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Cardiovascular drugs and diuretics
Cardiovascular drugs and diuretics Paul Merlob and Corinna Weber-Schöndorfer
4.6
4.6.1 β-Receptor blockers
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4.6.2 Hydralazine
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4.6.3 α-Methyldopa713 4.6.4 Calcium antagonists
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4.6.5 ACE inhibitors
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4.6.6 Angiotensin-II receptor-antagonists (sartan)
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4.6.7 Other antihypertensives
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4.6.8 Antihypotensives
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4.6.9 Digitalis
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4.6.10 Antiarrhythmics
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4.6.11 Vasodilators and circulatory drugs
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4.6.12 Diuretics
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There are cardiovascular drugs and diuretics that can be used during pregnancy and lactation. The decision to continue these medications during lactation depends on many factors. Some of these factors include the well-being of the mother, the blood/milk barrier, the pharmacological activity of the drug, and the consequences for the infant. The recommended drugs of choice are those which are best studied and do not show unwanted adverse effects for either the mother or the child. Drugs should be avoided if there is insufficient experience, like the sartans. If not, the safest cardiovascular or diuretic drugs should be used and the therapeutic choice should be changed to the preferred agents. This can be possible without interrupting breastfeeding.
4.6.1 β-Receptor blockers Circulatory symptoms and hypoglycemia have been cited in connection with the intake of β-receptor blockers via mother’s milk. However, by contrast to prenatal exposure, such effects are less likely during breastfeeding, due essentially to the relatively low concentrations of these drugs in infant blood. Bradycardia, hypotension and tachypnea have been seen in connection with acebutolol, which has a half-life of 3–4 hours and 26% plasma protein binding (PPB). Therefore, mathematically, the baby has received about 5–10% of the maternal dose per kg of bodyweight (Boutroy 1986). Drugs During Pregnancy and Lactation. http://dx.doi.org/10.1016/B978-0-12-408078-2.00031-7 Copyright © 2015 Elsevier B.V. All rights reserved.
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4.6.1 β-Receptor blockers
In particular, the active metabolite, diacetolol (half-life 8 to 13 hours), accumulates in the mother’s milk with an unusually high milk/plasma (M/P) ratio of up to 24.7. Atenolol has a half-life of 6 to 7 hours, a minimal PPB, and is hydrophilic. A recent study (Eyal 2010) examines the influence of atenolol on breastfed babies at 2 to 4 weeks of age (n = 32), 3 to 4 months (n = 22) and 6 to 8 months (n = 17). The maternal dose was between 25 and 200 mg/day. The M/P ratio was, on average, greater than 4.9, whereby the average relative infant dose was less than 15%. Infant doses of 34.8% (after 2 to 4 weeks) or 17.8% after 3 to 4 months were noted. Atenolol was not detected in the serum of any of the babies at 3 to 4 months. Further, whether maternal atenolol had a depressive effect on the heart rate in crying infants has been examined and no effect has been noted in this single study. However, Schimmel (1989) describes a breastfed infant who had toxic concentrations of atenolol acquired from her mother (dose 50 mg twice daily). This full-term infant at the age of 5 days had been transferred to the neonatal intensive care unit because of cyanosis and two episodes of bradycardia (80 beats/min). Forty-eight hours after discontinuing breastfeeding, the atenolol concentration in the baby’s serum was 2010 ng/mL and 24 hours later it was 140 ng/mL. The possible accumulation of atenolol in human milk and infant serum should be considered before prescribing, because safer β-blockers can be used during breastfeeding. Betaxolol has a half-life of 14 to 22 hours and a PPB of 50%. The relative dose transmitted by the milk reaches a maximum of 4.3% shortly after birth (Morselli 1990). Labetalol, which is widely used in the USA, works as an α- and β-receptor blocker, has a half-life of 6 to 8 hours, and a PPB of 50%. With long-term treatment with 300 to 1,200 mg/day, a mother’s maximum milk concentration of 0.7 mg/L and an M/P ratio between 0.2 and 1.5 are reported. Thus, an infant would receive, at most, 0.1 mg/kg daily. This represents 0.3% of the maternal dose per kg bodyweight (survey by Bennett 1996). There is substantial experience available for metoprolol (half-life 3 to 4 hours, PPB 12%). With long-term therapy with 100 and 200 mg, a maximum of 0.7 mg/L is detected in the milk. The M/P ratio is 3. The daily dose for the infant is, nevertheless, 0.1 mg/kg at most. This represents 3.2% of the maternal weight-related dose. About 10% of the northern European population is thought to metabolize metoprolol slowly. This could be the reason why a plasma concentration of 45 μg/L is measured in one (symptom-free) infant. Among other breastfed infants, it is 0.5–3 μg/L (survey in Bennett 1996). The therapeutic concentration for adults is given as 93–881 μg/L. With oxprenolol, up to 1.5% of the maternal weight-related dose is transmitted to the baby (Fidler 1983). Also, the low transfer of oxprenolol via the mother’s milk (half-life 1 to 2 hours, PPB 80%) is confirmed in another study (Sioufi 1984). Shortly after birth, 3.1 μg/L of S-enantiomers of pindolol and 1.9 μg/L of its R-enantiomers are found in the milk of three breastfeeding mothers who took 20 mg pindolol (half-life 3–4 hours, PPB 40–60%) daily. This represents 0.36% of a maternal weight-related dose (Goncalves 2007). The transfer of mepindolol can be 5% of the maternal weight-related dose (survey in Bennett 1996). Among β-blockers propranolol is the most frequent studied and used drug. Propranolol has a PPB of 90% and a half-life of 3 to 6 hours. The maximum transfer of 0.4% into the mother’s milk is quite low (survey in Bennett 1996).
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With oral use of timolol, the portion of the maternal weight-related dose that is transmitted is 3.3% (Fidler 1983). Timolol is used primarily in eye drops for glaucoma treatment (Chapter 4.12.8). This leads to limited concentrations in the milk. Madadi (2008) calculated a relative dose of 0.024% if the mother puts drops in both eyes twice daily. There are insufficient data on bisoprolol (half-life 10–12 hours PPB 30%), carvedilol (half-life 6–10 hours PPB >98%), celiprolol half-life 5–6 hours, PPB 25%), nebivolol (half-life of 10–24 hours with slow metabolization, PPB of 98%), penbutolol (half-life of 20 hours PPB 80–98%), and talinolol to make a judgment. This also applies to esmolol (half-life 9 minutes, PPB 55%), which is indicated for i.v. injection with supraventricular tachycardias. Sotalol has a high risk for accumulation in infants (see also Section 4.6.10). Recommendation. During therapy with β-receptor blockers, breastfeeding is allowed. Metoprolol, oxprenolol, pindolol, propranolol and labetalol are preferred. Therapy with other β-blockers should be changed to one of the preferred agents if possible.
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4.6.3 α-Methyldopa
4.6.2 Hydralazine With 150 mg/day of hydralazine in the breast-feeding mother, a maximum of 130 μg/L is measured in the milk – which is 20 μg/kg per day or 1% of the therapeutic dose for an infant (Liedholm 1982). Following parenteral administration of 10–40 mg, an average of 47 μg/L, including the hydralazine metabolites, was measured in mother’s milk. The M/P ratio was 0.5. With this therapy, up to 108 μg/L of hydralazine was found in the plasma of breastfed infants (Lamont 1986). By comparison, the plasma concentration in an infant being treated with 2 mg/kg was given as 1,700 μg/L. No toxic symptoms have been observed while breastfeeding. Dihydralazine can be evaluated as if hydralazine.
4.6.3 α-Methyldopa With daily treatment with 250–2,000 mg of α-methyldopa, up to 1.14 mg/L is measured in the milk. The M/P ratio is 0.2– 0.5. For the infant, a daily dose of 0.17 mg/kg can be calculated, which represents 3.2% of the maternal dose per kg (survey in Bennett 1996). Only in one of three infants could the medication be detected in plasma (90 μg/L). For the mother, it is 4,250 μg/L. No toxic symptoms are observed in the infant. α-methyldopa can promote milk production as a result of increased prolactin secretion (Bennett 1996). Recommendation. Breastfeeding is permitted with α-methyldopa.
4.6 Cardiovascular drugs and diuretics
Recommendation. Breastfeeding is permitted with hydralazine.
