he Galactopharmacopedia

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1 Shan non J Hum et al.j Lact Hum 16(3), Lact 2000Beta 16(3), 2000 Blockers and Lac ta tion he Galactopharmacopedia Beta Blockers and Lactation: An Update Meghan E. Shan non, PharmD, Su san E. Malecha, PharmD, and Amy J. Cha, PharmD Abstract Beta-adrenergic an tag o nists are one of the most com monly used class of agents in the treat - ment of hypertension. They have also dem on strated util ity in the treat ment of an gina pectoris and cer tain arrhythmias and for the re duc tion in mor tal ity fol low ing a myo car dial in farction. The use of this class of agents cre ates the po ten tial for beta-blocker ex po sure among lac tating women. This re view fo cuses on the most up-to-date data re gard ing the more com mon agents metoprolol, atenolol, propranolol, carvedilol, nadolol, sotalol, and betaxolol and their safety in lac tat ing women. J Hum Lact 2000;16(3): Keywords: breastfeeding, lactation, beta blocker, hypertension Beta blockers are some of the most com monly used agents for the treat ment of hypertension. Since the 1950s, numerous clinical tri als have sup ported the use of selec tive beta blockers as first-line ther apy for patients with chronic hyper ten sion, angina pectoris, and cer tain arrhythmias and for the reduc tion of cardiovascu lar mor tal ity in hemodynamically sta ble patients with definite or suspected acute myocardial infarction. The pop u lar ity of this class of agents cre ates a potential for beta-blocker expo sure among women of child bear ing age. Physicians are warned against prescribing certain beta blockers to women in their sec ond or third tri mes ter of preg nancy due to the potential risk of significant fetal harm, includ ing low birth weight or size, cardiorespi ratory depres sion, mild hypoglycemia, and growth retar - dation. 1-3 Because only case reports or small obser vational stud ies for beta-blocker expo sure dur ing Meghan E. Shan non is a drug in for ma tion res i dent at Searle Pharmaceuticals in Skokie, Illinois, and at the University of Illinois at Chicago. Susan E. Malecha is director of Cardiovascular Applied Therapeutics at Global Healthcare Re sources at Searle. Amy J. Cha is as sis tant di rec tor of new prod uct de vel op ment at Global Healthcare Re sources at Searle. Ad dress corre spon dence to Su san E. Malecha, PharmD, 5200 Old Or chard Road, Skokie, IL USA; su san.e.malecha@monsanto.com. J Hum Lact 16(3), 2000 Copy right 2000 In ter na tional Lactation Con sul tant As so ci a tion preg nancy are avail able, the degree of risk for betablocker fetopathy is unknown. This arti cle, the third of a three-part series, focuses on the most up-to-date infor ma tion regard ing beta blockers and lac ta tion. Reviews of the cur rent data on lac ta tion with the group of antihypertensives, cal cium chan nel antag o nists (J Hum Lact. 2000;16:61-64), and angiotensin convert ing enzyme inhib i tors/angio ten sin recep - tor blockers (J Hum Lact. 2000;16: ) have been pub lished previously. Beta Blockers The degree of excre tion into breast milk of dif fer ent beta-blockers (Fig ure 1) is depend ent on their indi vidual pharmacokinetic parameters and therefore cannot be char ac ter ized as a class. Although infor ma tion is avail able on sev eral dif fer ent agents, most data focus on metoprolol, atenolol, and propranolol. Other agents, such as sotalol, nadolol, carvedilol, and betaxolol have been included in this review. All beta blockers have the poten tial to cross into breast milk. The con cern, as with all agents used by lactat ing women, is the risk of harm to the infant. Fol lowing ini ti a tion or dose increase of beta blockers, infants should be mon i tored for the signs and symp toms of adrenergic blockade, which manifests as respiratory depres sion, hypoglycemia, leth argy, and bradycardia. 240

