SOTALOL

Fetal Risk Summary

Sotalol is a sympatholytic agent indicated for the treatment of cardiac arrhythmias. The antiarrhythmic action of the drug includes both Class II (b-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. It has also been used for hypertension. Sotalol is a racemic mixture of the d- and l-isomers. Only the l-isomer exhibits b-adrenergic blocking activity (without intrinsic sympathomimetic activity), but both isomers have Class III antiarrhythmic properties (1).

Sotalol was not teratogenic in rats and rabbits given doses 9 and 7 times the maximum recommended human dose on a body surface area basis (MRHD), respectively, during organogenesis (2). In rabbits, a dose 16 times the MRHD, but not 8 times, resulted in a slight increase in fetal death that was thought to be related to maternal toxicity. Fetal resorptions were observed in rats at 18 times the MRHD, but not at 2.5 times (2).

In a 1996 study, the embryotoxicity of d-sotalol in rats was shown to be gestational-age related and resulted from dose-dependent bradycardia in in vitro (rat embryo culture) and in vivo (pregnant rat) experiments (3). In embryo cultures, the minimum effective concentration (15 µg/mL) for causing significant bradycardia was about 5 times the human therapeutic plasma concentration (3 µg/mL) achieved in pregnant women after a 400-mg oral dose (3). In nine pregnant rats, a single oral dose (1000 mg/kg) was administered on gestational day 13. No malformations were observed, but a resorption rate of almost 14% was noted (3).

The pharmacokinetics of sotalol in the 3rd trimester (32–36 weeks' gestation) of pregnancy and in the postpartum (at 6 weeks) period was reported in 1983 (4).

Sotalol crosses the placenta to the fetus (5,6,7 and 8). Twelve hypertensive pregnant women were prescribed sotalol (final daily dose 200–800 mg) beginning at 10–31 weeks' gestation (5). The mean gestational age at delivery was 37.7 weeks (range 32–40 weeks). The mean maternal plasma concentration of sotalol at delivery was 1.8 ± 0.3 µg/mL, nearly identical to the mean umbilical cord plasma level of 1.7 ± 0.3 µg/mL. In six women, the mean amniotic fluid concentration of sotalol was 7.0 ± 2.7 µg/mL. No data were provided on the time interval between the last sotalol dose and the collection of plasma samples. In a second study, eight women scheduled for elective cesarean section were given 80 mg of the drug orally 3 hours before the procedure (6). The mean maternal concentration of sotalol at surgery was 0.68 ± 0.24 µg/mL, compared with the mean umbilical vein concentration of 0.32 ± 0.09 µg/mL, a fetal:maternal ratio of 0.47. A 1990 report described the use of sotalol, 80 mg twice daily, in one woman throughout gestation (7). A cesarean section was performed at approximately 37 weeks' gestation, 11 hours after the last dose. Maternal plasma and umbilical cord sotalol concentrations were 0.95 and 1.35 µg/mL, respectively, a ratio of 1.42. Maternal and cord serum concentrations of sotalol at delivery from a woman treated with 80 mg 3 times daily throughout a 42 week gestation were 0.77 and 0.65 µg/mL (fetal:maternal ratio 0.84), respectively (8).

Sotalol was used in 12 pregnant women for the treatment of hypertension (dosage and gestational weeks when therapy was begun are detailed above) (5). No fetal adverse effects attributable to the drug were observed, but bradycardia (90–110 beats/minute), lasting up to 24 hours, was discovered in five of the six newborns with continuous heart rate monitoring. In a 1987 report, sotalol, in increasing doses up to 480 mg/day during a 12-day period, was combined with digoxin beginning at 31 weeks' gestation in an unsuccessful attempt to treat a hydropic fetus with supraventricular tachycardia (9). Therapy was eventually changed to amiodarone plus digoxin with return of a normal fetal heart rate and resolution of the fetal edema. A normal infant was delivered at 38 weeks' gestation who was alive and well at 10 months of age.

A 23-year-old woman was treated throughout gestation with sotalol and flecainide for bursts of ventricular tachycardia and polymorphous ventricular premature complexes associated with an aneurysm of the left ventricle (7). A normal infant was delivered at approximately 37 weeks' gestation by cesarean section. No adverse effects of drug exposure, including bradycardia, were noted in the newborn, who was growing normally at 1 year of age.

A 2000 retrospective study evaluated the use of sotalol for fetal tachycardia in 21 pregnant women (10). The fetal arrhythmias were atrial flutter (AF) (N=10), supraventricular tachycardia (SVT) (N=10), and ventricular tachycardia (VT) (N=1). Hydrops fetalis was present in nine fetuses. Sinus rhythm was established in eight fetuses with AF and six with SVT, but four deaths (19%) occurred (one with AF and three with SVT). Two newborns (one each with AF and SVT), both successfully converted to a sinus rhythm in utero, had significant neurologic morbidity consisting of intracranial hemorrhage in one and cerebral hypoxic ischemia in the other. The authors concluded that sotalol was effective in AF, but the mortality and low conversion rate in fetuses with SVT indicated that the risks of sotalol outweighed the benefits in this group (10).

Several reviews have examined the use of b-adrenergic blockers in human pregnancy, concluding that these agents are relatively safe for the fetus (11,12,13 and 14). Some b-blockers, however, may cause intrauterine growth retardation and reduced placental weight (e.g., see Atenolol and Propranolol). Treatment beginning early in the 2nd trimester results in the greatest weight reductions. This toxicity has not been consistently demonstrated in other agents within this class, but the relatively few pharmacologic differences among the drugs suggest that the reduction in fetal and placental weights probably occurs with all at some point. The lack of toxicity documentation may reflect the number and type of patients studied, the duration of therapy, or the dosage used, rather then a true difference among b-blockers. Although growth retardation is a serious concern, the benefits of maternal therapy with b-blockers may, in some cases, outweigh the risks to the fetus and must be judged on a case-by-case basis.

