest. Monitor heart rate and rhythm in patients receiving RAPIBLYK injection. Reduce or stop RAPIBLYK injection for bradyarrhythmia.

5.3 Cardiac Failure Beta-blockers, like RAPIBLYK, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenic shock. At the first sign or symptom of impending cardiac failure, stop RAPIBLYK injection and start supportive therapy <span class="opacity-50 text-xs">[see Overdosage ( 10 )]</span> .

5.4 Reactive Airways Disease Patients with reactive airways disease should, in general, not receive beta-blockers. Because of its relative beta-1 selectivity and titratability, RAPIBLYK injection may be titrated to the lowest possible effective dose. In the event of bronchospasm, stop the infusion immediately; a beta-2 stimulating agent may be administered with appropriate monitoring of ventricular rates.

5.5 Use in Patients with Diabetes Mellitus and Hypoglycemia Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus, patients who are fasting (i.e., surgery, not eating regularly, or are vomiting), or children. Monitor for signs and symptoms of hypoglycemia in patients receiving RAPIBLYK.

5.6 Infusion Site Reactions Infusion site reactions such as pain, swelling and erythema have occurred with the use of RAPIBLYK injection. Avoid infusions into small veins or through a butterfly catheter. If a local infusion site reaction develops, use an alternative infusion site and avoid extravasation.

5.7 Use in Patients with Prinzmetal’s Angina Beta-blockers may exacerbate anginal attacks in patients with Prinzmetal’s angina because of unopposed alpha receptor–mediated coronary artery vasoconstriction.

5.8 Use in Patients with Pheochromocytoma If RAPIBLYK injection is used in the setting of pheochromocytoma, administer RAPIBLYK in combination with an alpha-blocker, and only after the alpha-blocker has been initiated. Administration of beta-blockers without opposing alpha blockade in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure from the attenuation of beta receptor-mediated vasodilation in skeletal muscle.

5.9 Use in Patients with Peripheral Circulatory Disorders RAPIBLYK injection may exacerbate peripheral circulatory disorders, such as Raynaud’s disease or syndrome, and peripheral occlusive vascular disease.

5.10 Abrupt Discontinuation of RAPIBLYK Injection Severe exacerbations of angina, myocardial infarction, and ventricular arrhythmias have been reported in patients with coronary artery disease upon abrupt discontinuation of beta-blocker therapy. Observe patients for signs of myocardial ischemia when discontinuing RAPIBLYK injection.

5.11 Hyperkalemia Beta-blockers, including RAPIBLYK injection, can cause increases in serum potassium and hyperkalemia. The risk is increased in patients with risk factors such as renal impairment. Intravenous administration of beta-blockers has been reported to cause potentially life-threatening hyperkalemia in hemodialysis patients. Monitor serum electrolytes during therapy with RAPIBLYK injection.

5.12 Use in Patients with Metabolic Acidosis Beta-blockers have been reported to cause hyperkalemic renal tubular acidosis. Acidosis in general may be associated with reduced cardiac contractility.

5.13 Use in Patients with Hyperthyroidism Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate thyroid storm; therefore, monitor patients for signs of thyrotoxicosis when withdrawing beta blocking therapy.

5.14 Use in Patients at Risk of Severe Acute Hypersensitivity Reactions When using beta-blockers, patients at risk of anaphylactic reactions may be more reactive to allergen exposure (accidental, diagnostic, or therapeutic). Patients using beta-blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic or anaphylactoid reactions <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .

INTERACTIONS Negative Inotropes and Chronotropes: Avoid ( 7.1 ) Sympathomimetics, Positive Inotropes and Vasoconstrictors: Avoid ( 7.2 )

Catecholamine Depleting

Drugs: Monitor blood pressure and heart rate ( 7.3 ).

7.1 Negative Inotropes and Chronotropes Avoid concomitant use of RAPIBLYK with negative inotropes and medications that slow heart rate or cardiac conduction. Beta-blockers, like RAPIBLYK, can cause depression of myocardial contractility and increase the risk of bradycardia or heart block. Concomitant use of RAPIBLYK with negative inotropes or chronotropes may augment these effects <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )( 5.3 )]</span> .

7.2 Sympathomimetics, Positive Inotropes and Vasoconstrictors Beta adrenergic agonists will antagonize the effects of RAPIBLYK and may attenuate the heart rate lowering effects of RAPIBLYK. Positive inotropes and vasoconstrictors may attenuate the heart rate and blood pressure lowering effects of RAPIBLYK.

7.3 Catecholamine Depleting Drugs Observe patients treated with RAPIBLYK plus a catecholamine depletor (e.g., reserpine, monoamine oxidase inhibitors) for hypotension or marked bradycardia, which may cause vertigo, syncope, or postural hypotension. Catecholamine depleting drugs may have an additive effect when given with beta-blockers, which may increase the risk of hypotension or marked bradycardia related vertigo, syncope, or postural hypotension <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> .