2 J Hum Lact 16(3), 2000 Beta Blockers and Lac ta tion 241 Figure 1. Sys temic beta blockers cur rently mar keted in the United States. Metoprolol Metoprolol is a cardioselective beta adrenergic recep tor blocker that has been extensively studied in lac tat ing woman. All reports and stud ies have dem onstrated a sub stan tial pas sage of drug into breast milk, with con cen tra tions being greater than those found in plasma. In a case eval u a tion by Liedholm et al., 4 accu - mu la tion of metoprolol was mea sured in three healthy, normotensive women who were given esca lat ing metoprolol doses of 50 to 100 mg twice daily for a total of 4 days at ces sa tion of nurs ing. The result ing AUC values were 2.6 to 3.7 times greater in milk than in serum. Another report by Kulas et al. 5 of three hyper ten sive women who were tak ing 100 mg of metoprolol showed that the milk con cen tra tion was con sis tently greater than the plasma con cen tra tion and fluc tu ated based on the nurs ing inter val. The AUC milk-plasma ratio ranged from 2.0 to 3.1. Despite these high milk con cen tra tions, infant plasma con cen tra tions were neg li gi ble. The authors of this study con cluded that the infant s expo - sure to metoprolol can be min i mized if nurs ing is not ini ti ated ear lier than 3 to 4 hours after dos ing. These data are sup ported by Sandstrom et al., 6 who eval u ated metoprolol breast milk con cen tra tions in three sub sets of women. Each group dem on strated higher metoprolol con cen tra tions in milk com pared to plasma, yet the dose to the infants was neg li gi ble. The first group con sisted of 10 hyper ten sive women who were treated with hydralazine and metoprolol (unknown dose). 6 Despite the find ing that the con centra tions in breast milk were on aver age three times higher than those in mater nal plasma, the amount of drug consumed by the neonate was negligible (less than 9 mcg/kg per feed ing). The sec ond group con sisted of nine women who were treated with 100 to 200 mg daily

3 242 Shan non et al. J Hum Lact 16(3), 2000 of metoprolol. 7 On aver age, the con cen tra tion of metoprolol in breast milk was 3.5 times higher than in plasma. Based on a 4 kg infant con sum ing one liter of breast milk per day, a daily dose of 0.07 mg/kg would be ingested by the infant, which is 20 to 40 times less than the nor mal dose for a hyper tensive patient. The final group con sisted of five women treated for high blood pres sure with metoprolol alone or in com bi na tion with hydralazine. 8 The con cen tra tion of metoprolol in milk was once again three times that found in plasma (1182 and 364 nmol/l, respec tively). Despite the exten sive degree of dis tri bu tion seen with metoprolol, the Amer i- can Acad emy of Pedi at rics con sid ers metoprolol to be com pat i ble with breast feed ing. 9 Atenolol The pub lished data on the degree of atenolol pass ing into breast milk are con flict ing. Some reports dem onstrate equivalent concentra tions in blood and milk, whereas others show significantly higher concentrations in breast milk. A case report by Fowler et al. 10 of a 26-year-old woman who was tak ing atenolol 100 mg daily for hyper ten sion through out her preg nancy doc u ments sim i lar con cen tra tions of atenolol in mater nal serum and breast milk. Although plasma atenolol was undetect able in the neo nate, the neo na tal uri nary atenolol con cen tra tion was slightly above that in breast milk, exhibiting renal excretion of the small dose ingested via breast milk. Sim i larly, a case series by Thorley 11 exam - ined the pharmacokinetics of atenolol in five hyper tensive females who were given atenolol 100 mg daily during the puerperim. Two hours after dos ing, serum and milk sam ples were obtained. The mean milk con cen tration of atenolol was 630 ± 271 ng/ml, and the mean blood-milk ratio was 1.3. Atenolol seemed to be dis tributed between blood and milk in approx i mately the same pro por tions. No infants dem on strated symp toms of beta-adrenergic block ade. Assuming neo na tal milk intake of 500 ml per day, the cal cu lated max i mum daily dose received by the infant would be 0.3 mg. These reports