Handbook of clinical drug data - part 9 pps

ANTINEOPLASTICS AND IMMUNOSUPPRESSANTS
CYTOKINES
Interferons
An IV dose of 30 million units of interferon alfa-N3 resulted in only a slight increase over physio-
logic milk levels in one woman.
48
DNA INTERCALATING DRUGS
Doxorubicin
Doxorubicin and its primary active metabolite, doxorubicinol, appear in milk, with their highest
milk concentrations occurring 24 hr after a dose.
Mitoxantrone
Measurable levels of mitoxantrone occurred in milk for at least 28 days after 6 mg/kg was given
daily for 3 days.
49
MITOTIC INHIBITORS
Etoposide
Etoposide is undetectable in milk 24 hr after a dose.
49
MISCELLANEOUS ANTINEOPLASTICS
Hydroxyurea
Only small amounts of hydroxyurea are found in milk, but breastfeeding is not advised.
IMMUNOSUPPRESSANTS
Three infants reportedly were breastfed safely during maternal azathioprine use (75–100 mg/day)
after renal transplantation. Low concentrations of the azathioprine metabolite, mercaptopurine,
were found in milk. Breastfeeding can be undertaken with close infant monitoring for infection or
other signs of immunosuppression during azathioprine therapy, although there is concern over po-
tential carcinogenicity.
1,12
Maternal cyclosporine therapy results in the infant receiving ≤2% of
the mother’s mg/kg dosage.
50,51

At least 9 infants have been breastfed safely for 4–12 months
during maternal therapy with cyclosporine, prednisone, and azathioprine. Infant serum cyclo-
sporine levels were undetectable (<30 µg/L), renal function was unaffected, and the infants
grew normally.
50,51
Tacrolimus colostrum concentrations are about 50% of maternal serum con-
centrations.
52
The implications of these low concentrations for the infant are not known.
CARDIOVASCULAR DRUGS
ANTIARRHYTHMIC DRUGS
Some antiarrhythmics reach near-therapeutic serum concentrations in breastfed infants. Amio-
darone is excreted in amounts that might pose a hazard to the infant and it should not be used
during nursing.
1,53
Data on disopyramide indicate that infants can receive relatively large
amounts of the drug and its active metabolite, with serum concentrations near the therapeutic
range. Disopyramide can be used cautiously while breastfeeding older infants when other alterna-
tives are unacceptable. Observe the infant for anticholinergic symptoms, and monitor infant serum
concentrations if there is a concern. The anticholinergic activity of disopyramide might suppress
lactation. (See Anticholinergics.) Sparse data from one patient indicate that tocainide should be
used with caution during nursing. Because of its low oral bioavailability, maternal bretylium is
unlikely to harm nursing infants; 400 mg q 8 hr was taken orally by one mother while nursing, with
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no apparent effects on her infant. Infants receive trivial doses of digoxin via breastmilk. Amounts of
flecainide in milk are small and unlikely to affect the infant. Lidocaine concentrations in milk dur-
ing continuous IV infusion and epidural administration and in high doses as a local anesthetic are
low and poorly absorbed by the infant, so it poses no hazard to the infant
54–56
Amounts of mexile-
tine in milk are too low to be detected in the serum of breastfed infants. Procainamide and its ac-
tive metabolite, N-acetylprocainamide, are found in milk in fairly small concentrations; pro-
cainamide may be used with caution in nursing mothers. Propafenone milk concentrations are very
low, but no clinical experience has been reported.
57
Quinidine excretion seems inconsequential.
ANTIHYPERTENSIVE DRUGS
Certain antihypertensives are less desirable than others during nursing. Breastfed infants have
serum clonidine concentrations approaching those of the mother.
1,58
Clonidine and guanfacine
also can decrease prolactin secretion. These drugs must be used with caution during breastfeed-
ing and avoided if possible. Avoid reserpine because it can cause nasal stuffiness and increased
tracheobronchial secretions in the infant. The angiotensin-converting enzyme (ACE) inhibitors,
benazepril, captopril, and enalapril, are found in small amounts and no adverse effects have
occurred in breastfed infants.
1,59
In addition, milk ACE activity was in the normal range after a
dose of enalapril. These ACE inhibitors are good choices during lactation; others have not been
studied. Limited data indicate that low-dose, short-term use of hydralazine (ie, a few days post-

partum) is safe. There is limited information on oral minoxidil in milk, but amounts are small.
However, use minoxidil with caution, particularly when therapy involves large dosages and long-
term use. Several studies indicate that methyldopa is excreted in unimportant amounts.
β-ADRENERGIC BLOCKING DRUGS
The excretion of ␤-blockers into breastmilk has been studied extensively. The infant’s dosage dif-
fers greatly among the different compounds, allowing a range of choices. The most water-soluble
drugs reach the infant in the greatest amounts because of low serum protein binding. Water-
soluble agents also have the longest half-lives, are renally eliminated, and therefore are more
likely to accumulate in infants. Maternal therapy with atenolol and acebutolol have resulted in
adverse effects (eg, bradycardia, hypotension, tachypnea, and cyanosis) in breastfed infants.
These two drugs, as well as betaxolol, nadolol, sotalol, and timolol, should be avoided in moth-
ers of newborn infants or when high dosage is required. Oxprenolol and mepindolol excretions
are intermediate and should be avoided in neonates. Propranolol, metoprolol, and labetalol are
excreted in low enough quantities to allow nursing even in the neonatal period.
CALCIUM-CHANNEL BLOCKING DRUGS
Case reports indicate that only small amounts of diltiazem, nifedipine, nimodipine, and ni-
trendipine are excreted into milk.
1,60
Several case reports indicate that the amounts of verapamil
and norverapamil in milk and infant serum are low. Verapamil appears to be safe during nursing.
CENTRAL NERVOUS SYSTEM DRUGS
ANTICONVULSANTS
Breastfed infants can achieve serum anticonvulsant concentrations that produce pharmacologic
effects. Mild drowsiness, irritability, and feeding difficulties are common in the infants of mothers
taking sedating anticonvulsants, especially during the early neonatal period.
1,61
Breastfeeding can
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mitigate withdrawal symptoms in infants whose mothers took sedating anticonvulsants during preg-
nancy, and withdrawal symptoms have been observed after abrupt weaning. Serum concentration
monitoring in breastfed infants might be indicated, particularly in infants who are excessively drowsy,
feed poorly, or gain weight inadequately. Long-term effects of exposure are not well studied. Infants
of mothers taking anticonvulsants might have more difficulty nursing and breastfed for a shorter du-
ration, possibly because of negative or equivocal safety advice given by health professionals.
62–64
No data are available for some of the newer anticonvulsants such as felbamate, gabapentin,
levetiracetam, oxcarbazepine, tiagabine, and topiramate. Breastfeeding is not recommended
during felbamate use.
65–67
Carbamazepine
Carbamazepine and its major active metabolite are excreted into milk and can be detected in
nursing infants’ serum; concentrations are usually low but near the therapeutic range in some in-
fants. Two cases of hepatic dysfunction in breastfed neonates have been reported. Poor feeding
also has been reported. Carbamazepine can be used during lactation, but close observation of the
infant for jaundice and other signs of possible adverse idiosyncratic effects is advisable.
67
Mea-
surement of infant serum concentration might be indicated if symptoms occur.
Clonazepam
Serum concentrations of clonazepam were low in two nursing infants, and no effects were noted.
1
In another infant, breastfeeding increased serum concentrations over those present at birth.
68