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4.6.4 Calcium antagonists
4.6.4 Calcium antagonists There is no information on the transfer of amlodipine into the m other’s milk. Two case reports describe age-appropriate development with a maternal dose of 5 and 10 mg/day (Szucs 2010, Ahn 2007). In 11 mothers, only limited amounts of nicardipine are detected in mother’s milk under steady-state conditions (Jarreau 2000). For a few days postpartum, seven mothers have received nicardipine in an hourly dose of 1–6.5 mg for treating preeclampsia. Less than 0.3 μg/day nicardipine in the mother’s milk, or between 0.015 and 0.004% of a therapeutic infant dose, is calculated for these mother–child pairs (Bartels 2006). With nifedipine and its active pyridine metabolites, a maximum of 2–10 μg/kg/day is transmitted to the infant when the mother has taken 30–90 mg/day. That is less than 5% of a weight-related child’s dose (Ehrenkranz 1989). Average values of 2% and less are probably even more realistic (Manninen 1991, Penny 1989). Nifedipine is also used successfully to treat Raynaud phenomenon of the breast nipple. Anderson (2004) reports on 12 breastfeeding women complaining of pain in the nipple, which was finally diagnosed as Raynaud phenomenon. Those mothers, who chose nifedipine therapy, had rapid relief from the symptoms. Interestingly, eight of the 12 women and their children had previously been treated with antimycotics because of a suspected Candida albicans infection. A further case report describes good tolerance of nifedipine for vasospasms of the nipple (Page 2006). In a retrospective review of 22 cases of breastfeeding mothers diagnosed with Raynaud phenomenon of the nipple, previous treatment for Candida mastitis with oral or topical antifungals was ineffective in 20 cases (91%). Of the 12 patients who tolerated a trial with nifedipine, 10 (83%) report a decrease or resolved nipple pain during lactation. Thus, nifedipine and not the antifungal, appears to be an effective treatment of Raynaud phenomenon of the nipple (Barrett 2013). With 6 × 60 mg of nimodipine, maximum concentrations of 3.5 μg/L in the mother’s milk have been described (Tonks 1995). Mathematically, this would be only 0.01% of the weight-related maternal dose. A further case confirms this limited transfer of nimodipine (Carcas 1996). With nitrendipine, a maximum relative dose of 0.6%, including its metabolites, can reach the infant (White 1989). During therapy with the calcium antagonists mentioned, no intolerance in the breastfed infant has been described. By contrast felodipine, gallopamil, isradipine, lercanidipine, manidipine, nilvadipine and nisoldipine have been insufficiently studied. For verapamil and diltiazem, see Section 4.6.10. Both have been considered as appropriate during breastfeeding by the American Academy of Pediatrics (2001). The relative infant dose was 0.2% for verapamil and 0.9% for diltiazem and thus, the relative amount of these drugs transferred to the breastfed infant is quite small. In some cases no verapamil is detected in infant’s plasma. Recommendation. Breastfeeding is permitted during therapy with calcium antagonists. Depending on the indication, diltiazem, nicardipine, nifedipine, nitrendipine and verapamil are the calcium antagonists of choice while breastfeeding. Individual doses of other calcium antagonists do not require any limitation of breastfeeding, but the therapy should be changed.
4.6.6 Angiotensin-II receptor-antagonists (sartan)
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4.6.5 ACE inhibitors
4 Lactation
In nine mother–baby pairs with a daily dosage of 20 mg of benazepril, a maximum of 0.003 μg, including the active metabolite, benazeprilate, is measured per liter of milk. For an exclusively breastfed baby, this represents 0.00014% of the maternal weight-related dose (Kaiser 1989). With 300 mg captopril daily, 4.7 μg/L milk is reported. The M/P ratio is 0.03. The infant receives up to 0.7 μg/kg/day. This represents about 0.014% of the maternal weight-related dose (Devlin 1981). Enalapril can be similarly evaluated. The relative dose for the infant is about 0.1% (Rush 1991, Redman 1990, Huttunen 1989). By contrast to the maternal serum, there is no lowering of the angiotensin-converting enzyme found in milk samples (Huttunen 1989). No undesirable effects on the infant have been described. Quinapril concentrations are reported for six mother-child pairs. The drug could not be detected in any of the milk samples. Based on the detection limit, the maximum estimated relative infant dose is 1.6% (Begg 2001). There are insufficient data to evaluate cilazapril, fosinopril, lisinopril, moexipril, perindopril, ramipril, spirapril, trandolapril and zofenopril. Following the use of ACE inhibitors in late pregnancy, kidney function disturbances as extreme as anuria requiring dialysis have been noted in the newborn (Chapter 2.8), but not during breastfeeding. For this reason, the American Academy of Pediatrics (2001) considers the use of those ACE inhibitors that have been tested extensively to be acceptable during breastfeeding.
4.6.6 Angiotensin-II receptor-antagonists (sartan) There is insufficient experience with the use of candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan during breastfeeding. Since very serious kidney function disturbances in the newborn can occur after using sartans in late pregnancy (Chapter 2.8.6) and there are no data on transfer into the mother’s milk, this group of drugs should be avoided during breastfeeding. This applies particularly for premature and young infants. Recommendation. Sartans should be avoided during breastfeeding. The accidental administration of a single dose does not require weaning. However, the therapy should be changed.
4.6 Cardiovascular drugs and diuretics
Recommendation. Benazepril, captopril, enalapril as well as quinapril may be prescribed during breastfeeding if β-blockers, calcium antagonists or methyldopa are not effective or indicated. As a safety measure, at least with premature infants and young infants under two months, attention should be paid to edema and the course of weight gain as indicators for disturbed kidney function. The accidental prescribing of another ACE inhibitor does not require any limitation of breastfeeding but changing the therapy is advisable.
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4.6.7 Other antihypertensives
4.6.7 Other antihypertensives Peripherally acting antiadrenergic agents With prazosin, the relative dose is a maximum of 3% in one mother–child pair studied (manufacturer’s report). There is no published experience with bunazosin, doxazosin and terazosin. A single case report (Jensen 2013) provides the first quantitative data on the transfer of doxazosin into human milk. A 37-year-old woman receives two oral doses of 4 mg doxazosin 24 hours apart for urinary stones. Venous blood and milk are collected at different intervals after these two doses. The average and maximum milk concentrations are 2.9 and 4.2 μg/L. These values correspond to estimated relative infant doses of 0.06 and 0.09%, respectively. These very low results provide some reassurance for breastfeeding women who may benefit from doxazosin treatment. Urapidil is well absorbed orally, has a PPB of 80%, and an elimination half-life of 5 hours after oral administration and 3 hours after i.v. injection. Two newborns, breastfed while their mothers were taking urapidil medication, did not develop any side effects (author’s unpublished observations).
Centrally acting antiadrenergic agents In long-term clonidine therapy with 240–290 μg daily, clonidine is reported to levels of 2.8 μg/L in milk. For the infant, this means a maximum of 8% of the maternal, weight-related dose. With 0.3–0.6 μg/L in the infant’s plasma, a near-therapeutic concentration is reached (Hartikainen-Sorri 1987). In another study involving on-going therapy with 75 μg/day, a maximum of 7% was measured for the exclusively breastfed infant in whose plasma no active ingredient could be detected (<0.096 ng/mL). There was 0.6 μg/L reported in milk and 0.3 μg/L in maternal plasma (Bunjes 1993). No undesirable effects, such as a drop in blood pressure, were observed in the infants. Following daily administration of 200 μg moxonidine to five mothers during the first few postpartum days, a maximum of 2.7 μg/L was reported in milk. Mathematically, that is 12% of the maternal weight-related dose for an exclusively breastfed baby. The M/P ratio has been estimated to be 1–2 (cited in Schaefer 1998). There are no data on the passage of reserpine into the mother’s milk. The half-life of several days would suggest accumulation of reserpine in the infant.
Other antihypertensives Five percent of the weight-related dose of minoxidil passes into the milk. The exposed infant demonstrates no symptoms (Valdivieso 1985). Aliskiren is a renin inhibitor, which should be avoided during breastfeeding. Diazoxide is only approved for therapy for hypoglycemia. No information exists on the passage into the mother’s milk of this drug or for sodium-nitroprusside, which is used in intensive medicine. Phenoxybenzamine is indicated for treatment of pheochromocytoma. However, there is no experience on its use during breastfeeding.
4.6.10 Antiarrhythmics
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Recommendation. The antihypertensives mentioned in this section should not be prescribed during breastfeeding. If treatment has begun, this does not require weaning; however, a change in therapy should be arranged.
4.6.8 Antihypotensives
Recommendation. Hypotension should be treated primarily without medication. Individual dosing of dihydroergotamine during breastfeeding is acceptable. The accidental intake of other drugs does not require an interruption of breastfeeding.
4 Lactation
Ergotamine derivatives such as dihydroergotamine can, as prolactin inhibitors, reduce milk production. There is insufficient experience on etilefrine, amezinium metilsulfate and midodrine.
4.6.9 Digitalis With ongoing therapy of 250–750 μg digoxin daily (half-life about 36 hours), concentrations between 0.4 and 1.9 μg/L have been reported in mother’s milk. With an M/P ratio of about 0.8, the dose transferred to the infant is, at most, 0.3 μg/kg/day. This is considerably lower than the usual maintenance dose in children of 10 μg/kg/day. No digoxin was measurable in the infant’s plasma when the mother had taken 250 μg/day and with 750 μg/day, 0.2 μg/L (therapeutic level 0.5–2 μg/L) was detected (survey in Bennett 1996). There are no studies on digitoxin and derivatives.
4.6.10 Antiarrhythmics Antiarrhythmics will be discussed below according to their classification (Chapter 2.8.15).
Class IA With daily administration of 1,800 mg quinidine (hydrochloride), a maximum of 9 mg/L is detected in milk. For exclusively breastfed infants, this is 1.3 mg/kg daily or about 4% of the maternal weight-related dose. The M/P ratio is 0.9 (Hill 1979). Despite possible accumulation due to the infant’s delayed metabolization, the American Academy of Pediatrics (2001) stated that there is no cause for concern about using quinidine during breastfeeding. There are no case reports on symptoms in breastfed children.
4.6 Cardiovascular drugs and diuretics
Recommendation. The use of digoxin is no cause for concern during breastfeeding.
