FDA Approves New Intravenous Loading Regimen for Sotalol Facilitated Under Model-Informed Drug Development (MIDD) Paired Meeting Pilot Program

FDA Approves New Intravenous Loading Regimen for Sotalol Facilitated Under Model-Informed Drug Development (MIDD) Paired Meeting Pilot Program

On March 6, 2020, the U.S. Food and Drug Administration (FDA) approved a supplemental New Drug Application (sNDA) for sotalol hydrochloride injection providing dosage instructions for use of an intravenous (IV) infusion loading regimen to achieve steady state concentrations, thereby reducing the hospital stay required with initiation, up-titration, or re-initiation of sotalol treatment. The development program for this sNDA was facilitated by meetings between the applicant, AltaThera Pharmaceuticals, and the FDA under the Prescription Drug User Fee Act (PDUFA) VI Model-Informed Drug Development (MIDD) Paired Meeting Pilot Program.

Sotalol is an antiarrhythmic indicated for the maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL) in patients with symptomatic AFIB/AFL] who are currently in sinus rhythm, and for the treatment of life-threatening ventricular tachycardia. The recommended sotalol dosage depends on target oral dose and creatinine clearance, as described in the detailed dosing recommendations in the full prescribing information linked below. Sotalol can cause life threatening ventricular tachycardia associated with QT interval prolongation, and QTc prolongation is directly related to the concentration of sotalol. Under the current paradigm, patients are required to be hospitalized when treatment with oral sotalol is initiated or re-initiated, for at least 3 days or until steady-state drug levels are achieved, in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. The approved supplement provides dosage instructions for use of an IV infusion loading regimen of sotalol to achieve oral steady state peak concentration faster and is intended to reduce the length of hospital stay.

FDA evaluation focused on using a modeling and simulation (M&S) approach proposed by the applicant, in lieu of clinical studies, to support an IV loading regimen. The FDA’s MIDD Paired Meeting Pilot Program provided a forum for deeper engagement and alignment on the model development and in silico dosing evaluation strategies that could be used to support a regulatory submission. This prior alignment enabled the FDA to focus on critical elements of the modeling exercise and informed the need for updating the model during the sNDA review. The interactive effort between the applicant and FDA yielded pragmatic precision dosing recommendations and monitoring instructions to implement the new sotalol IV loading regimen safely in the general patient population, as well as for patients with renal impairment.

Detailed information regarding sotalol dosage and administration, monitoring instructions, and important warnings and precautions, including life threatening ventricular tachycardia associated with QT interval prolongation, can be found in the full prescribing information for sotalol hydrochloride injection linked below.  For additional information on the MIDD Paired Meeting Pilot Program, please visit https://go.usa.gov/xdtdP.

Full prescribing information is available at https://go.usa.gov/xdJQe.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.