Clonazepam has been detected in the serum of a breastfed neonate whose mother was receiving
the drug before and after delivery but was undetectable in 4 others.
69
Observation of the infant for
drowsiness and monitoring of the infant’s serum concentration might be indicated.
Ethosuximide
Breastfed infants can attain ethosuximide serum concentrations near the therapeutic range, and
some infants might become drowsy or fussy. Breastfeed with caution and keep the mother’s
serum concentrations as low as possible while remaining in the therapeutic range. Infant serum
drug concentration monitoring is indicated.
Lamotrigine
Lamotrigine concentrations in infants breastfed during maternal lamotrigine therapy have ranged
from 22 to 85% of the maternal serum concentration, but no adverse effects have been reported
with these relatively high levels.
67,70,71
Infants can be allowed to nurse, but close monitoring for
side effects such as rash (which can be life-threatening), drowsiness, or poor sucking is essential.
Obtain an infant serum concentration if adverse effects are suspected and discontinue breastfeed-
ing if rash occurs.
Phenobarbital
The effect of phenobarbital is unpredictable: drowsiness leading to feeding difficulties can occur;
breastfeeding can prevent withdrawal symptoms in infants whose mothers took phenobarbital dur-
ing pregnancy; and withdrawal symptoms have been observed after abrupt weaning. Phenobarbi-
tal can be used in low to moderate dosages but monitor infant behavior, weight gain, and, if there
is concern, serum concentrations. Sometimes breastfeeding must be discontinued because of ex-
cessive drowsiness and poor weight gain.
Phenytoin
Only small amounts of phenytoin are excreted into milk. Rarely, infants might experience idiosyn-
cratic reactions such as cyanosis and methemoglobinemia, but infants generally tolerate phenytoin
in milk well.

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Primidone
Primidone and its metabolites (phenylethylmalonamide, phenobarbital, and parahydroxypheno-
barbital) appear in milk in large amounts. Considerations are the same as those for phenobarbital.
(See Phenobarbital.)
Valproic Acid
Milk concentrations of valproate are low, and usually no effects occur in infants. One case of prob-
able infant thrombocytopenic purpura from valproate in milk has been reported.
72
Observe infants
for rare idiosyncratic effects such as thrombocytopenia and hepatotoxicity.
67
Vigabatrin
Limited data from two mothers indicate that a breastfed infant would receive <4% of the mother’s
mg/kg dose of vigabatrin.
73
Zonisamide
Peak milk concentrations were 9–10 mg/L with a maternal dose of 300 mg/day in one mother. No
data are available on effects in breastfed infants.
74

ANTIDEPRESSANTS
Heterocyclic Antidepressants
Most of these drugs have not been well studied during lactation. Some investigators recommend
against the use of antidepressants because of theoretical (but undemonstrated) long-term effects on
infants’ neurologic development; others consider tricyclic antidepressants to be acceptable. Fol-
low-up for 1–3 yr in a small group of breastfed infants indicates no adverse effects on growth and
development.
75
Another study found that breastfed infants of mothers taking dothiepin had cognitive
development equal to controls at 3 yr of age.
76
Sedating TCAs and those with active metabolites (eg,
amitriptyline, doxepin, and imipramine) might be less desirable than other TCAs. Respiratory de-
pression was reported in one breastfed infant whose mother was taking doxepin 25 mg tid, but an
infant whose mother was taking 150 mg at night had no problems. Another report found poor suck-
ing and swallowing, muscle hypotonia, and vomiting in a 9-day-old whose mother was taking dox-
epin 35 mg/day.
77
Maternal dosages of amitriptyline up to 150 mg/day, clomipramine 150 mg/day,
desipramine 300 mg/day, imipramine 200 mg/day, or nortriptyline 125 mg/day have not caused
observable effects in the infants studied. In several infants, nortriptyline serum concentrations were
undetectable with maternal nortriptyline dosages of up to 125 mg/day or amitriptyline 175
mg/day.
69,78,79
One nortriptyline metabolite has been detected in low levels in the serum of breastfed
infants without adverse consequences.
78,80
Nortriptyline (and probably the other secondary amine,
desipramine) is the TCA of choice during breastfeeding. Doxepin should be avoided. Giving the drug
as a single dose at bedtime and skipping nighttime feeding(s) can further minimize infant exposure. A

dose of 250 mg/day of amoxapine or 100–150 mg/day of maprotiline produces low drug concen-
trations in milk, but effects of these drugs on infants have not been well studied.
Selective Serotonin Reuptake Inhibitors
Although the average daily dosages of fluoxetine and norfluoxetine in milk are about 7% of the
mother’s weight-adjusted dosages, some mothers excrete as much as 12% of a dosage and the
drugs’ half-lives are very long.
81
One case of colic (increased crying, decreased sleep, watery
stools, and vomiting) and unexplained high serum concentrations were reported in a breastfed
6-week-old infant. The infant improved after switching to formula and colic reappeared with
rechallenge. Other case reports include seizure-like activity, irritability, hyperglycemia and
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glycosuria, and withdrawal symptoms.
81
Norfluoxetine is often detectable in infants’ serum.
69,81,82
Fluoxetine in breastmilk had no effect on neurologic development in 4 infants,
83
but a larger retro-
spective study found that fluoxetine can reduce the growth rate of infants who are exposed via
breastmilk from birth.
84
Fluoxetine should be avoided during breastfeeding if possible, although