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4.6.10 Antiarrhythmics
With disopyramide, up to 15% of the maternal weight-related dose can apparently be taken in by the infant. Between 0.1 and 0.5 mg/L are reported in the plasma of some children. The therapeutic level for adults is above 3 mg/L. No symptoms are described in breastfed children (survey in Bennett 1996). After a single dose of 100 mg, the relative dose is 3% of the maternal weight-related dose. There is no experience available for ajmaline and prajmalium bitartrate during breastfeeding.
Class IB Following i.v. administration of about 1,000 mg lidocaine and the resulting therapeutic plasma concentration of 5 μg/mL in the mother, a transfer of 1.8% of the weight-related dose has been observed (Zeisler 1986). A similar proportion is calculated following administration as a local anesthetic (Lebedevs 1993). With long-term therapy using 600 mg mexiletine daily, a milk concentration to 0.96 mg/L has been reported for one mother. This represents 0.14 mg/kg/day or 1.4% of the maternal weight-related dose for the infant, whose plasma mexiletine was not detectable (Lewis 1981). For another infant, already prenatally exposed to mexiletine, growth disturbances and, 5 months after weaning, a questionable seizure has been reported. The development that followed has been reported as unremarkable (Lownes 1987). A connection with the exposure via the mother’s milk was unlikely.
Class IC Flecainide is reported in milk from several mothers in long-term treatment with 2 × 100 mg daily at concentrations of 0.27–1.53 μg/mL (McQuinn 1990, Wagner 1990). Based on the highest value, an infant could get approximately 7% of the maternal weight-related dose. The American Academy of Pediatrics (2001) does not object to the use of this drug during breastfeeding as it is also used therapeutically in newborns. Propafenone has a PPB of 83%. After a single dose of 150 mg of propafenone, an M/P ratio of <1 and a weight-related dose of 0.1% were calculated (Wakaumi 2005).
Class II For β-receptor-blockers, see Section 4.6.1.
Class III Amiodarone has a very long half-life of 2–4 weeks. It consists of just about 40% iodide (see Chapter 4.11.6). In the mother’s milk of one woman who had taken amiodarone at the end of her pregnancy for a number of reasons including fetal indications, only after 25 days was the active ingredient no longer detectable. Her breastfed infant had no side effects and the thyroid function was also normal (Hall 2003). With long-term therapy using 400 mg/day, a maximum of 16.4 mg/L of milk plus 6.5 mg/L of the metabolite, desethylamiodarone (DA), was reported (survey in Bennett, 1996). Based on this, the total amount of active substance, including the metabolite, which an infant could receive, would be a maximum
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Class IV With on-going treatment using 240–360 mg verapamil daily, up to 0.3 mg/L is reported in milk. The M/P ratio lies between 0.2 and 0.9. The daily amount taken in by the infant is given as a maximum of 0.05 mg/ kg. This represents about 1% of the maternal dose per kg of bodyweight. In the plasma of one of the breastfed infants, 2.1 μg/L is detected. No undesirable side effects have been described (survey in Bennett 1996). For diltiazem, the results from only one patient are similar to those of verapamil including the drug measurement (Okada 1985). There is no experience on gallopamil. Adenosine cannot be classified in any of the classic antiarrhythmic groups. Because of its extremely short half-life and the very brief time for which it is used, it should not be considered a cause for concern during breastfeeding. The anticholinergic, ipratropium bromide is available orally and by i.v. injection as a treatment for bradycardia. In the latter form, the elimination half-life is 1.6 hours. There are just not enough data available on its transfer into the mother’s milk as for vernakalant. Recommendation. In Class IA antiarrhythmics, quinidine can be used while breastfeeding. Long-term use requires careful monitoring especially of liver enzymes. Lidocaine is the drug of choice in the Class 1B and mexiletine as a possible alternative. Flecainide is the Class 1C drug of choice. Within the Class II-antiarrhythmics (β-receptor blockers) propranolol and metoprolol are preferable (Section 4.6.1). Should a representative of Class III be absolutely necessary, sotalol is preferable to the iodide-containing amiodaron but the follow-up of the infant is necessary for signs of β-blockade. Verapamil and diltiazem, as representatives of Class IV, are well tolerated during breastfeeding. The same can be assumed for adenosine. If treatment with an antiarrhythmic, which is not recommended, has begun, weaning is not necessarily required. We suggest only changing the treatment and continuing breastfeeding.
4.6.11 Vasodilators and circulatory drugs The nitrates, isosorbide mononitrates, isosorbide dinitrate and nitroglycerin or glyceryl trinitrate and pentaerythritol tetranitrate are insufficiently
4 Lactation
of 3.5 mg/kg/day or 51.5% of the maternal weight-related dose. Up to 0.4 mg/L (therapeutic level 1.0–2.7 mg/L) was detected in the infant’s plasma. In later studies, lower concentrations of amiodarone plus DA (up to 5 mg/L) were reported in mother’s milk and infant’s plasma (up to 0.15 mg/L) (Moretti 1995, Plomp 1992). With sotalol, which has an M/P ratio of 3–5, an infant can receive 20–40% of the maternal weight-related dose, that is, up to 3 mg/kg daily (Hackett 1990, Wagner 1990). Because of a moderately long half-life, a high oral bioavailability, very low protein binding (0%) and 80 to 90% renal excretion, sotalol has a high risk for accumulation in infants. There is no experience on dronedarone available.
4.6 Cardiovascular drugs and diuretics
4.6.11 Vasodilators and circulatory drugs
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4.6.12 Diuretics
investigated during breastfeeding. Short half-lives and the temporary use argue against a toxic risk for the breastfed baby. Other cardiac/coronary therapeutics such as molsidomine, ranolazine, ivabradine and trapidil are insufficiently studied with respect to their tolerance during breastfeeding. Naftidrofuryl and its primary metabolite LS74 appear only in trace levels in milk. Within 72 hours, only about 300 μg of the total 3,500 mg administered, had been excreted into milk. Thereby, an infant would receive 0.1% of the maternal weight-related dose per kg and day (report of the manufacturer Lipha). There are no known toxic effects on the infant. Following a one-time oral administration of 400 mg of pentoxifylline, a maximum concentration of 1 mg/L milk, including the active metabolites, has been reported (Witter 1985). Based on this result, the infant would receive 0.5% of the weight-related adult dose per feed. No toxic effects have been described to date. There is only little information on ginkgo biloba and, therefore, it should be avoided during pregnancy and lactation if possible (Dugoua 2006). There is also no clinical experience available on a medication approved for improving the peripheral arterial circulation, alprostadil alfadex, a prostaglandin, that inhibits the thrombocyte aggregation and acts as a vasodilator or for pentosan polysulfate, a heparinoid with anticoagulatory and fibrinolytic properties. The substance passes into the milk of rats in negligible amounts. There are also no data for the drugs betahistine, cinnarizine and flunarizine used for dizziness. Flunarizine has a very long half-life of 18 days and therefore should not be prescribed during breastfeeding, as an accumulation in the child’s body cannot be eliminated. Recommendation. Short-term use of nitrates is justifiable for relevant indications. Using the other drugs mentioned here does not require an interruption of breastfeeding, but the therapy should be changed.
4.6.12 Diuretics With diuretic therapy, milk production can decrease, especially if there is already some lactational deficiency. Displacement of bilirubin from PPB in newborns has been discussed for furosemide and the thiazides. A risk for kernicterus is not considered a realistic possibility. Chlortalidone has a half-life of 44 hours or more. Long-term treatment with 50 mg/day leads to comparatively high concentrations in the milk with values to 0.86 mg/L. The very high maternal plasma concentrations lead to an M/P ratio of only about 0.06. The maximum dose an infant would receive is given as 0.13 mg/kg/day. This represents 15.5% of the maternal weight-related dose. No symptoms of intolerance have been observed in breastfed infants (Mulley 1982). Furosemide has an M/P ratio of 0.5–0.8 (Wilson 1980). There are no indications of any particular intolerance in breastfed infants. With long-term treatment using 50 mg of hydrochlorothiazide daily, 0.12 mg/L at most is found in the milk. The dose received by the infant would be 0.02 mg/kg daily – that is, 2.2% of the maternal weight-related dose (Miller 1982).
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Spironolactone is a potassium-saving diuretic. As soon as it is absorbed, it is changed into the active metabolite, canrenone, which is up to 98% bound to plasma protein. In animal studies, canrenone is carcinogenic at very high doses. No such carcinogenicity has been reported in human beings. The M/P ratio lies between 0.5 and 0.7. With ongoing treatment of 100 mg daily, a maximum milk concentration of 0.1 mg/L has been found. For the infant, this would mean a daily intake of 0.016 mg/kg, meaning only 1.2% of the maternal weight-related dose (Phelps 1977). There are insufficient data to make a judgment on amiloride, bendroflumethiazide, bumetanide, clopamide, eplerenone, indapamide, mefruside, piretanide, torasemide, triamterene and xipamide.
Recommendation. Diuretics should not be used primarily for treating hypertension during breastfeeding. However, when a diuretic is urgently needed, moderately dosed treatment with hydrochlorothiazide can be considered. Should furosemide be indicated, this can also be prescribed. Spironolactone should be reserved for special indications such as primary hyperaldosteronism, ascites, nephritic syndrome and the like. Chlortalidone is contraindicated because of its high relative dose. The other drugs mentioned should be avoided due to insufficient experience. Single doses, however, do not require limitation of breastfeeding, but the therapy should be changed.