con flict with that of White et al., 12 who report on a 23-year-old woman eval u ated after receiv ing daily doses rang ing from 25 to 100 mg. The peak breast milk con cen tra tions ranged from 2.9 to 3.6 times those found in plasma. The plasma atenolol con cen tra tion in the infant was unde tect able, and the infant did not demon strate any symp toms of adrenergic block ade. It was cal cu lated that a mater nal daily dose of 100 mg would expose the infant to 0.13 mg of atenolol per feed ing. Sim i lar results were seen in a case series by Liedholm, 13 which looked at seven hyper ten sive women receiv ing atenolol (5 patients received 100 mg; 2 patients received 50 mg). Blood and milk con cen tra tions were obtained before the final dose was admin is tered and 3, 6, 9, and 12 hours later. For all patients, milk con cen tra tions were sig nif i cantly higher than those found in plasma. The mean AUC in milk was 4.5 times higher than that found in plasma. It was con cluded that the cal cu lated infant serum con cen tra tions would be low, yet the infant should be monitored for symptoms of beta-adrenergic block ade. Greater variations in plasma concentrations were seen in a case series by Kulas et al. 5 of 4 hyper ten sive women who received a daily dose of 100 mg. The AUC milk-plasma ratios ranged from 1.1 to 3.1. Higher drug con cen tra tions were found in the milk, yet they were neg li gi ble in the infant plasma. The authors con cluded that avoid ance of breast feed ing for 3 to 4 hours after dos ing reduces the infant s possible drug expo sure. Although mea sured con cen tra tions in milk are low, as detailed by these stud ies, one case of a neo nate experi enc ing toxic effects has been doc u mented. 14 Because of postpartum hyper ten sion, the mother was pre scribed atenolol 50 mg twice daily while breast feed ing. At 5 days of age, the baby girl became cyanotic and bradycardic. Breast feed ing was dis con tin ued on day 8 of the baby s life, and the infant was clin i cally nor mal 6 hours later. Breast milk obtained 1.5 hours after a 50 mg dose showed a con cen tra tion of 469 ng/ml. The infant serum concentration 48 hours after breastfeeding was 2010 ng/ml and 24 hours later was 140 ng/ml. Using an estimated volume of distribution of 0.55 L/kg, it was cal cu lated that the infant must have absorbed a min i- mum daily dose of 8.97 mg of the 100 mg atenolol dose (50 mg twice daily) taken by the mother. The authors stressed the poten tial risk of breast feed ing dur ing atenolol ther apy. The Amer i can Acad emy of Pedi at rics has rec ommended that safer alter na tives over atenolol should be used. 15 Propranolol Propranolol is a nonselective beta-adrenergic blocker that has been shown to be secreted into breast milk. Bauer et al. 16 eval u ated both con tin u ous dos ing (40 mg 4 times daily) as well as sin gle dos ing of 40 mg in a 30-year-old postpartum woman who was treated for

4 J Hum Lact 16(3), 2000 Beta Blockers and Lac ta tion 243 pre ma ture ventric u lar beats. After the sin gle dose, both milk and plasma con cen tra tions peaked 2 to 3 hours after dos ing. Breast milk con cen tra tions were less than 40% of the peak plasma con cen tration. After continuous dos ing, peak con cen tra tions in the milk were 64% of those found in plasma 3 hours after the final dose. However, propranolol concentrations in plasma and milk were equal 8 hours after the final dose. Through out dos ing, no signs of adrenergic block ade were seen in the infant. Using the peak propranolol con cen tra tion (42 ng/ml propranolol in breast milk) after dos age of 160 mg/day, and assum ing that the infant s milk inges tion does not exceed 500 ml/day, the cal cu lated max i mum infant load would be mg/day. The max i mum safe neo na tal dose is esti mated to be 0.60 mg/kg/day. These authors con clude that the dos age ingested by the breastfed infant would be con sid er ably lower than the ther a- peu tic dose. How ever, close obser va tion for signs of adrenergic block ade should be car