older infants might be less susceptible to fluoxetine’s effects than newborns. Monitor infants care-
fully for behavioral symptoms and adequate weight gain. Citalopram reaches the infant in
dosages of about 5% of the mother’s mg/kg dosage.
85–87
The manufacturer states that drowsi-
ness and weight loss in breastfed infants have occurred, and uneasy sleep occurred in the infant
of a mother taking citalopram.
88
Citalopram is not a good choice while breastfeeding a newborn.
Infants receive a dose <1% of the maternal fluvoxamine dose. Several infants grew and devel-
oped normally with maternal fluvoxamine use.
89,90
With paroxetine, infants receive about 1.5% of
the maternal dosage. Of 23 infants studied, only 1 had detectable serum concentrations of parox-
etine. No adverse behavioral or growth effects have been observed in studies, but one case of in-
fant agitation and feeding difficulties has been reported.
91–93
Sertraline dosage to the breastfed
infant is <2% of the maternal dosage; concentrations in infant serum are usually low to unde-
tectable, platelet serotonin is unaffected, and no adverse effects on growth have been seen in
controlled follow-up.
94–97
One case of infant agitation and one of somnolence and developmental
difficulties have been reported spontaneously to Australian authorities.
97
Sertraline and paroxetine
are considered the SSRIs of choice during breastfeeding, especially with a neonate.
Monoamine Oxidase Inhibitors
There are no data on the amounts of older nonselective MAOIs excreted into milk. Because of their
potential for toxicity and lactation inhibition, avoid MAOIs during nursing. With moclobemide, a

reversible MAO-A inhibitor not available in the United States, infants receive a dose <1% of the
mother’s dose and no side effects have been reported in a small number of infants studied.
98,99
Other Antidepressants
Bupropion and its metabolites were undetectable in one 14-month-old infant whose mother was
taking 300 mg/day and nursing twice daily.
99,100
Nefazodone and trazodone dosages in the in-
fant are <1% of the mother’s mg/kg dosage, but only a few cases have been reported.
1,101
One
case of drowsiness, lethargy, poor feeding, and inability to maintain normal body temperature was
reported in a small preterm breastfed infant whose mother was taking nefazodone 300 mg/day.
102
Infants receive venlafaxine doses of up to 9.2% of the mother’s mg/kg dosage and the active
metabolite is detectable in the infant’s serum. Although adverse effects were not seen in 3 breast-
fed infants, caution should be used with venlafaxine until more experience is gained.
99
ANTIPSYCHOTIC DRUGS
Data on the use of antipsychotics during lactation are sparse.
103–105
Phenothiazines and thiox-
anthenes pass into milk somewhat unpredictably but usually in small amounts. Drowsiness can
occur with the more sedating agents, such as chlorpromazine. Other effects, such as extrapyra-
midal symptoms, are possible but have not been reported. Limited follow-up, ranging from 15
months to 6 yr, indicates no long-term effects on infant development in most infants. However,
3 infants whose mothers were taking large dosages of chlorpromazine (200–600 mg/day) and
haloperidol (20–40 mg/day) in combination showed deterioration of mental and psychomotor de-
velopmental scores over the first 12–18 months of life.
106

Nine other infants whose mothers were
taking lower dosages of a single antipsychotic (including haloperidol up to 20 mg/day) showed
normal development. It appears that maternal phenothiazines, thioxanthenes, and haloperidol
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cause no problems for nursing infants unless dosages are at the high end of the range or combi-
nations of drugs are used.
104,105
Breastfeeding during clozapine use in 4 infants resulted in seda-
tion in 1 and agranulocytosis in another, which resolved with discontinuation; nursing is not rec-
ommended during clozapine use.
100,107
Exposure of 2 infants to olanzapine in breastmilk for a
few days each caused no untoward events, but more experience is needed.
108
One mother taking
risperidone excreted about 4% of her mg/kg dosage into breastmilk; no infant side effects were
noted.
109
ANXIOLYTICS, SEDATIVES, AND HYPNOTICS
Many sedatives and hypnotics pass into breastmilk in measurable and potentially important

amounts. Minimize sedative and hypnotic intake during lactation.
Anesthetics, General
Compared with epidural anesthesia, general anesthesia used during cesarean delivery can de-
crease the frequency and duration of breastfeeding.
19
Excretion of most inhalation anesthetics in
breastmilk has not been well studied. Blood levels of anesthetic gases such as desflurane, enflu-
rane, halothane, isoflurane, nitrous oxide, and sevoflurane drop rapidly after termination of
anesthesia, are predicted to pass poorly into milk, and are probably poorly absorbed by the in-
fant.
19,20
Etomidate milk levels drop rapidly after a dose and should pose little risk to the infant.
110
Amounts of propofol in milk are small and do not have good oral bioavailability in the infant. Typi-
cal IV doses of methohexital or thiopental for induction of anesthesia produce low concentra-
tions in milk that do not cause effects in the infant.
1,18,110
Current opinion suggests that breast-
feeding can be resumed as soon as the mother has recovered sufficiently from general anesthesia
to nurse.
19,20
Barbiturates
These drugs can stimulate metabolism of endogenous compounds in the infant when small
amounts pass into milk. Short-acting agents are preferable to long-acting agents because smaller
amounts are excreted into milk. Large single doses might have more potential for causing infant
drowsiness than multiple small doses. (See also Anesthetics, General; Anticonvulsants.)
Benzodiazepines
Long-acting benzodiazepines and those with active metabolites (eg, diazepam) can accumulate
and cause adverse effects in infants, especially with repeated doses, and in neonates because of
their immature excretory mechanisms. Bromazepam taken by the mother might have contributed

to the death of her 4-week-old breastfed infant with a 5-day history of apneic episodes.
111
A sin-
gle dose of diazepam for short dental, surgical, or diagnostic procedures is not likely to cause se-
dation in infants past the neonatal period.
18
Milk alprazolam concentrations are low,
112
but infant
drowsiness and withdrawal symptoms have been reported with alprazolam use during nursing.
1,5
When oral therapy is essential, the short-acting agents, oxazepam or lorazepam, are preferred;
temazepam also might be acceptable.
103,113
Midazolam concentrations in milk are low and un-
likely to affect the infant after a single dose or short course of therapy.
19,114
Chloral Hydrate
Chloral hydrate and its active metabolite, trichloroethanol, appear in milk in dosages that approx-
imate an infant sedative dosage and are detectable for up to 24 hr after a single dose. Using an-
other hypnotic is advisable during nursing.
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Zaleplon