4 Lactation
References
Ahn HK, Nava-Ocampo AA, Han JY et al. Exposure to amlodipine in the first trimester of pregnancy and during breastfeeding. Hypertens Pregnancy 2007; 26: 179–87. American Academy of Pediatrics, Committee on Drugs. The transfer of drugs and other chemicals into human breast milk. Pediatrics 2001; 108: 776–89. Anderson JE, Held N, Wright K. Raynauds’s phenomenon of the nipple: a treatable cause of painful breastfeeding. Pediatrics 2004; 113: 360–4. Barrett ME, Heller MM, Stone HF et al. Raynaud Phenomenon of the nipple in breastfeeding mothers. An underdiagnosed cause. JAMA Dermatol 2013; 149: 300–6. Bartels P, Hanff L, Mathot R et al. Nicardipine in pre-eclamptic patients: placental transfer and disposition in breast milk. BJOG 2006; 114: 230–3. Begg EJ, Robson RA, Gardiner SJ et al. Quinapril and its metabolite quinaprilat in human milk. Br J Clin Pharmacol 2001; 51: 478–81. Bennett PN (ed.). Drugs and Human Lactation. 2nd edn, Amsterdam, New York, Oxford: Elsevier 1996. Boutroy MJ, Bianchetti G, Dubruc C et al. To nurse when receiving acebutolol: is it dangerous for the neonate? Eur J Clin Pharmacol 1986; 30: 137–9. Bunjes R, Schaefer C, Holzinger D. Clonidine and breast-feeding. Clin Pharm 1993; 12: 178–9. Carcas AJ, Abad-Santos F, de Rosendo JM et al. Nimodipine transfer into human breast milk and cerebrospinal fluid. Ann Pharmacother 1996; 30: 148–50. Devlin RG, Fleiss PN. Captopril in human blood and breast milk. J Clin Pharmacol 1981; 21: 110–13. Dugoua JJ, Mills E, Perri D et al. Safety and efficacy of ginkgo (Ginkgo biloba) during pregnancy and lactation. Can J Clin Pharmacol 2006; 13: e277–84. Ehrenkranz RA, Ackermann BA, Hulse JD. Nifedipine transfer into human milk. J Pediatr 1989; 114: 478–80. Eyal S, Kim JD, Anderson GD et al. Atenolol pharmacokinetics and excretion in breast milk during the first 6 to 8 months postpartum. J Clin Pharmacol 2010; 50: 1301–9. Fidler J, Smith V, de Sweet M. Excretion of oxprenolol and timolol in breast milk. Br J Obstet Gynaecol 1983; 90: 961–5.
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References
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References
Goncalves PV, Cavalli RC, Cunha SP et al. Determination of pindolol enantiomers in amniotic fluid and breast milk by high-performance liquid chromatography: applications to pharmacokinetics in pregnant and lactating women. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 852: 640–5. Hackett LP, Wojnar-Horton RE, Dusci LJ et al. Excretion of sotalol in breast milk. Br J Clin Pharmacol 1990; 29: 277–8. Hall CM, McCormick KP. Amiodarone and breast feeding. Arch Dis Child Fetal Neonatal Ed 2003; 88: F255. Hartikainen-Sorri AL, Heikkinen JE, Koivisto M. Pharmacokinetics of clonidine during pregnancy and nursing. Obstet Gynecol 1987; 69: 598–600. Hill LM, Malkasian GD Jr. The use of quinidine sulfate throughout pregnancy. Obstet Gynecol 1979; 54: 366–8. Huttunen K, Gronhagen-Riska C, Fyhrquist F. Enalapril treatment of a nursing mother with slightly impaired renal function. Clin Nephrol 1989; 31: 278. Jarreau PH, Le Beller C, Guillonneau M et al. Excretion of nicardipine in human milk. Paediatr Perinat Drug Ther 2000; 4: 28–30. Jensen BP, Dalrymple JM, Begg EJ. Transfer of doxazosin into breast milk. J Hum Lact 2013; 29: 150–3. Kaiser G, Ackermann R, Dieterle W et al. Benazepril and benazeprilat in human plasma and breast milk. IV. World Conference on Clinical Pharmacology and Therapeutics, July 1989. Lamont RE, Elder MG. Transfer of hydralazine across the placenta and into breast milk. J Obstet Gynaecol 1986; 7: 47–8. Lebedevs TH, Wojnar-Horton RE, Yapp P et al. Excretion of lignocaine and its metabolite monoethylglycinexylidide in breast milk following its use in a dental procedure. A case report. J Clin Periodontol 1993; 20: 606–8. Lewis AM, Johnston A, Patel L et al. Mexiletine in human blood and breast milk. Postgrad Med J 1981; 57: 546–7. Liedholm H, Wahlin-Boll E, Hansson A et al. Transplacental passage and breast milk concentrations of hydralazine. Eur J Clin Pharmacol 1982; 21: 417–9. Lownes HE, Ives TJ. Mexiletine use in pregnancy and lactation. Am J Obstet Gynecol 1987; 157: 446–7. Madadi P, Koren G, Freeman DJ et al. Timolol concentrations in breast milk of a woman treated for glaucoma: calculation of neonatal exposure. J Glaucoma 2008; 17: 329–31. McQuinn RL, Pisani A, Wafa S et al. Flecainide excretion in human breast milk. Clin Pharmacol Ther 1990; 48: 262–7. Manninen AK, Juhakoski A. Nifedipine concentrations in maternal and umbilical serum, amniotic fluid, breast milk and urine of mothers and offspring. Int J Clin Pharmacol Res 1991; 11: 231–6. Miller ME, Cohn RD, Burghart PH. Hydrochlorothiazide disposition in a mother and her breast-fed infant. J Pediatr 1982; 101: 789–91. Moretti M: Presentation at the 8th International Conference of the Organisation of Teratogen Information Services (OTIS) in San Diego, 1995. Morselli PL, Boutroy MJ, Bianchetti G et al. Placental transfer and perinatal pharmacokinetics of betaxolol. Eur J Clin Pharmacol 1990; 38: 477–83. Mulley BA, Parr GD, Pau WK et al. Placental transfer of chlortalidone and its elimination in maternal milk. Eur J Clin Pharmacol 1982; 13: 129–31. Okada M, Inoue H, Nakamura Y et al. Excretion of diltiazem in human milk. N Engl J Med 1985; 312: 992–3. Page SM, McKenna DS. Vasospasm of the nipple presenting as painful lactation. Obstet Gynecol 2006; 108: 806–8. Penny WJ, Lewis MJ: Nifedipine is excreted in human milk. Eur J Clin Pharmacol 1989; 36: 427–8. Phelps DL, Karim A. Spironolactone: relationship between concentrations of dethioacetylated metabolite in human serum and milk. J Pharm Sci 1977; 66: 1203. Plomp TA, Vulsma T, de Vijlder JJM. Use of amiodarone during pregnancy. Eur J Obstet Gynecol Reprod Biol 1992; 43: 201–7. Redman CW, Kelly JG, Cooper WD. The excretion of enalapril and enalaprilat in human breast milk. Eur J Clin Pharmacol 1990; 38: 99. Rush JE, Snyder BA, Barrish A et al. Comment. Clin Nephrol 1991; 35: 234. Schaefer HG, Toublanc N, Weimann HJ. The pharmacokinetics of moxonidine. Rev Contemp Pharmacother 1998; 9: 481–90.
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Schimmel MS, Eidelman AJ, Wilschanski MA et al. Toxic effects of atenolol consumed during breastfeeding. J Pediatr 1989; 114: 476–8. Sioufi A, Hillion D, Lumbroso P et al. Oxprenolol placental transfer, plasma concentrations in newborns and passage into breast milk. Br J Clin Pharmacol 1984; 18: 453–6. Szucs KA, Axline SE, Rosenman MB. Maternal membranous glomerulonephritis and successful exclusive breastfeeding. Breastfeed Med 2010; 5: 123–6. Tonks AM. Nimodipine levels in breast milk. Aust N Z J Surg 1995; 65: 693–4. Valdivieso A, Valdes G, Spiro TE et al. Minoxidil in breast milk. Ann Int Med 1985; 102: 135. Wagner X, Jouglard J, Moulin M et al. Coadministration of flecainide acetate and soltalol during pregnancy: lack of teratogenic effects, passage across the placenta, and excretion into human breast milk. Am Heart J 1990; 119: 700–2. Wakaumi M, Tsuruoka S, Sakamoto K et al. Pilsicainide in breast milk from a mother: comparison with disopyramide and propafenone. Br J Clin Pharmacol 2005; 59: 120–2. White WB, Yeh SC, Krol GJ. Nitrendipine in human plasma and breast milk. Eur J Clin Pharmacol 1989; 36: 531–4. Wilson JT, Brown RD, Cherek DR et al. Drug excretion in human breast milk: principles, pharmacokinetics and projected consequences. Clin Pharmacokinet 1980; 5: 1–66. Witter FR, Smith RV. The excretion of pentoxyfylline and its metabolites into human breast milk. Am J Obstet Gynecol 1985; 151: 1094–7. Zeisler JA, Gaarder TD, de Mesquita SA. Lidocaine excretion in breast milk. Drug Intell Clin Pharmacol 1986; 20: 691–3.