ried out, espe cially in new born infants, because an imma ture hepatic microsomal enzyme sys tem places them at an increased risk for drug accu mu la tion. These findings are consistent with others find ings. Thorley 17 looked at five women who were receiv ing propranolol 40 mg twice daily. The mean blood-milk ratio 2 hours after dos ing was found to be 2.0. Case reports by Tay lor and Turner 18 and Levitan and Manion 19 involving doses rang ing from 30 to 40 mg daily also dem on strated milk lev els to be lower than those found in plasma. In both cases, the infant was devoid of any adrenergic symp toms, and the amount of drug to which the infant was exposed was found to be neg li gi ble. A study of three lac tat ing women by Living stone et al. 20 and Smith et al. 21 eval u ated the pharmacokinetics of propranolol and its metab o lites, propranolol glucuronide and naphthoxylatic acid, in breast milk and plasma. The dose needed to achieve ade quate blood pres sure con trol was 30 to 160 mg/day. The mean peak levels of plasma propranolol and its met a bolic prod ucts did not differ significantly. Although two infants developed hypoglycemia, regard less of cau sal ity, typ i cal doses ingested by nurs ing infants were cal cu lated to be approx i mately 0.1% of the mater nal dose. In this study, propranolol was dosed dur ing preg nancy, and it was stated that the infants would be sub ject to much higher doses in utero. From these data, the authors sug gest that breast feed ing while receiv ing treat ment with propranolol is safe. The Amer i can Acad emy of Pedi atrics sup ports this rec ommendation. 9 Carvedilol It has been doc u mented in ani mal stud ies that carvedilol is excreted into milk; how ever, the degree of pas sage in humans is unknown. 22 There fore, the man u- facturers recommended that the possible risks to the infant be weighed against the ben e fits to the mother. Nadolol Nadolol is a long-act ing beta blocker that exhib its a small degree of pro tein bind ing. There is lit tle infor mation about the safety of nadolol to the infant when used by lactating mothers. The most exten sive data have been reported by Devlin et al., 23 who stud ied 12 normotensive lac tat ing females who took 80 mg daily for 5 con sec u- tive days. Milk and serum lev els were obtained before, dur ing, and after dos ing. Twenty hours after dos ing, drug lev els in milk were con sid er ably higher than those found in the serum, ± 47.1 ng/ml and ± 16.7 ng/ml, respec tively. Based on daily milk pro duc tion of 1 liter and a mean steady-state milk level of ng/ml, it was cal cu lated that the total amount of nadolol in mater nal milk would be mcg/kg/day. Assuming equivalent dosing on a weight basis for adults and chil - dren, a 5 kg infant would receive 2% to 7% of the ther a- peu tic infant dose (0.5 to 2.5 mg/kg/day). It was concluded that nadolol should be used with cau tion in lactating women. Another case report by Fox et al. 24 of a 37-year-old hyper ten sive woman who was tak ing 20 mg daily also dem on strates pas sage into breast milk. Milk lev els 36 hours after dos ing were 146 ng/ml. Based on the above findings, the American Academy of Pediatrics finds nadolol compatible with breastfeeding, but due to limited data, it is rec om mended that infants be mon i tored for symp toms of beta block ade. 9 Sotalol Sotalol is a beta blocker used most often for the treatment of ven tric u lar arrhythmias. O Hare et al. 25 stud ied the effects of sotalol in five hyper ten sive women. Each received an ini tial daily dose of 200 mg, with dose escala tion in 200 mg/day incre ments to achieve a blood pressure of less than 140/90 mm Hg. Mean drug con cen trations were 10.5 ug/ml in milk and 2.3 ug/ml in mater nal plasma, result ing in a milk-plasma ratio of 4.6. No adverse events were seen in the breast fed infants. O Hare et al. con cluded that due to the high sotalol lev - els obtained, a pos si ble risk to the infant may be evi dent and there fore use should be avoided dur ing lac ta tion.