The dose in milk is very small and the drug disappears from breastmilk rapidly.
115
Zolpidem
Zolpidem milk concentrations are low for 3 hr after a dose and undetectable thereafter.
116
LITHIUM
Lithium in milk can adversely affect the infant when its elimination is impaired, as in dehydration
or in neonates or premature infants. Neonates also can have transplacentally acquired serum
lithium levels. The long-term effects of lithium on infants are not known; many investigators con-
sider lithium therapy a contraindication to breastfeeding, but others do not. Lithium may be used
cautiously in mothers who are carefully selected for their ability to monitor their full-term infants.
Discontinue breastfeeding immediately if the infant appears restless or looks ill. Measurement of
serum lithium concentrations in the infant can help rule out lithium toxicity.
1,67,80
PARKINSONISM DRUGS
Dopamine Agonists
Some ergot alkaloids have dopaminergic activity that can suppress prolactin release and lactation.
Bromocriptine was used therapeutically for this purpose but has lost this indication in the United
States because of potentially serious maternal toxicity (ie, stroke, death).
Levodopa
Levodopa decreases serum prolactin in non-nursing women with hyperprolactinemia and galactor-
rhea in a dose-dependent fashion and inhibits lactation in animals at high dosages.
1
One mother
taking sustained-release levodopa/carbidopa 200 mg/50 mg qid successfully breastfed her infant
whose development was normal at age 2 yr.
117
GASTROINTESTINAL DRUGS
ACID-PEPTIC THERAPY
Antacids

Although aluminum, calcium, and magnesium antacids are partially absorbed, they are unlikely
to appreciably increase concentrations of these ions in milk and are safe to use.
Histamine H
2
-Blockers
Cimetidine is concentrated in milk because of ion trapping and possibly active secretion;
118
rani-
tidine doses in milk are lower. Famotidine and nizatidine have the lowest concentrations in milk
and are preferred during nursing.
Proton Pump Inhibitors
Omeprazole and lansoprazole have not been adequately studied. In one mother, omeprazole
milk levels were low and her newborn infant was breastfed without harm.
119
Sucralfate
Because sucralfate is virtually nonabsorbable, it might be preferable to H
2
-receptor antagonists.
GASTROINTESTINAL MOTILITY
Antidiarrheals
Nonabsorbable products such as kaolin-pectin are preferred in nursing mothers. The loper-
amide prodrug loperamide oxide results in only small amounts of loperamide in breastmilk.
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Diphenoxylate excretion into milk has not been studied. One or two small doses of loperamide or
diphenoxylate daily should pose little risk to the nursing infant. Avoid bismuth subsalicylate be-
cause salicylate is absorbable.
Cathartics and Laxatives
Some anthraquinone derivatives, such as aloe and cascara, and other stimulant cathartics (eg,
phenolphthalein) should be avoided during nursing because of a laxative effect in breastfed in-
fants. Laxatives that are nonabsorbable or poorly absorbed, such as bulk-forming (eg, psyllium),
osmotic (eg, magnesium or phosphate salts), or stool-softening (eg, docusate) types, are pre-
ferred during lactation. Senna in moderate dosages is acceptable if other measures fail.
Bisacodyl is virtually unabsorbed from the GI tract and should be safe.
Gastrokinetic Agents
Metoclopramide elevates serum prolactin via central dopaminergic antagonism and results in in-
creased milk production and a more rapid transition from colostrum to mature milk. It can be used
therapeutically in mothers who are producing insufficient quantities of milk, such as the mothers
of premature or sick infants or adoptive mothers. Although infant dosages of metoclopramide from
milk are low, the infant’s serum prolactin concentrations can become elevated. Metoclopramide
can induce depression, so caution is warranted. Limiting the duration of metoclopramide therapy
to 14 days is essential, and it should not be used in mothers with a history of depression. Dom-
peridone (not available in the U.S.) also has been used to increase milk supply and results in
lower milk drug levels than metoclopramide.
120,121
MISCELLANEOUS GASTROINTESTINAL DRUGS
Mesalamine Derivatives
Small amounts of sulfasalazine and sulfapyridine have been found in milk and infants’ sera after
oral sulfasalazine use. The small amount of sulfapyridine released should cause no bilirubin displace-
ment. Olsalazine is not detectable in milk, but its metabolite, N-acetyl-5-ASA, is found in small
amounts.

122
Small amounts of mesalamine and larger amounts of its metabolite are found in milk
after oral administration.
123
Diarrhea has been reported in infants of mothers using mesalamine deriva-
tives, but a controlled study found the frequency of diarrhea to be no greater than that in infants of un-
treated mothers.
124
Sulfasalazine and mesalamine and its derivatives may be used during nursing.
Ursodiol
Ursodiol was undetectable in the milk of 1 lactating mother, and her nursing infant developed nor-
mally during therapy.
125
Maternal ursodiol therapy decreased the bile acid concentration in
colostrum and was found in trivial amounts in breastmilk in 16 mothers with intrahepatic cholesta-
sis of pregnancy.
126
Their infants showed no adverse effects.
HEMATOLOGIC DRUGS
COAGULANTS AND ANTICOAGULANTS
Coumarins
Amounts of warfarin in milk are of no clinical consequence with a maternal dosage of ≤12
mg/day because of extensive protein binding. Higher dosages have not been studied. Other
coumarin derivatives (eg, acenocoumarol, dicumarol, and phenprocoumon) also appear to be
safe.
127
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HEMATOLOGIC DRUGS
Heparins
Although minimal documentation exists, it is unlikely that heparin or low-molecular-weight hep-
arins (eg, enoxaparin, dalteparin) pass into milk or are absorbed orally by the infant; anti-
coagulant activity was undetectable in 1 breastfed infant whose mother received 20–40 mg/day
of enoxaparin.
128
Hirudin was not detectable in milk.
129
Indandiones
Anisindione and phenindione are contraindicated because infant hemorrhage has occurred.
127
HORMONES AND SYNTHETIC SUBSTITUTES
ADRENAL HORMONES
Corticosteroids
Prednisone and prednisolone excretions into milk are minimal even with large oral doses.
130
The
infant dosage can be reduced even further by using prednisolone rather than prednisone and
avoiding nursing for 3–4 hr after a dose. Three infants have been breastfed during long-term ma-
ternal use of methylprednisolone 6–8 mg/day with apparent safety. Large IV doses of cortico-
steroids or use of long-acting agents such as dexamethasone have not been studied, and cau-
tion is warranted. Depot injections, inhaled corticosteroids (eg, beclomethasone, fluticasone), or
topical corticosteroids should present little or no risk to the infant because of low maternal serum
concentrations. However, topical application to the nipple has caused adverse effects in the infant
because of direct ingestion.
131