4.6 Cardiovascular drugs and diuretics
References
4.6
4.6.1 β-Receptor blockers
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4.6.2 Hydralazine
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4.6.3 α-Methyldopa713 4.6.4 Calcium antagonists
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4.6.5 ACE inhibitors
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4.6.6 Angiotensin-II receptor-antagonists (sartan)
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4.6.7 Other antihypertensives
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4.6.8 Antihypotensives
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4.6.9 Digitalis
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4.6.10 Antiarrhythmics
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4.6.11 Vasodilators and circulatory drugs
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4.6.12 Diuretics
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There are cardiovascular drugs and diuretics that can be used during pregnancy and lactation. The decision to continue these medications during lactation depends on many factors. Some of these factors include the well-being of the mother, the blood/milk barrier, the pharmacological activity of the drug, and the consequences for the infant. The recommended drugs of choice are those which are best studied and do not show unwanted adverse effects for either the mother or the child. Drugs should be avoided if there is insufficient experience, like the sartans. If not, the safest cardiovascular or diuretic drugs should be used and the therapeutic choice should be changed to the preferred agents. This can be possible without interrupting breastfeeding.
4.6.1 β-Receptor blockers Circulatory symptoms and hypoglycemia have been cited in connection with the intake of β-receptor blockers via mother’s milk. However, by contrast to prenatal exposure, such effects are less likely during breastfeeding, due essentially to the relatively low concentrations of these drugs in infant blood. Bradycardia, hypotension and tachypnea have been seen in connection with acebutolol, which has a half-life of 3–4 hours and 26% plasma protein binding (PPB). Therefore, mathematically, the baby has received about 5–10% of the maternal dose per kg of bodyweight (Boutroy 1986). Drugs During Pregnancy and Lactation. http://dx.doi.org/10.1016/B978-0-12-408078-2.00031-7 Copyright © 2015 Elsevier B.V. All rights reserved.
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In particular, the active metabolite, diacetolol (half-life 8 to 13 hours), accumulates in the mother’s milk with an unusually high milk/plasma (M/P) ratio of up to 24.7. Atenolol has a half-life of 6 to 7 hours, a minimal PPB, and is hydrophilic. A recent study (Eyal 2010) examines the influence of atenolol on breastfed babies at 2 to 4 weeks of age (n = 32), 3 to 4 months (n = 22) and 6 to 8 months (n = 17). The maternal dose was between 25 and 200 mg/day. The M/P ratio was, on average, greater than 4.9, whereby the average relative infant dose was less than 15%. Infant doses of 34.8% (after 2 to 4 weeks) or 17.8% after 3 to 4 months were noted. Atenolol was not detected in the serum of any of the babies at 3 to 4 months. Further, whether maternal atenolol had a depressive effect on the heart rate in crying infants has been examined and no effect has been noted in this single study. However, Schimmel (1989) describes a breastfed infant who had toxic concentrations of atenolol acquired from her mother (dose 50 mg twice daily). This full-term infant at the age of 5 days had been transferred to the neonatal intensive care unit because of cyanosis and two episodes of bradycardia (80 beats/min). Forty-eight hours after discontinuing breastfeeding, the atenolol concentration in the baby’s serum was 2010 ng/mL and 24 hours later it was 140 ng/mL. The possible accumulation of atenolol in human milk and infant serum should be considered before prescribing, because safer β-blockers can be used during breastfeeding. Betaxolol has a half-life of 14 to 22 hours and a PPB of 50%. The relative dose transmitted by the milk reaches a maximum of 4.3% shortly after birth (Morselli 1990). Labetalol, which is widely used in the USA, works as an α- and β-receptor blocker, has a half-life of 6 to 8 hours, and a PPB of 50%. With long-term treatment with 300 to 1,200 mg/day, a mother’s maximum milk concentration of 0.7 mg/L and an M/P ratio between 0.2 and 1.5 are reported. Thus, an infant would receive, at most, 0.1 mg/kg daily. This represents 0.3% of the maternal dose per kg bodyweight (survey by Bennett 1996). There is substantial experience available for metoprolol (half-life 3 to 4 hours, PPB 12%). With long-term therapy with 100 and 200 mg, a maximum of 0.7 mg/L is detected in the milk. The M/P ratio is 3. The daily dose for the infant is, nevertheless, 0.1 mg/kg at most. This represents 3.2% of the maternal weight-related dose. About 10% of the northern European population is thought to metabolize metoprolol slowly. This could be the reason why a plasma concentration of 45 μg/L is measured in one (symptom-free) infant. Among other breastfed infants, it is 0.5–3 μg/L (survey in Bennett 1996). The therapeutic concentration for adults is given as 93–881 μg/L. With oxprenolol, up to 1.5% of the maternal weight-related dose is transmitted to the baby (Fidler 1983). Also, the low transfer of oxprenolol via the mother’s milk (half-life 1 to 2 hours, PPB 80%) is confirmed in another study (Sioufi 1984). Shortly after birth, 3.1 μg/L of S-enantiomers of pindolol and 1.9 μg/L of its R-enantiomers are found in the milk of three breastfeeding mothers who took 20 mg pindolol (half-life 3–4 hours, PPB 40–60%) daily. This represents 0.36% of a maternal weight-related dose (Goncalves 2007). The transfer of mepindolol can be 5% of the maternal weight-related dose (survey in Bennett 1996). Among β-blockers propranolol is the most frequent studied and used drug. Propranolol has a PPB of 90% and a half-life of 3 to 6 hours. The maximum transfer of 0.4% into the mother’s milk is quite low (survey in Bennett 1996).
713
With oral use of timolol, the portion of the maternal weight-related dose that is transmitted is 3.3% (Fidler 1983). Timolol is used primarily in eye drops for glaucoma treatment (Chapter 4.12.8). This leads to limited concentrations in the milk. Madadi (2008) calculated a relative dose of 0.024% if the mother puts drops in both eyes twice daily. There are insufficient data on bisoprolol (half-life 10–12 hours PPB 30%), carvedilol (half-life 6–10 hours PPB >98%), celiprolol half-life 5–6 hours, PPB 25%), nebivolol (half-life of 10–24 hours with slow metabolization, PPB of 98%), penbutolol (half-life of 20 hours PPB 80–98%), and talinolol to make a judgment. This also applies to esmolol (half-life 9 minutes, PPB 55%), which is indicated for i.v. injection with supraventricular tachycardias. Sotalol has a high risk for accumulation in infants (see also Section 4.6.10). Recommendation. During therapy with β-receptor blockers, breastfeeding is allowed. Metoprolol, oxprenolol, pindolol, propranolol and labetalol are preferred. Therapy with other β-blockers should be changed to one of the preferred agents if possible.
4 Lactation
4.6.3 α-Methyldopa
4.6.2 Hydralazine With 150 mg/day of hydralazine in the breast-feeding mother, a maximum of 130 μg/L is measured in the milk – which is 20 μg/kg per day or 1% of the therapeutic dose for an infant (Liedholm 1982). Following parenteral administration of 10–40 mg, an average of 47 μg/L, including the hydralazine metabolites, was measured in mother’s milk. The M/P ratio was 0.5. With this therapy, up to 108 μg/L of hydralazine was found in the plasma of breastfed infants (Lamont 1986). By comparison, the plasma concentration in an infant being treated with 2 mg/kg was given as 1,700 μg/L. No toxic symptoms have been observed while breastfeeding. Dihydralazine can be evaluated as if hydralazine.
4.6.3 α-Methyldopa With daily treatment with 250–2,000 mg of α-methyldopa, up to 1.14 mg/L is measured in the milk. The M/P ratio is 0.2– 0.5. For the infant, a daily dose of 0.17 mg/kg can be calculated, which represents 3.2% of the maternal dose per kg (survey in Bennett 1996). Only in one of three infants could the medication be detected in plasma (90 μg/L). For the mother, it is 4,250 μg/L. No toxic symptoms are observed in the infant. α-methyldopa can promote milk production as a result of increased prolactin secretion (Bennett 1996). Recommendation. Breastfeeding is permitted with α-methyldopa.
4.6 Cardiovascular drugs and diuretics
Recommendation. Breastfeeding is permitted with hydralazine.