Newborns exposed near delivery should be closely observed during the first 24–48 hours for signs and symptoms of b-blockade. Long-term effects of in utero exposure to this class of drugs have not been studied but warrant evaluation.

[*Risk Factor D if used in 2nd or 3rd trimesters.]

Breast Feeding Summary

Sotalol is concentrated in human milk with milk levels 3–5 times those in the mother's plasma (5,7,8). Twenty paired samples of breast milk and maternal blood were obtained from 5 of the 12 women treated during and after pregnancy with sotalol for hypertension (dosage detailed above) (5). Specific details of dosage and the timing of sample collection in relationship to the last dose were not given. The mean concentrations in milk and plasma were 10.5 ± 1.1 µg/mL (range 4.8–20.2 µg/mL) and 2.3 ± 0.3 µg/mL (range 0.8–5.0 µg/mL), respectively. The mean milk:plasma ratio was 5.4 (range 2.2–8.8). No b-blockade effects were observed in the five nursing infants, including the one infant who had bradycardia at birth. The mother of this infant produced the highest concentrations of sotalol in milk (20.2 µg/mL) observed in the study (5).

A woman treated throughout gestation with sotalol (80 mg twice daily) and flecainide was continued on these drugs during the postpartum period (7). The infant was not breast-fed. Simultaneous milk and plasma samples were drawn 3 hours after the second dose of the day on the 5th and 7th postpartum days. The milk and plasma concentrations on day 5 were 5 and 1.4 µg/mL, respectively, compared with 4.4 and 1.60 µg/mL, respectively, on day 7. The two milk:plasma ratios were 3.57 and 2.75, respectively.

Sotalol, 80 mg 3 times daily, was taken by a woman throughout a 42-week gestation and during the first 14 days of the postpartum period, at which time the dose was reduced to 80 mg twice daily (8). On the 5th postpartum day, milk and serum levels, approximately 6.5 hours after a dose (prefeeding), were 4.06 and 0.72 µg/mL, respectively, a ratio of 5.6. A postfeeding milk sample collected 0.7 hour later yielded a concentration of 3.65 µg/mL. The study was repeated on the 105th postpartum day, yielding prefeeding milk and serum concentrations 2.8 hours after the last dose of 2.36 and 0.97 µg/mL (ratio 2.4), respectively. A postfeeding milk level 0.5 hour later was 3.16 µg/mL. The authors calculated that the infant was consuming about 20%–23% of the maternal dose. No adverse effects were observed in the infant, who continued to develop normally throughout the study period.

Although symptoms of b-blockade, such as bradycardia and hypotension, were not observed in the nursing infants described above, these effects have been noted with other b-adrenergic blockers (see also Acebutolol, Atenolol, and Nadolol) and may occur with sotalol. Long-term effects of exposure to b-blockers from milk have not been studied but warrant evaluation. The American Academy of Pediatrics considers sotalol to be compatible with breast feeding (15).

References

1. American Hospital Formulary Service. Drug Information 2000. Bethesda, MD: American Society of Health-System Pharmacists, 2000:1596–1600.
2. Product information. Betapace. Berlex Laboratories, 2001.
3. Webster WS, Brown-Woodman PDC, Snow MD, Danielsson BRG. Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity. Teratology 1996;53:168-75.
4. O'Hare MF, Leahey W, Murnaghan GA, McDevitt DG. Pharmacokinetics of sotalol during pregnancy. Eur J Clin Pharmacol 1983;24:521–4.
5. O'Hare MF, Murnaghan GA, Russell CJ, Leahey WJ, Varma MPS, McDevitt DG. Sotalol as a hypotensive agent in pregnancy. Br J Obstet Gynaecol 1980;87:814–20.
6. Erkkola R, Lammintausta R, Liukko P, Anttila M. Transfer of propranolol and sotalol across the human placenta. Their effect on maternal and fetal plasma renin activity. Acta Obstet Gynecol Scand 1982;61:31–4.
7. Wagner X, Jouglard J, Moulin M, Miller AM, Petitjean J, Pisapia A. Coadministration of flecainide acetate and sotalol during pregnancy: lack of teratogenic effects, passage across the placenta, and excretion in human breast milk. Am Heart J 1990;119:700–2.
8. Hackett LP, Wojnar-Horton RE, Dusci LJ, Ilett KF, Roberts MJ. Excretion of sotalol in breast milk. Br J Clin Pharmacol 1990;29:277–8.
9. Arnoux P, Seyral P, Llurens M, Djiane P, Potier A, Unal D, Cano JP, Serradimigni A, Rouault F. Amiodarone and digoxin for refractory fetal tachycardia. Am J Cardiol 1987;59:166–7.
10. Oudijk MA, Michon MM, Kleinman CS, Kapusta L, Stoutenbeek P, Visser GHA, Meijboom EJ. Sotalol in the treatment of fetal dysrhythmias. Circulation 2000;101:2721–6.
11. Tamari I, Eldar M, Rabinowitz B, Neufeld HN. Medical treatment of cardiovascular disorders during pregnancy. Am Heart J 1982;104:1357–63.
12. Rotmensch HH, Elkayam U, Frishman W. Antiarrhythmic drug therapy during pregnancy. Ann Intern Med 1983;98:487–97.
13. Sandstrom B. Clinical trials of adrenergic antagonists in pregnancy hypertension. Acta Obstet Gynecol Scand 1984;Suppl 118:57–60.
14. Lubbe WF. Treatment of hypertension in pregnancy. J Cardiovasc Pharmacol 1990;16(Suppl 7):S110–3.
15. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.