ANTIDIABETIC DRUGS
Insulin
Diabetic mothers using insulin may nurse their infants. However, it has been found empirically that
the mother might need to reduce her insulin dosage to 55–75% of the prepregnancy dosage.
Close monitoring is required postpartum because the return to prepregnancy insulin dosage has
been variably reported to take 1–6 weeks.
132,133
Sulfonylureas
Tolbutamide is excreted in milk in small amounts that should cause no harm. The manufacturer
reports that chlorpropamide concentrations in milk are low, but no published clinical data are
available on this or other sulfonylureas.
CONTRACEPTIVES
Estrogen–Progestin Combinations
Although present in milk in small amounts, estrogens and progestins are readily metabolized by
nursing infants. Rare case reports of breast enlargement in infants have been attributed to
estrogen-containing oral contraceptives. These effects occur primarily with products containing
>50 ␮g of estrogen. These high-estrogen contraceptives also markedly suppress lactation,
especially when administered immediately postpartum. When currently available low-dose
estrogen–progestin combination contraceptives are begun ≥6 weeks postpartum, a dramatic
immediate effect on milk supply is usually not seen, but long-term negative effects on milk yield
lead to early feeding supplementation and discontinuation of breastfeeding and decreased infant
growth. An 8-year follow-up of breastfed infants of mothers taking contraceptives containing
ethinyl estradiol 50 ␮g found no adverse effects on the infants’ development or behavior.
Progestin-only contraceptives are preferred during lactation.
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HORMONES AND SYNTHETIC SUBSTITUTES
Progestin Only
No immediate effects have been reported with progestin-only contraceptives such as levo-
norgestrel implants, depot medroxyprogesterone acetate, or oral norethindrone or norgestrel.
Progestin-only contraceptives generally have no effect on, or enhance, milk supply and might ex-
tend the duration of lactation. Although infant growth might undergo a slight, transient depres-
sion after insertion of levonorgestrel implants, large multicenter studies have found no effect
of progestin-only contraceptives on growth and development of infants and children up to pu-
berty.
134–137
Early (ie, immediately postpartum) initiation of these agents is controversial. Because
physiologic postpartum progesterone withdrawal is a primary stimulus for lactation, it appears best
to wait for at least 3 days postpartum before starting a progestin-only contraceptive.
138
One small
study found no adverse effects on lactation or infant growth when depot medroxyprogesterone
was given immediately postpartum,
139
but anecdotal reports of lactation suppression with immedi-
ate postpartum administration exist. Progestin-only contraceptives started 6 weeks postpartum are
the preferred hormonal contraceptives during lactation.
140,141
(See also Progesterone.)
FEMALE SEX HORMONES
Progesterone
Contraceptive use via implants (investigationally) or intrauterine devices transfers little proges-

terone to the breastfed infant, and any drug in milk is minimally absorbed by the infant.
1,140,141
Milk progesterone concentrations have not been measured after higher doses used to treat pre-
menstrual syndrome.
THYROID AND ANTITHYROID DRUGS
Iodides
Inorganic iodide is contraindicated during breastfeeding because of possible thyroid suppression
and rash. Topical and vaginal povidone–iodine in nursing mothers results in elevated milk iodine
concentrations and occasional thyroid suppression in nursing infants. Avoid povidone–iodine
preparations while nursing and minimize their use during delivery.
Thioamides
Propylthiouracil is the antithyroid drug of choice during lactation; little passes into milk and infant
thyroid suppression does not occur. Dosages as high as 750 mg/day have been given to nursing
mothers with no adverse effects in their infants.
142
Methimazole 20 mg/day or carbimazole (a
methimazole prodrug) 15 mg/day also can be used, but these drugs pass into milk in greater
quantities and have longer half-lives than propylthiouracil.
143
Infants of mothers who took 20
mg/day of methimazole while nursing had no decrease in intellectual or physical development at
age 1 yr.
144
A potential for idiosyncratic reactions (eg, agranulocytosis) and hypothyroidism exists,
and measurement of the infant’s serum thyroxine and TSH concentrations at 2–4-week intervals
might be prudent during maternal antithyroid drug use.
Thyroid Hormones
Normal lactation requires thyroid hormones. Levothyroxine (T
4
) passes into milk poorly, although

liothyronine (T
3
) might pass in more physiologically relevant amounts. Milk concentrations of thy-
roid hormones have not been measured after exogenous administration, but a physiologic replace-
ment dosage of levothyroxine to a breastfeeding mother is not expected to result in excessive thy-
roid administration to the infant. Replacement therapy with liothyronine or supraphysiologic
maternal levothyroxine dosage might transfer larger amounts of liothyronine to the infant.
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HORMONES AND SYNTHETIC SUBSTITUTES
Protirelin
Protirelin (thyrotropin-releasing hormone [TRH]) causes an increase in prolactin secretion and can
enhance milk yield.
145
MISCELLANEOUS HORMONAL AGENTS
Ergot Alkaloids
Ergonovine can lower postpartum serum prolactin concentrations, but methylergonovine appar-
ently does not. Methylergonovine is not found in milk in important quantities. Short-term, low-dose
regimens of these agents immediately postpartum pose no hazard to the infant, but methyl-
ergonovine is preferred because it does not inhibit lactation. Courses of these drugs given
several days postpartum can expose the infant to greater risk of ergot side effects because of
the larger amount of milk consumed at this age.
Calcitriol
Calcitriol requirements in hypoparathyroid women decrease during lactation. Failure to substan-
tially decrease (by up to two-thirds) the calcitriol dosage results in maternal hypercalcemia.

146,147
Desmopressin
Desmopressin is excreted in negligible amounts into milk and is poorly absorbed orally by the in-
fant, so it appears safe to use.
Human Growth Hormone
Somatropin can increase milk production in mothers with an insufficient milk supply.
148,149
RENAL AND ELECTROLYTES
DIURETICS
Large dosages of short-acting thiazide-type diuretics (eg, hydrochlorothiazide), usual dosages of
loop diuretics (eg, furosemide), or long-acting thiazide-type diuretics (eg, chlorthalidone and
bendroflumethiazide) can suppress lactation and should be avoided. Long-acting agents also
can accumulate in infants’ serum. Low dosages of short-acting thiazide-type diuretics should pose
no problems to the infant or suppress lactation. Acetazolamide appears in milk in small amounts
that are unlikely to harm the infant. The amounts of spironolactone and its metabolites in milk
are inconsequential.
ELECTROLYTES
Bisphosphonates
Pamidronate was used successfully in one patient to treat bone loss associated with reflex sym-
pathetic dystrophy. The drug was undetectable in breastmilk.
150
Fluoride
Fluoride supplementation is not recommended during the first 6 months after birth; from 6 months
to 3 yr of age, fluoride supplementation of the breastfed infant is recommended only if the
mother’s water supply contains <0.3 ppm fluoride.
151
Magnesium Sulfate
When given IV, magnesium sulfate increases milk magnesium concentrations only slightly. Oral
absorption of magnesium is poor, so maternal magnesium therapy is not a contraindication to
breastfeeding.