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4.6.4 Calcium antagonists
4.6.4 Calcium antagonists There is no information on the transfer of amlodipine into the m other’s milk. Two case reports describe age-appropriate development with a maternal dose of 5 and 10 mg/day (Szucs 2010, Ahn 2007). In 11 mothers, only limited amounts of nicardipine are detected in mother’s milk under steady-state conditions (Jarreau 2000). For a few days postpartum, seven mothers have received nicardipine in an hourly dose of 1–6.5 mg for treating preeclampsia. Less than 0.3 μg/day nicardipine in the mother’s milk, or between 0.015 and 0.004% of a therapeutic infant dose, is calculated for these mother–child pairs (Bartels 2006). With nifedipine and its active pyridine metabolites, a maximum of 2–10 μg/kg/day is transmitted to the infant when the mother has taken 30–90 mg/day. That is less than 5% of a weight-related child’s dose (Ehrenkranz 1989). Average values of 2% and less are probably even more realistic (Manninen 1991, Penny 1989). Nifedipine is also used successfully to treat Raynaud phenomenon of the breast nipple. Anderson (2004) reports on 12 breastfeeding women complaining of pain in the nipple, which was finally diagnosed as Raynaud phenomenon. Those mothers, who chose nifedipine therapy, had rapid relief from the symptoms. Interestingly, eight of the 12 women and their children had previously been treated with antimycotics because of a suspected Candida albicans infection. A further case report describes good tolerance of nifedipine for vasospasms of the nipple (Page 2006). In a retrospective review of 22 cases of breastfeeding mothers diagnosed with Raynaud phenomenon of the nipple, previous treatment for Candida mastitis with oral or topical antifungals was ineffective in 20 cases (91%). Of the 12 patients who tolerated a trial with nifedipine, 10 (83%) report a decrease or resolved nipple pain during lactation. Thus, nifedipine and not the antifungal, appears to be an effective treatment of Raynaud phenomenon of the nipple (Barrett 2013). With 6 × 60 mg of nimodipine, maximum concentrations of 3.5 μg/L in the mother’s milk have been described (Tonks 1995). Mathematically, this would be only 0.01% of the weight-related maternal dose. A further case confirms this limited transfer of nimodipine (Carcas 1996). With nitrendipine, a maximum relative dose of 0.6%, including its metabolites, can reach the infant (White 1989). During therapy with the calcium antagonists mentioned, no intolerance in the breastfed infant has been described. By contrast felodipine, gallopamil, isradipine, lercanidipine, manidipine, nilvadipine and nisoldipine have been insufficiently studied. For verapamil and diltiazem, see Section 4.6.10. Both have been considered as appropriate during breastfeeding by the American Academy of Pediatrics (2001). The relative infant dose was 0.2% for verapamil and 0.9% for diltiazem and thus, the relative amount of these drugs transferred to the breastfed infant is quite small. In some cases no verapamil is detected in infant’s plasma. Recommendation. Breastfeeding is permitted during therapy with calcium antagonists. Depending on the indication, diltiazem, nicardipine, nifedipine, nitrendipine and verapamil are the calcium antagonists of choice while breastfeeding. Individual doses of other calcium antagonists do not require any limitation of breastfeeding, but the therapy should be changed.
4.6.6 Angiotensin-II receptor-antagonists (sartan)
715
4.6.5 ACE inhibitors
4 Lactation
In nine mother–baby pairs with a daily dosage of 20 mg of benazepril, a maximum of 0.003 μg, including the active metabolite, benazeprilate, is measured per liter of milk. For an exclusively breastfed baby, this represents 0.00014% of the maternal weight-related dose (Kaiser 1989). With 300 mg captopril daily, 4.7 μg/L milk is reported. The M/P ratio is 0.03. The infant receives up to 0.7 μg/kg/day. This represents about 0.014% of the maternal weight-related dose (Devlin 1981). Enalapril can be similarly evaluated. The relative dose for the infant is about 0.1% (Rush 1991, Redman 1990, Huttunen 1989). By contrast to the maternal serum, there is no lowering of the angiotensin-converting enzyme found in milk samples (Huttunen 1989). No undesirable effects on the infant have been described. Quinapril concentrations are reported for six mother-child pairs. The drug could not be detected in any of the milk samples. Based on the detection limit, the maximum estimated relative infant dose is 1.6% (Begg 2001). There are insufficient data to evaluate cilazapril, fosinopril, lisinopril, moexipril, perindopril, ramipril, spirapril, trandolapril and zofenopril. Following the use of ACE inhibitors in late pregnancy, kidney function disturbances as extreme as anuria requiring dialysis have been noted in the newborn (Chapter 2.8), but not during breastfeeding. For this reason, the American Academy of Pediatrics (2001) considers the use of those ACE inhibitors that have been tested extensively to be acceptable during breastfeeding.
4.6.6 Angiotensin-II receptor-antagonists (sartan) There is insufficient experience with the use of candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan during breastfeeding. Since very serious kidney function disturbances in the newborn can occur after using sartans in late pregnancy (Chapter 2.8.6) and there are no data on transfer into the mother’s milk, this group of drugs should be avoided during breastfeeding. This applies particularly for premature and young infants. Recommendation. Sartans should be avoided during breastfeeding. The accidental administration of a single dose does not require weaning. However, the therapy should be changed.
4.6 Cardiovascular drugs and diuretics
Recommendation. Benazepril, captopril, enalapril as well as quinapril may be prescribed during breastfeeding if β-blockers, calcium antagonists or methyldopa are not effective or indicated. As a safety measure, at least with premature infants and young infants under two months, attention should be paid to edema and the course of weight gain as indicators for disturbed kidney function. The accidental prescribing of another ACE inhibitor does not require any limitation of breastfeeding but changing the therapy is advisable.
716
4.6.7 Other antihypertensives
4.6.7 Other antihypertensives Peripherally acting antiadrenergic agents With prazosin, the relative dose is a maximum of 3% in one mother–child pair studied (manufacturer’s report). There is no published experience with bunazosin, doxazosin and terazosin. A single case report (Jensen 2013) provides the first quantitative data on the transfer of doxazosin into human milk. A 37-year-old woman receives two oral doses of 4 mg doxazosin 24 hours apart for urinary stones. Venous blood and milk are collected at different intervals after these two doses. The average and maximum milk concentrations are 2.9 and 4.2 μg/L. These values correspond to estimated relative infant doses of 0.06 and 0.09%, respectively. These very low results provide some reassurance for breastfeeding women who may benefit from doxazosin treatment. Urapidil is well absorbed orally, has a PPB of 80%, and an elimination half-life of 5 hours after oral administration and 3 hours after i.v. injection. Two newborns, breastfed while their mothers were taking urapidil medication, did not develop any side effects (author’s unpublished observations).
Centrally acting antiadrenergic agents In long-term clonidine therapy with 240–290 μg daily, clonidine is reported to levels of 2.8 μg/L in milk. For the infant, this means a maximum of 8% of the maternal, weight-related dose. With 0.3–0.6 μg/L in the infant’s plasma, a near-therapeutic concentration is reached (Hartikainen-Sorri 1987). In another study involving on-going therapy with 75 μg/day, a maximum of 7% was measured for the exclusively breastfed infant in whose plasma no active ingredient could be detected (<0.096 ng/mL). There was 0.6 μg/L reported in milk and 0.3 μg/L in maternal plasma (Bunjes 1993). No undesirable effects, such as a drop in blood pressure, were observed in the infants. Following daily administration of 200 μg moxonidine to five mothers during the first few postpartum days, a maximum of 2.7 μg/L was reported in milk. Mathematically, that is 12% of the maternal weight-related dose for an exclusively breastfed baby. The M/P ratio has been estimated to be 1–2 (cited in Schaefer 1998). There are no data on the passage of reserpine into the mother’s milk. The half-life of several days would suggest accumulation of reserpine in the infant.
Other antihypertensives Five percent of the weight-related dose of minoxidil passes into the milk. The exposed infant demonstrates no symptoms (Valdivieso 1985). Aliskiren is a renin inhibitor, which should be avoided during breastfeeding. Diazoxide is only approved for therapy for hypoglycemia. No information exists on the passage into the mother’s milk of this drug or for sodium-nitroprusside, which is used in intensive medicine. Phenoxybenzamine is indicated for treatment of pheochromocytoma. However, there is no experience on its use during breastfeeding.
4.6.10 Antiarrhythmics
717
Recommendation. The antihypertensives mentioned in this section should not be prescribed during breastfeeding. If treatment has begun, this does not require weaning; however, a change in therapy should be arranged.
4.6.8 Antihypotensives
Recommendation. Hypotension should be treated primarily without medication. Individual dosing of dihydroergotamine during breastfeeding is acceptable. The accidental intake of other drugs does not require an interruption of breastfeeding.
4 Lactation
Ergotamine derivatives such as dihydroergotamine can, as prolactin inhibitors, reduce milk production. There is insufficient experience on etilefrine, amezinium metilsulfate and midodrine.
4.6.9 Digitalis With ongoing therapy of 250–750 μg digoxin daily (half-life about 36 hours), concentrations between 0.4 and 1.9 μg/L have been reported in mother’s milk. With an M/P ratio of about 0.8, the dose transferred to the infant is, at most, 0.3 μg/kg/day. This is considerably lower than the usual maintenance dose in children of 10 μg/kg/day. No digoxin was measurable in the infant’s plasma when the mother had taken 250 μg/day and with 750 μg/day, 0.2 μg/L (therapeutic level 0.5–2 μg/L) was detected (survey in Bennett 1996). There are no studies on digitoxin and derivatives.
4.6.10 Antiarrhythmics Antiarrhythmics will be discussed below according to their classification (Chapter 2.8.15).
Class IA With daily administration of 1,800 mg quinidine (hydrochloride), a maximum of 9 mg/L is detected in milk. For exclusively breastfed infants, this is 1.3 mg/kg daily or about 4% of the maternal weight-related dose. The M/P ratio is 0.9 (Hill 1979). Despite possible accumulation due to the infant’s delayed metabolization, the American Academy of Pediatrics (2001) stated that there is no cause for concern about using quinidine during breastfeeding. There are no case reports on symptoms in breastfed children.
4.6 Cardiovascular drugs and diuretics
Recommendation. The use of digoxin is no cause for concern during breastfeeding.