5 244 Shan non et al. J Hum Lact 16(3), 2000 The exten sive pas sage of sotalol into breast milk is fur ther sup ported by two case reports. 26,27 In a 22-yearold woman with pal pi ta tions from cardiomyopathy who was tak ing 240 mg of sotalol daily, the milk-serum ratios var ied depend ing on the time since feed ing and the mater nal dose but ranged from 2.43 to Based on an aver age milk intake of 0.15 kg/day, it was cal culated that the infant would receive 20% to 23% of the mater nal dose (0.41 to 0.58 mg/kg). The dose rec ommended for an infant is 2 to 4 mg/kg/day. From this information, the author recommended breastfeeding only if close mon i tor ing of the infant could be pro vided. In another case report, a 23-year-old woman was tak ing sotalol 80 mg twice daily and flecainide for ven tric u lar tachy car dia and pre ma ture ven tric u lar com plexes. 27 Milk and serum lev els were obtained on days 5 and 7 postpartum, result ing in a milk-plasma ratio of 3.57 and 2.75, respec tively. Based on the above reports, the American Academy of Pediatrics finds sotalol to be com pat i ble with breast feed ing. 9 Betaxolol Betaxolol is a cardioselective beta-adrenoreceptor antag o nist that exhib its exten sive bioavailability, low protein binding, and high lipid solubility. The effects of betaxolol were stud ied in three hyper tensive women who were tak ing 10 mg daily for 24 to 72 hours after delivery. 28 Milk-to-serum concentrations ranged from 2.0 to 11.6, sug gest ing accu mu la tion of betaxolol in breast milk. It was deter mined that with inges tion of 300 to 500 ml of milk per day, the dose given to the infant would be to 0.03 mg/kg/day. Ref er ence doses in adults are 0.15 to 0.30 mg/kg/day. The use of betaxolol has not been stud ied in infants and chil dren. The Amer i- can Acad emy of Pediatrics 9 and the man u fac turer of betaxolol 29 rec om mend that infants whose moth ers are taking betaxolol be monitored for symptoms of beta block ade. Con clu sion The choice of antihypertensive ther apy in lac tat ing women, when pharmacological intervention is needed, is depend ent on the patient s response to medication and the amount of drug excreted in the milk. Based on the lit er a ture reviewed, metoprolol, propranolol, and nadolol may be considered compatible with lactation. Due to the limited or conflicting data available on atenolol, carvedilol, sotalol, and betaxolol, sim i lar con - clu sions can not be drawn. Although many of these agents have been deemed safe, the infant should be carefully monitored for symptoms of beta blockade on ini ti a tion of ther apy or dose increase. Both the cli ni cian and the mother have to con sider the risk-ben e fit ratio when mater nal med i ca tion is pre scribed. Ref er ences 1. Inderal (Prod uct in sert). Wyeth-Ayerst Laboratories, Philadelphia, Pa. 2. Fox RE, et al. Neonatal effects of maternal nadolol therapy. Am J Obstet Gynecol. 1985;152: Lip GY, et al. Ef fect of atenolol on birth weight. Am J Cardiol. 1997;79: Liedholm H, Melander A, Bitzen PO, et al. Accumula tion of atenolol and metoprolol in hu man breast milk. Eur J Clin Pharmacol. 