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RENAL AND ELECTROLYTES
ANTIGOUT AGENTS
Allopurinol
This drug and its active metabolite, oxypurinol, are excreted into milk in nearly therapeutic
amounts, and oxypurinol is detectable in the nursing infant’s serum in near-therapeutic levels.
152
Although one infant breastfed without harm during maternal allopurinol therapy, observe infants
for side effects, especially hypersensitivity reactions. If possible, give allopurinol to the mother in a
single dose after the last nursing of the day.
Colchicine
Several infants have been breast-fed safely during long-term, low-dose administration of
colchicine to the mother for familial Mediterranean fever.
153,154
The amount excreted in milk indi-
cates that toxicity might occur with higher dosages.
153
Colchicine decreases milk production and
alters milk composition in animals when infused into the udder. Use it with great caution and in
low dosages when breastfeeding, especially with a neonate.
RESPIRATORY DRUGS

ANTIASTHMATICS
Anticholinergics
Excretion of anticholinergics into milk has not been studied. Theoretical hazards of the orally ab-
sorbable compounds include anticholinergic effects such as drying of secretions, temperature ele-
vations, and CNS disturbances in the infant. Anticholinergics might inhibit lactation by inhibiting
growth hormone and oxytocin secretion.
1,155
Observe infants carefully for anticholinergic symp-
toms and signs of decreased lactation (eg, insatiety, poor weight gain) when anticholinergics are
given to the mother. It is unlikely that inhaled ipratropium affects the infant or milk production.
Terbutaline
Oral administration results in low milk terbutaline concentrations, causes no symptoms in breastfed
infants, and is not expected to decrease milk supply. Other ␤
2
-receptor agonists (eg, albuterol) ap-
pear safe to use orally, but inhaler products should transfer less drug to the infant and are preferred.
Theophylline
Maternal theophylline use occasionally can cause irritability and fretful sleep in infants. Newborn
infants are most likely to be affected because of their slow elimination and low serum protein
binding of theophylline. There is no need to avoid theophylline products; however, keep maternal
serum concentrations in the lower part of the therapeutic range and measure infant serum con-
centrations if side effects occur. The related drug dyphylline is excreted into milk in greater
amounts and is best avoided.
ANTIHISTAMINES
There are few studies on antihistamine use during lactation. One study found drowsiness or irri-
tability in 12% of breastfed infants whose mothers took antihistamines.
5
Older sedating (and more
anticholinergic) antihistamines are more problematic because they can affect the infant and might
suppress lactation. (See Anticholinergics.) Nonsedating antihistamines are preferred agents for

long-term therapy. However, single bedtime doses of a sedating antihistamine after the last feeding
of the day might be adequate and minimize the amount the infant receives. Avoid sedating antihis-
tamines in high dosages, in SR formulations, or in combinations with sympathomimetic agents.
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RESPIRATORY DRUGS
Cetirizine
Cetirizine has not been studied and is not a preferred agent because of its sedative and anticholin-
ergic effects.
Cyproheptadine
Cyproheptadine lowers maternal serum prolactin and should be avoided during lactation.
Fexofenadine
Based on terfenadine experience, fexofenadine is likely to be well tolerated by breastfed in-
fants.
5,156
Loratadine
Loratadine is excreted into milk in seemingly unimportant amounts.
Triprolidine
Only small amounts of triprolidine are found in breastmilk.
COUGH AND COLD
␣-Adrenergic sympathomimetics decrease milk flow in animals by central inhibition of secretion
and release of oxytocin and by peripheral vasoconstriction, which limits the access of oxytocin to
myoepithelial cells in the mammary glands. Norepinephrine also might decrease prolactin re-
lease. Although these effects are not well documented in humans, lactation inhibition seems to
occur with oral decongestant (eg, pseudoephedrine) use; therefore, sympathomimetic nasal

sprays (eg, oxymetazoline) are recommended over oral decongestant products. Pseudoephedrine
also can cause irritability in some infants.
5
MISCELLANEOUS DRUGS
CHOLINERGIC DRUGS
Six infants of mothers treated with neostigmine for myasthenia gravis were reportedly breastfed
successfully. Neostigmine was not found in milk, but 1 infant appeared to have abdominal cramps
after each breastfeeding. Pyridostigmine has been used safely during breastfeeding in 3 patients
with myasthenia gravis.
Baclofen
Only small amounts of baclofen appear in milk, and it may be used in nursing mothers with caution.
Bupivacaine
Bupivacaine appears in milk in small amounts when administered to the mother by intrapleural or
epidural routes but has no effect on the infant.
55
Epidural analgesia with bupivacaine postcesarean
section improved breastfeeding performance in one study.
157
(See also Lidocaine in Antiarrhyth-
mics.)
Dantrolene
Several dantrolene doses totaling 720 mg IV over 2 days to a postpartum mother yielded peak
milk levels of 12 mg/L. Dantrolene half-life in milk was 9.2 hr.
158
Pyridoxine
In high doses (200–600 mg/day), pyridoxine has been used therapeutically to suppress lactation,
although it is often not effective. With usual dosages found in foods and low-dose vitamin supple-
ments, pyridoxine has no effect on prolactin or lactation.
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MISCELLANEOUS DRUGS
Radiopharmaceuticals
Exposure of the infant to excessive amounts of radioactivity is usually the primary concern raised
by administration of radiopharmaceuticals to nursing mothers, rather than any pharmacologic toxi-
city of the agent. Some, but not all, radiopharmaceuticals require discontinuation of breastfeeding,
at least temporarily, after administration to a nursing mother. Radioactive iodine compounds are
the most dangerous and might require complete cessation of breastfeeding. The period needed for
milk radioactivity to decline (by means of radioactive decay and maternal excretion) to a safe expo-
sure level depends on several factors: dosage, biological half-life, radionuclide half-life, and “con-
tamination” with other isotopes. The age of the infant, potential for oral absorption of the radionu-
clide from the infant’s GI tract, and threshold level that is considered safe are also important
factors. Measurement of milk radioactivity can aid in determining when breastfeeding can resume.
Consult specialty sources for more detailed information.
159,160
Retinoids
Acitretin passes into breastmilk in a quantity sufficient to merit avoidance of nursing while taking
it. Although there is no information on use during lactation, the manufacturers of oral isotretinoin
and topical tretinoin state that they are not compatible with nursing. Based on the systemic
bioavailability of tretinoin applied topically to a small area such as the face, it is unlikely that harm-
ful amounts reach the infant via breastmilk. Avoid contact of the infant’s skin with treated areas of
the mother’s skin.
Vaccines