718
4.6.10 Antiarrhythmics
With disopyramide, up to 15% of the maternal weight-related dose can apparently be taken in by the infant. Between 0.1 and 0.5 mg/L are reported in the plasma of some children. The therapeutic level for adults is above 3 mg/L. No symptoms are described in breastfed children (survey in Bennett 1996). After a single dose of 100 mg, the relative dose is 3% of the maternal weight-related dose. There is no experience available for ajmaline and prajmalium bitartrate during breastfeeding.
Class IB Following i.v. administration of about 1,000 mg lidocaine and the resulting therapeutic plasma concentration of 5 μg/mL in the mother, a transfer of 1.8% of the weight-related dose has been observed (Zeisler 1986). A similar proportion is calculated following administration as a local anesthetic (Lebedevs 1993). With long-term therapy using 600 mg mexiletine daily, a milk concentration to 0.96 mg/L has been reported for one mother. This represents 0.14 mg/kg/day or 1.4% of the maternal weight-related dose for the infant, whose plasma mexiletine was not detectable (Lewis 1981). For another infant, already prenatally exposed to mexiletine, growth disturbances and, 5 months after weaning, a questionable seizure has been reported. The development that followed has been reported as unremarkable (Lownes 1987). A connection with the exposure via the mother’s milk was unlikely.
Class IC Flecainide is reported in milk from several mothers in long-term treatment with 2 × 100 mg daily at concentrations of 0.27–1.53 μg/mL (McQuinn 1990, Wagner 1990). Based on the highest value, an infant could get approximately 7% of the maternal weight-related dose. The American Academy of Pediatrics (2001) does not object to the use of this drug during breastfeeding as it is also used therapeutically in newborns. Propafenone has a PPB of 83%. After a single dose of 150 mg of propafenone, an M/P ratio of <1 and a weight-related dose of 0.1% were calculated (Wakaumi 2005).
Class II For β-receptor-blockers, see Section 4.6.1.
Class III Amiodarone has a very long half-life of 2–4 weeks. It consists of just about 40% iodide (see Chapter 4.11.6). In the mother’s milk of one woman who had taken amiodarone at the end of her pregnancy for a number of reasons including fetal indications, only after 25 days was the active ingredient no longer detectable. Her breastfed infant had no side effects and the thyroid function was also normal (Hall 2003). With long-term therapy using 400 mg/day, a maximum of 16.4 mg/L of milk plus 6.5 mg/L of the metabolite, desethylamiodarone (DA), was reported (survey in Bennett, 1996). Based on this, the total amount of active substance, including the metabolite, which an infant could receive, would be a maximum
719
Class IV With on-going treatment using 240–360 mg verapamil daily, up to 0.3 mg/L is reported in milk. The M/P ratio lies between 0.2 and 0.9. The daily amount taken in by the infant is given as a maximum of 0.05 mg/ kg. This represents about 1% of the maternal dose per kg of bodyweight. In the plasma of one of the breastfed infants, 2.1 μg/L is detected. No undesirable side effects have been described (survey in Bennett 1996). For diltiazem, the results from only one patient are similar to those of verapamil including the drug measurement (Okada 1985). There is no experience on gallopamil. Adenosine cannot be classified in any of the classic antiarrhythmic groups. Because of its extremely short half-life and the very brief time for which it is used, it should not be considered a cause for concern during breastfeeding. The anticholinergic, ipratropium bromide is available orally and by i.v. injection as a treatment for bradycardia. In the latter form, the elimination half-life is 1.6 hours. There are just not enough data available on its transfer into the mother’s milk as for vernakalant. Recommendation. In Class IA antiarrhythmics, quinidine can be used while breastfeeding. Long-term use requires careful monitoring especially of liver enzymes. Lidocaine is the drug of choice in the Class 1B and mexiletine as a possible alternative. Flecainide is the Class 1C drug of choice. Within the Class II-antiarrhythmics (β-receptor blockers) propranolol and metoprolol are preferable (Section 4.6.1). Should a representative of Class III be absolutely necessary, sotalol is preferable to the iodide-containing amiodaron but the follow-up of the infant is necessary for signs of β-blockade. Verapamil and diltiazem, as representatives of Class IV, are well tolerated during breastfeeding. The same can be assumed for adenosine. If treatment with an antiarrhythmic, which is not recommended, has begun, weaning is not necessarily required. We suggest only changing the treatment and continuing breastfeeding.
4.6.11 Vasodilators and circulatory drugs The nitrates, isosorbide mononitrates, isosorbide dinitrate and nitroglycerin or glyceryl trinitrate and pentaerythritol tetranitrate are insufficiently
4 Lactation
of 3.5 mg/kg/day or 51.5% of the maternal weight-related dose. Up to 0.4 mg/L (therapeutic level 1.0–2.7 mg/L) was detected in the infant’s plasma. In later studies, lower concentrations of amiodarone plus DA (up to 5 mg/L) were reported in mother’s milk and infant’s plasma (up to 0.15 mg/L) (Moretti 1995, Plomp 1992). With sotalol, which has an M/P ratio of 3–5, an infant can receive 20–40% of the maternal weight-related dose, that is, up to 3 mg/kg daily (Hackett 1990, Wagner 1990). Because of a moderately long half-life, a high oral bioavailability, very low protein binding (0%) and 80 to 90% renal excretion, sotalol has a high risk for accumulation in infants. There is no experience on dronedarone available.
4.6 Cardiovascular drugs and diuretics
4.6.11 Vasodilators and circulatory drugs
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4.6.12 Diuretics
investigated during breastfeeding. Short half-lives and the temporary use argue against a toxic risk for the breastfed baby. Other cardiac/coronary therapeutics such as molsidomine, ranolazine, ivabradine and trapidil are insufficiently studied with respect to their tolerance during breastfeeding. Naftidrofuryl and its primary metabolite LS74 appear only in trace levels in milk. Within 72 hours, only about 300 μg of the total 3,500 mg administered, had been excreted into milk. Thereby, an infant would receive 0.1% of the maternal weight-related dose per kg and day (report of the manufacturer Lipha). There are no known toxic effects on the infant. Following a one-time oral administration of 400 mg of pentoxifylline, a maximum concentration of 1 mg/L milk, including the active metabolites, has been reported (Witter 1985). Based on this result, the infant would receive 0.5% of the weight-related adult dose per feed. No toxic effects have been described to date. There is only little information on ginkgo biloba and, therefore, it should be avoided during pregnancy and lactation if possible (Dugoua 2006). There is also no clinical experience available on a medication approved for improving the peripheral arterial circulation, alprostadil alfadex, a prostaglandin, that inhibits the thrombocyte aggregation and acts as a vasodilator or for pentosan polysulfate, a heparinoid with anticoagulatory and fibrinolytic properties. The substance passes into the milk of rats in negligible amounts. There are also no data for the drugs betahistine, cinnarizine and flunarizine used for dizziness. Flunarizine has a very long half-life of 18 days and therefore should not be prescribed during breastfeeding, as an accumulation in the child’s body cannot be eliminated. Recommendation. Short-term use of nitrates is justifiable for relevant indications. Using the other drugs mentioned here does not require an interruption of breastfeeding, but the therapy should be changed.
4.6.12 Diuretics With diuretic therapy, milk production can decrease, especially if there is already some lactational deficiency. Displacement of bilirubin from PPB in newborns has been discussed for furosemide and the thiazides. A risk for kernicterus is not considered a realistic possibility. Chlortalidone has a half-life of 44 hours or more. Long-term treatment with 50 mg/day leads to comparatively high concentrations in the milk with values to 0.86 mg/L. The very high maternal plasma concentrations lead to an M/P ratio of only about 0.06. The maximum dose an infant would receive is given as 0.13 mg/kg/day. This represents 15.5% of the maternal weight-related dose. No symptoms of intolerance have been observed in breastfed infants (Mulley 1982). Furosemide has an M/P ratio of 0.5–0.8 (Wilson 1980). There are no indications of any particular intolerance in breastfed infants. With long-term treatment using 50 mg of hydrochlorothiazide daily, 0.12 mg/L at most is found in the milk. The dose received by the infant would be 0.02 mg/kg daily – that is, 2.2% of the maternal weight-related dose (Miller 1982).
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Spironolactone is a potassium-saving diuretic. As soon as it is absorbed, it is changed into the active metabolite, canrenone, which is up to 98% bound to plasma protein. In animal studies, canrenone is carcinogenic at very high doses. No such carcinogenicity has been reported in human beings. The M/P ratio lies between 0.5 and 0.7. With ongoing treatment of 100 mg daily, a maximum milk concentration of 0.1 mg/L has been found. For the infant, this would mean a daily intake of 0.016 mg/kg, meaning only 1.2% of the maternal weight-related dose (Phelps 1977). There are insufficient data to make a judgment on amiloride, bendroflumethiazide, bumetanide, clopamide, eplerenone, indapamide, mefruside, piretanide, torasemide, triamterene and xipamide.
Recommendation. Diuretics should not be used primarily for treating hypertension during breastfeeding. However, when a diuretic is urgently needed, moderately dosed treatment with hydrochlorothiazide can be considered. Should furosemide be indicated, this can also be prescribed. Spironolactone should be reserved for special indications such as primary hyperaldosteronism, ascites, nephritic syndrome and the like. Chlortalidone is contraindicated because of its high relative dose. The other drugs mentioned should be avoided due to insufficient experience. Single doses, however, do not require limitation of breastfeeding, but the therapy should be changed.