1981;20: Kulas J, Lunell NO, Ros ing U, et al. Atenolol and metoprolol: A com par i- son of their ex cre tion into hu man breast milk. Acta Obstet Gynecol Scand Suppl. 1984;118: Sandstrom B, Lindeberg S, Lundborg P, et al. Dis po si tion of the adrenergic blocker metoprolol in the late preg nant women, the amniotic fluid, the cord blood and the ne o nate. Clin Exp Hypertens. 1983;B2: Sandstrom B. Metoprolol ex cre tion into breast milk. Br J Clin Pharmacol. 1980;9: Sandstrom B. Antihypertensive treat ment with the adrenergic beta-receptor blocker metoprolol during pregnancy. Gynecol Obstet In vest. 1978;9: Com mit tee on Drugs, Amer i can Acad emy of Pe di at rics. The trans fer of drugs and chem i cals into hu man milk. Pe di at rics. 1994;93: Fowler MB, Brudenell M, Jack son G, et al. Es sen tial hy per ten sion and pregnancy: Suc cess ful out come with atenolol. Br J Clin Pract. 1984; 38: Thorley KJ, McAinsh J. Levels of the beta blockers atenolol and propranolol in the breast milk of women treated for hy per ten sion in pregnancy. Biopharm Drug Dispos. 1983;4: White WB, Andreoli JW, Wong SH, et al. Atenolol in hu man plasma and breast milk. Obstet Gynecol. 1984;63:42S-44S. 13. Lideholm H. Transplacental pas sage and breast milk ac cumulation of atenolol in hu mans. Drugs. 1983;25(suppl 2): Schimmel MS, Eidelman AJ, Wilschanski MA, et al. Toxic ef fects of atenolol con sumed dur ing breast feed ing. J Pediatr. 1989;114: Briggs GG, Free man RK, Yaffe SJ. Drugs in pregnancy and lac ta tion. 5th ed. Bal ti more, Md: Wil liams & Wilkins; Bauer JH, Pape B, Zajicek J, et al. Propranolol in hu man plasma and breast milk. Am J Cardiol. 1979; 43: Thorley KJ. Pharmacokinetics of atenolol in pregnancy and lactation. Drugs. 1983;25(suppl 2): Tay lor EA, Turner P. Anti-hyper tensive ther apy with propranolol dur ing pregnancy and lactation. Postgrad Med J. 1981;57: Levitan AA, Manion JC. Propranolol ther apy dur ing pregnancy and lac - tation. Am J Cardiol. 1973;32: Living stone I, Craswell PW, Bevan EB. Propranolol in preg nancy: Three year prospective study. Clin Exp Hypertens. 1983;B2: Smith MT, Living stone I, Hooper WD, et al. Propranolol, propranolol glucuronide, and naphthoxylactic acid in breast milk and plasma. Ther Drug Monit. 1983;5: Coreg (Product insert). SmithKline Beecham Pharmaceuticals, Philadelphia, Pa; Devlin RG, Duchin KL, Fleiss PM. Nadolol in hu man se rum and breast milk. Br J Clin Pharmcol. 1981;12: Fox RE, Marx C, Stark AR. Neo na tal ef fects of ma ter nal nadolol ther apy. Am J Obstet Gynecol. 1985;152:

6 J Hum Lact 16(3), 2000 Beta Blockers and Lac ta tion O Hare MF, Murnaghan GA, Rus sell CJ, et al. Sotalol as a hypotensive agent in preg nancy. Br J Obstet Gynaecol. 1980;87: Hackett LP, Wojnar-Hor ton RE, Dusci LJ, et al. Ex cre tion of sotalol in breast milk. Br J Clin Pharmacol. 1990;29: Wag ner X, Jouglard J, Mou lin M, et al. Coadministration of flecainide ace tate and sotalol dur ing preg nancy: Lack of teratogenic ef fects, pas sage across the pla centa, and ex cre tion in hu man breast milk. Am Heart J. 1990;119: Morselli PL, Boutroy MJ, Bianchetti G, et al. Pla cental transfer and perinatal pharmacokinetics of betaxolol. Eur J Clin Pharmacol. 1990;38: Kerlone (Prod uct in sert). Searle, Skokie, Ill; 1997.