Breastfeeding is not a contraindication to the use of any vaccine (live or inactivated) in the nursing
mother.
161
DIAGNOSTIC AGENTS
Iodinated Contrast Media
Iopanoic acid contains free iodide that can be detected in milk. (See Iodides.) Diatrizoate, io-
damide, iohexol, metrizoate, and metrizamide are detectable in milk after IV administration. Al-
though no adverse effects have been reported in infants, breastfeeding probably should be with-
held for a period after administration of most iodinated contrast media, the period depending on its
rate of elimination. A few hours is probably adequate after an IV pyelogram. Large amounts of io-
dine are excreted into milk for weeks after lymphangiography with ethiodized oil, and nursing
should be discontinued after this procedure.
Fluorescein
Fluorescein is detectable in milk after IV or topical administration. After IV administration, it had a
milk half-life of 62 hr in one mother. The drug might present a risk to neonates who are undergo-
ing phototherapy. Temporarily withholding nursing after fluorescein use (especially IV) seems ap-
propriate in this situation.
Gadolinium
Gadodiamide and gadopentetate, used in magnetic resonance imaging, are detectable in milk
but have poor oral absorption and are rapidly excreted renally. Suspension of breastfeeding is not
necessary after use of these agents.
162
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DRUGS FOR NONMEDICAL USE

Alcohol
Alcohol equilibrates rapidly between blood and milk, resulting in milk concentrations equivalent to
simultaneous blood concentrations. Peak maternal serum alcohol levels occur later (1 hr after the
drink) in nursing mothers than in non-nursing women;
163
alteration in milk odor parallels milk alco-
hol levels.
164,165
Potential effects on infants depend on the pattern of use. Drunkenness (deep,
unarousable sleep with snoring, deep respiration, no reaction to pain, inability to suck, excessive
perspiration, and a feeble pulse) was reported after maternal binge drinking. Pseudo-Cushing syn-
drome was reported in the infant of a chronic alcoholic mother. One prospective study suggests
that as little as 1 drink daily can cause slight impairment of the infant’s motor development; the
impairment increases in a dose-dependent fashion.
166
Infants suck more but consume less milk
after maternal alcohol ingestion.
164
Alcohol also affects lactation; it inhibits the milk ejection reflex
in a dose-dependent fashion, with single doses >2 g/kg completely blocking suckling-induced
oxytocin release. Animal studies show that alcohol consumption results in a reduced suckling-
induced prolactin release and reduced milk yield. An unknown substance in beer increases mater-
nal serum prolactin; this effect also occurs with nonalcoholic beer.
1,167
Use alcohol in moderation
during lactation and withhold nursing temporarily after alcohol consumption, with the duration de-
pendent on the amount consumed—at least 2 hr per drink is suggested.
168
Amphetamine
In a mother taking amphetamine 20 mg/day therapeutically, amphetamine concentrations in milk

were less than those in serum and no adverse effects on the infant were noted. However, there is
likely to be substantial intersubject variation in excretion, and concentrations in milk have not been
measured during high-dose abuse of amphetamines. Anecdotally, infants breastfed by ampheta-
mine abusers seem to experience drug-induced behavioral abnormalities such as agitation and cry-
ing. Amphetamine also inhibits prolactin release and, in high dosages, can interfere with lactation.
Caffeine
Anecdotal reports of infant jitteriness and difficulty sleeping have been reported with very high ma-
ternal intake of caffeine, but infant serum caffeine concentrations were not measured. Systematic
studies have indicated that caffeine and its metabolites are excreted into milk in relatively small
amounts with usual maternal intake and infants are usually not affected, even with high maternal
intake.
1,169,170
Effects are more likely in premature and newborn infants because of their greatly
diminished ability to metabolize caffeine.
Cocaine
Although not well studied in humans, the chemical nature of cocaine and results from animal
studies indicate that it probably appears in milk in amounts that affect the infant. Cocaine was
detectable in milk for 24–36 hr after use. In addition, serum cholinesterase, which is needed to
metabolize the drug, is low in newborns. Cocaine and its toxic metabolite can be detected in milk
and can cause adverse effects (vomiting, diarrhea, irritability, and dilated pupils) in breastfed in-
fants. Convulsions occurred in an infant whose mother used topical cocaine to treat sore nipples.
Breastfeeding is not recommended when the mother is a chronic cocaine user, and even occa-
sional use of cocaine is discouraged during breastfeeding. Withhold breastfeeding for at least
24 hr after occasional cocaine use.
1,171
Heroin
Abuse can result in high enough concentrations in milk to cause addiction or alleviate withdrawal
symptoms in infants; however, breastfeeding is not a reliable method of preventing withdrawal.
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DRUGS FOR NONMEDICAL USE
Most authorities consider breastfeeding safe during methadone maintenance in doses up to 80
mg/day.
1,172
Marijuana
Marijuana excretion into milk is not well studied, but dronabinol (tetrahydrocannabinol) can reach
high concentrations in milk and be detected in the infant, particularly with heavy maternal use.
Short-term effects in infants have not been reported, but a decrement in motor development at
age 1 yr in the infants of marijuana-smoking mothers was reported in one study. Marijuana lowers
serum prolactin slightly in nonlactating women and oxytocin release in rodents. One survey indi-
cated that women who smoke marijuana breastfed for a shorter duration than nonusers and that
the effect appears to be dose related.
173
Avoid breastfeeding in heavy marijuana users and during
therapeutic dronabinol use. Withhold breastfeeding for several hours after occasional marijuana
use and use caution to avoid exposing the infant to marijuana smoke.
Phencyclidine
Phencyclidine is concentrated in milk and remains detectable in milk for weeks after heavy use.
Avoid breastfeeding after phencyclidine use; a sufficient duration of abstinence has not been defined.
Tobacco
Nicotine and its metabolite, cotinine, are excreted into breastmilk in amounts proportional to the
number of cigarettes smoked by the mother.

