Altathera Pharmaceuticals, Llc

Altathera Pharmaceuticals, Llc Drugs

• Sotalol Hydrochloride
  

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  Sotalol Hydrochloride

  

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  2.1 General Rules and Safety Measures of Intravenous Sotalol Therapy

  For the safety of the patient, the safety measures required of oral sotalol administration must also be applied for intravenous route. To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol should be hospitalized for at least three days or until steady state drug levels are achieved, in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Initiate intravenous sotalol therapy in the presence of personnel trained in the management of serious ventricular arrhythmias. Perform a baseline ECG to determine the QT interval and measure and normalize serum potassium and magnesium levels before initiating therapy with starting sotalol injection. Measure serum creatinine and calculate an estimated creatinine clearance in order to establish the appropriate dosing interval for sotalol.

  If the baseline QT is greater than 450 ms (JT >330 ms if QRS over 100 ms), sotalol is not recommended. The patient's creatinine clearance should be calculated using the one of several formulas. The Cockcroft-Gault formula to determine creatinine clearance is:

  When serum creatinine is given in µmol/L, divide the value by 88.4 (1 mg/dL = 88.4 µmol/L).

  Start sotalol therapy only if the baseline QT interval is <450 ms. During initiation and titration, monitor the QT interval after the completion of each infusion. If the QT interval prolongs to 500 ms or greater, reduce the dose, decrease the infusion rate, or discontinue the drug.

  Administer sotalol twice daily in patients with a creatinine clearance >60 mL/min or once daily) in patients with a creatinine clearance between 40 and 60 mL/min. Sotalol is not recommended in patients with a creatinine clearance <40 mL/min. The recommended initial IV dose of sotalol is 75 mg (once or twice daily) and is initiated as shown in the dosing algorithm described below. The 75 mg dose can be titrated upward to 112.5 or 150 mg after at least 3 days [see Dosage and Administration (2.5)].

  2.2 Dose of Intravenous Sotalol

  The bioavailability of oral sotalol is between 90% and 100%. The corresponding dose of intravenous sotalol is, therefore, slightly less than that of the oral dose. The effects of the initial intravenous dose must be monitored and the dose titrated either upward or downward, if needed, based on clinical effect, QT interval, or adverse reactions.

  Table 1: Conversion from Oral Sotalol to Intravenous Sotalol Oral dose Once or twice daily Intravenous dose Once or twice daily Administered over 5 hours 80 mg 75 mg (5 mL sotalol injection) 120 mg 112.5 mg (7.5 mL sotalol injection) 160 mg 150 mg (10 mL sotalol injection)

  2.3 Preparation of Sotalol Infusion

  Intravenous sotalol must be diluted for infusion. Appropriate diluents are saline, 5% dextrose in water (D5W), or Ringer's lactate. Usually, prepare in a volume of 100-250 mL. Use a volumetric infusion pump to infuse intravenous sotalol at a constant rate. The following table compensates for dead space in the infusion set.

  Table 2: Sotalol Infusion Preparation to Compensate for Dead Space in Infusion Set Target Dose Sotalol Injection Diluent Volume Prepared Volume to Infuse 75 mg 6 mL 114 mL 120 mL 100 mL 112.5 mg 9 mL 111 mL 100 mL 150 mg 12 mL 108 mL 100 mL         75 mg 6 mL 294 mL 300 mL 250 mL 112.5 mg 9 mL 291 mL 250 mL 150 mg 12 mL 288 mL 250 mL

  2.4 Initiation of Intravenous Sotalol Therapy

  The starting dose of intravenous sotalol is 75 mg infused over 5 hours once or twice daily based on the creatinine clearance. Monitor ECG for excessive increase in QTc.

  2.5 Upward Titration of Dose

  If the 75 mg dose of intravenous sotalol does not reduce the frequency of relapses of life threatening ventricular arrhythmias or symptomatic AFIB/AFL and is tolerated without excessive (i.e., to >500 ms) QTc prolongation, increase the dose to 112.5 mg infused over 5 hours, once or twice daily depending upon the creatinine clearance. Continue to monitor QTc during dose escalations.