4 Lactation
References
Ahn HK, Nava-Ocampo AA, Han JY et al. Exposure to amlodipine in the first trimester of pregnancy and during breastfeeding. Hypertens Pregnancy 2007; 26: 179–87. American Academy of Pediatrics, Committee on Drugs. The transfer of drugs and other chemicals into human breast milk. Pediatrics 2001; 108: 776–89. Anderson JE, Held N, Wright K. Raynauds’s phenomenon of the nipple: a treatable cause of painful breastfeeding. Pediatrics 2004; 113: 360–4. Barrett ME, Heller MM, Stone HF et al. Raynaud Phenomenon of the nipple in breastfeeding mothers. An underdiagnosed cause. JAMA Dermatol 2013; 149: 300–6. Bartels P, Hanff L, Mathot R et al. Nicardipine in pre-eclamptic patients: placental transfer and disposition in breast milk. BJOG 2006; 114: 230–3. Begg EJ, Robson RA, Gardiner SJ et al. Quinapril and its metabolite quinaprilat in human milk. Br J Clin Pharmacol 2001; 51: 478–81. Bennett PN (ed.). Drugs and Human Lactation. 2nd edn, Amsterdam, New York, Oxford: Elsevier 1996. Boutroy MJ, Bianchetti G, Dubruc C et al. To nurse when receiving acebutolol: is it dangerous for the neonate? Eur J Clin Pharmacol 1986; 30: 137–9. Bunjes R, Schaefer C, Holzinger D. Clonidine and breast-feeding. Clin Pharm 1993; 12: 178–9. Carcas AJ, Abad-Santos F, de Rosendo JM et al. Nimodipine transfer into human breast milk and cerebrospinal fluid. Ann Pharmacother 1996; 30: 148–50. Devlin RG, Fleiss PN. Captopril in human blood and breast milk. J Clin Pharmacol 1981; 21: 110–13. Dugoua JJ, Mills E, Perri D et al. Safety and efficacy of ginkgo (Ginkgo biloba) during pregnancy and lactation. Can J Clin Pharmacol 2006; 13: e277–84. Ehrenkranz RA, Ackermann BA, Hulse JD. Nifedipine transfer into human milk. J Pediatr 1989; 114: 478–80. Eyal S, Kim JD, Anderson GD et al. Atenolol pharmacokinetics and excretion in breast milk during the first 6 to 8 months postpartum. J Clin Pharmacol 2010; 50: 1301–9. Fidler J, Smith V, de Sweet M. Excretion of oxprenolol and timolol in breast milk. Br J Obstet Gynaecol 1983; 90: 961–5.
4.6 Cardiovascular drugs and diuretics
References
722
References
Goncalves PV, Cavalli RC, Cunha SP et al. Determination of pindolol enantiomers in amniotic fluid and breast milk by high-performance liquid chromatography: applications to pharmacokinetics in pregnant and lactating women. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 852: 640–5. Hackett LP, Wojnar-Horton RE, Dusci LJ et al. Excretion of sotalol in breast milk. Br J Clin Pharmacol 1990; 29: 277–8. Hall CM, McCormick KP. Amiodarone and breast feeding. Arch Dis Child Fetal Neonatal Ed 2003; 88: F255. Hartikainen-Sorri AL, Heikkinen JE, Koivisto M. Pharmacokinetics of clonidine during pregnancy and nursing. Obstet Gynecol 1987; 69: 598–600. Hill LM, Malkasian GD Jr. The use of quinidine sulfate throughout pregnancy. Obstet Gynecol 1979; 54: 366–8. Huttunen K, Gronhagen-Riska C, Fyhrquist F. Enalapril treatment of a nursing mother with slightly impaired renal function. Clin Nephrol 1989; 31: 278. Jarreau PH, Le Beller C, Guillonneau M et al. Excretion of nicardipine in human milk. Paediatr Perinat Drug Ther 2000; 4: 28–30. Jensen BP, Dalrymple JM, Begg EJ. Transfer of doxazosin into breast milk. J Hum Lact 2013; 29: 150–3. Kaiser G, Ackermann R, Dieterle W et al. Benazepril and benazeprilat in human plasma and breast milk. IV. World Conference on Clinical Pharmacology and Therapeutics, July 1989. Lamont RE, Elder MG. Transfer of hydralazine across the placenta and into breast milk. J Obstet Gynaecol 1986; 7: 47–8. Lebedevs TH, Wojnar-Horton RE, Yapp P et al. Excretion of lignocaine and its metabolite monoethylglycinexylidide in breast milk following its use in a dental procedure. A case report. J Clin Periodontol 1993; 20: 606–8. Lewis AM, Johnston A, Patel L et al. Mexiletine in human blood and breast milk. Postgrad Med J 1981; 57: 546–7. Liedholm H, Wahlin-Boll E, Hansson A et al. Transplacental passage and breast milk concentrations of hydralazine. Eur J Clin Pharmacol 1982; 21: 417–9. Lownes HE, Ives TJ. Mexiletine use in pregnancy and lactation. Am J Obstet Gynecol 1987; 157: 446–7. Madadi P, Koren G, Freeman DJ et al. Timolol concentrations in breast milk of a woman treated for glaucoma: calculation of neonatal exposure. J Glaucoma 2008; 17: 329–31. McQuinn RL, Pisani A, Wafa S et al. Flecainide excretion in human breast milk. Clin Pharmacol Ther 1990; 48: 262–7. Manninen AK, Juhakoski A. Nifedipine concentrations in maternal and umbilical serum, amniotic fluid, breast milk and urine of mothers and offspring. Int J Clin Pharmacol Res 1991; 11: 231–6. Miller ME, Cohn RD, Burghart PH. Hydrochlorothiazide disposition in a mother and her breast-fed infant. J Pediatr 1982; 101: 789–91. Moretti M: Presentation at the 8th International Conference of the Organisation of Teratogen Information Services (OTIS) in San Diego, 1995. Morselli PL, Boutroy MJ, Bianchetti G et al. Placental transfer and perinatal pharmacokinetics of betaxolol. Eur J Clin Pharmacol 1990; 38: 477–83. Mulley BA, Parr GD, Pau WK et al. Placental transfer of chlortalidone and its elimination in maternal milk. Eur J Clin Pharmacol 1982; 13: 129–31. Okada M, Inoue H, Nakamura Y et al. Excretion of diltiazem in human milk. N Engl J Med 1985; 312: 992–3. Page SM, McKenna DS. Vasospasm of the nipple presenting as painful lactation. Obstet Gynecol 2006; 108: 806–8. Penny WJ, Lewis MJ: Nifedipine is excreted in human milk. Eur J Clin Pharmacol 1989; 36: 427–8. Phelps DL, Karim A. Spironolactone: relationship between concentrations of dethioacetylated metabolite in human serum and milk. J Pharm Sci 1977; 66: 1203. Plomp TA, Vulsma T, de Vijlder JJM. Use of amiodarone during pregnancy. Eur J Obstet Gynecol Reprod Biol 1992; 43: 201–7. Redman CW, Kelly JG, Cooper WD. The excretion of enalapril and enalaprilat in human breast milk. Eur J Clin Pharmacol 1990; 38: 99. Rush JE, Snyder BA, Barrish A et al. Comment. Clin Nephrol 1991; 35: 234. Schaefer HG, Toublanc N, Weimann HJ. The pharmacokinetics of moxonidine. Rev Contemp Pharmacother 1998; 9: 481–90.
723
4 Lactation
Schimmel MS, Eidelman AJ, Wilschanski MA et al. Toxic effects of atenolol consumed during breastfeeding. J Pediatr 1989; 114: 476–8. Sioufi A, Hillion D, Lumbroso P et al. Oxprenolol placental transfer, plasma concentrations in newborns and passage into breast milk. Br J Clin Pharmacol 1984; 18: 453–6. Szucs KA, Axline SE, Rosenman MB. Maternal membranous glomerulonephritis and successful exclusive breastfeeding. Breastfeed Med 2010; 5: 123–6. Tonks AM. Nimodipine levels in breast milk. Aust N Z J Surg 1995; 65: 693–4. Valdivieso A, Valdes G, Spiro TE et al. Minoxidil in breast milk. Ann Int Med 1985; 102: 135. Wagner X, Jouglard J, Moulin M et al. Coadministration of flecainide acetate and soltalol during pregnancy: lack of teratogenic effects, passage across the placenta, and excretion into human breast milk. Am Heart J 1990; 119: 700–2. Wakaumi M, Tsuruoka S, Sakamoto K et al. Pilsicainide in breast milk from a mother: comparison with disopyramide and propafenone. Br J Clin Pharmacol 2005; 59: 120–2. White WB, Yeh SC, Krol GJ. Nitrendipine in human plasma and breast milk. Eur J Clin Pharmacol 1989; 36: 531–4. Wilson JT, Brown RD, Cherek DR et al. Drug excretion in human breast milk: principles, pharmacokinetics and projected consequences. Clin Pharmacokinet 1980; 5: 1–66. Witter FR, Smith RV. The excretion of pentoxyfylline and its metabolites into human breast milk. Am J Obstet Gynecol 1985; 151: 1094–7. Zeisler JA, Gaarder TD, de Mesquita SA. Lidocaine excretion in breast milk. Drug Intell Clin Pharmacol 1986; 20: 691–3.
4.6 Cardiovascular drugs and diuretics
References