  2.6 Dose for Ventricular Arrhythmias

  The recommended initial dose of intravenous sotalol is 75 mg infused over 5 hours, once or twice daily based on creatinine clearance. The dose may be increased in increments of 75 mg/day every 3 days. The usual therapeutic effect is observed with oral doses of 80 to 160 mg once or twice a day (corresponding to 75 to 150 mg intravenous sotalol). Oral doses as high as 240-320 mg once or twice a day (corresponding to 225 to 300 mg intravenous sotalol) have been utilized in patients with refractory life-threatening arrhythmias.

  2.7 Dose for Symptomatic AFIB/AFL

  In the U.S. multicenter dose-response study, 120 mg orally once or twice a day (corresponding to 112.5 mg intravenous sotalol) was found to be the most effective dose in prolonging the time to ECG- documented symptomatic recurrence of AFIB/AFL. If that dose level, at steady state, does not reduce the frequency of early relapse of arrhythmia and is tolerated without excessive QTc prolongation (>520 ms), increase the dose to 160 mg orally once or twice a day (corresponding to 150 mg intravenous sotalol).

  2.8 Dosing and Administration in Children

  Intravenous sotalol has not been studied in children. As in adults the following precautionary measures should be considered when initiating sotalol treatment in children: initiation of treatment in the hospital after appropriate clinical assessment; individualized regimen as appropriate; gradual increase of doses if required; careful assessment of therapeutic response and tolerability; and frequent monitoring of the QTc interval and heart rate. For children aged about 2 years and greater, with normal renal function, doses normalized for body surface area are appropriate for both initial and incremental dosing. Since the Class III potency in children [see Clinical Pharmacology (12.2)] is not very different from that in adults, reaching plasma concentrations that occur within the adult dose range is an appropriate guide. From pediatric pharmacokinetic data the following is recommended. For initiation of treatment, 30 mg/m2 three times a day (90 mg/m2 total daily dose) is approximately equivalent to the initial 160 mg total oral daily dose for adults. Subsequent titration to a maximum of 60 mg/m2 (approximately equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be guided by clinical response, heart rate and QTc, with increased dosing being carried out in-hospital. At least 36 hours should be allowed between dose increments to attain steady-state plasma concentrations of sotalol in patients with age-adjusted normal renal function.

  For children about 2 years or younger the above pediatric dosage should be reduced by a factor that depends heavily upon age, as shown in the following graph which shows age plotted on a logarithmic scale in months.

  For a child aged 20 months, the dosing suggested for children with normal renal function aged 2 years or greater should be multiplied by about 0.97; the initial starting dose would be (30 × 0.97) = 29.1 mg/m2, administered orally three times daily. For a child aged 1 month, the starting dose should be multiplied by 0.68; the initial starting dose would be (30 × 0.68) = 20 mg/m2, administered orally three times daily. For a child aged 1 week, the initial starting oral dose should be multiplied by 0.3; the starting dose would be (30 × 0.3) = 9 mg/m2. Similar calculations should be made for increased doses as titration proceeds. Since the half-life of sotalol decreases with decreasing age (below about 2 years), time to steady-state will also increase. Thus, in neonates the time to steady-state may be as long as a week or longer.

  In all children, individualization of dosage is required. As in adults sotalol should be used with particular caution in children if the QTc is greater than 500 ms on therapy and serious consideration should be given to reducing the dose or discontinuing therapy when QTc exceeds 550 ms.

  The use of oral sotalol in children with renal impairment has not been investigated. Sotalol elimination is predominantly via the kidney in the unchanged form. Use of sotalol in any age group with decreased renal function should be at lower doses or at increased intervals between doses. Monitoring of heart rate and QTc is most important. It will take much longer to reach steady-state with any dose and/or frequency of administration in these children.

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