1,174
The milk of smokers contains higher concentra-
tions of cadmium than the milk of nonsmokers; other toxins from smoke have not been measured.
Smokers also produce lower milk volumes, have lower milkfat content, use formula supplements
more often, and wean their infants from breastfeeding earlier than nonsmokers, in part because
nicotine lowers maternal basal prolactin concentrations.
175,176
Infants of smoking mothers have in-
creased infantile colic, large postnursing decreases in respiratory rate and oxygen saturation, and
more respiratory infections.
174
However, among infants of smokers, breastfeeding reduces the risk
of respiratory illness by half that of formula-fed infants.
177
In nonsmokers, breastfeeding reduces
the risk of sudden infant death syndrome compared with formula feeding, but smoking negates
this advantage.
178
Advise nursing mothers to (1) stop or decrease smoking to the greatest degree
possible, (2) not breastfeed right after smoking, and (3) not smoke in the same room with the in-
fant.
179
The use of nicotine chewing gum, topical patches, or nasal spray has not been studied
during lactation. Although they are not recommended by the manufacturer during nursing, these
products are likely to be less hazardous to the nursing infant than maternal smoking.
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114. Spigset O. Anaesthetic agents and excretion in breast milk. Acta Anaesthesiol Scand 1994;38:94–103.
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123. Klotz U, Harings-Kaim A. Negligible excretion of 5-aminosalicylic acid in breast milk. Lancet 1993;342:
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125. Rudi J et al. Therapie mit ursodeoxycholsäure bei primär biliärer zirrhose während der schwangerschaft.
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128. Guillonneau M et al. L’allaitement est possible en cas de traitment maternal par l’enoxaprine. Arch Pediatr
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130. Greenberger PA. Pharmacokinetics of prednisolone transfer to breast milk. Clin Pharmacol Ther 1993;53: 324–8.
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132. Alban Davies H et al. Insulin requirements of diabetic women who breast feed. BMJ 1989;298:1357–8.
133. Murtaugh MA et al. Energy intake and glycemia in lactating women with type 1 diabetes. J Am Diet Assoc
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135. Dunson TR et al. A multicenter clinical trial of a progestin-only oral contraceptive in lactating women. Con-
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only contraceptives during lactation: I. Infant growth. Contraception 1994;50:35–53.
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138. Kennedy KI et al. Premature introduction of progestin-only contraceptive methods during lactation. Contra-
ception 1997;55:347–50.
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urban community. Arch Pediatr Adolesc Med 1997;151:490–6.
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141. Díaz S, Croxatto HB. Contraception in lactating women. Curr Opin Obstet Gynecol 1993;5:815–22.
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143. Azizi F. Effect of methimazole treatment of maternal thyrotoxicosis on thyroid function in breast-feeding in-
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146. Caplan RH, Wickus GG. Reduced calcitriol requirements for treating hypoparathyroidism during lactation. A
case report. J Reprod Med 1993;38:914–8.
147. Cathébras P et al. Hypercalcémie induite par la lactation chez deux patientes hypoparathyroïdiennes traitees.
Rev Med Interne 1996;17:675–6.

148. Gunn AJ et al. Growth hormone increases breast milk volumes in mothers of preterm infants. Pediatrics
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149. Milsom SR et al. Potential role for growth hormone in human lactation insufficiency. Horm Res 1998;50:
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758–61.
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153. Guillonneau M et al. Colchicine is excreted at high concentrations in human breast milk. Eur J Obstet Gy-
necol Reprod Biol 1995;61:177–8. Letter.
154. Ben-Cherit E et al. Colchicine in breast milk of patients with familial Mediterranean fever. Arthritis Rheum
1996;39:1213–7.
155. Daniel JA et al. Methscopolamine bromide blocks hypothalamic-stimulated release of growth hormone in
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156. Lucas BD Jr et al. Terfenadine pharmacokinetics in breast milk in lactating women. Clin Pharmacol Ther
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157. Hirose M et al. The effect of postoperative analgesia with continuous epidural bupivacaine after cesarean sec-
tion on the amount of breast-feeding and infant weight gain. Anesth Analg 1996;82:1166–9.
158. Fricker RM et al. Secretion of dantrolene into breast milk after acute therapy of a suspected malignant hyper-
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163. da-Silva VA et al. Ethanol pharmacokinetics in lactating women. Braz J Med Biol Res 1993;26:1097–103.
164. Mennella JA, Beauchamp GK. The transfer of alcohol to human milk. Effects on flavor and the infant’s be-
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167. Mennella JA, Beauchamp GK. Beer, breast feeding, and folklore. Dev Psychobiol 1993;26:459–66.
168. Anderson PO. Alcohol and breastfeeding. J Hum Lact 1995;11:321–3.
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nomic classes. Biopharm Drug Dispos 1992;13:187–96.
170. Oo CY et al. Pharmacokinetics of caffeine and its demethylated metabolites in lactation: predictions of milk to
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171. Dickson PH et al. The routine analysis of breast milk for drugs of abuse in a clinical toxicology laboratory.
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172. Wojnar-Horton RE et al. Methadone distribution and excretion into breast milk of clients in a methadone
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174. Stepans MB, Wilkerson N. Physiologic effects of maternal smoking on breast-feeding infants. J Am Acad
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176. Hopkinson JM et al. Milk production by mothers of premature infants: influence of cigarette smoking. Pedi-
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178. Klonoff-Cohen HS et al. The effect of passive smoking and tobacco exposure through breast milk on sudden
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179. Håkansson A, Cars H. Maternal cigarette smoking, breast-feeding, and respiratory tract infections. A
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Pediatric Drug Therapy
William E. Murray
Pediatric drug therapy presents a challenge to the practitioner in many respects.
The pediatric population is comprised of a range of patient weights and organ ma-
turity. Often there are no pediatric-specific data in the literature from which to de-
rive appropriate dosage regimens. At times, medications must be used for which
data are extrapolated on the basis of limited pharmacokinetic knowledge about the
pediatric population. It must be remembered that children should not be treated as
“little adults” when designing dosage regimens. Dosage administration nomo-
grams derived from adult data should not be used in the pediatric population.
Pharmacodynamic responses for the majority of medications used in children are
even less well known. Children often react much differently from adults to certain
medications. Examples are the use of stimulants such as methylphenidate to con-
trol hyperactivity common with attention deficit disorders and paradoxical hyper-
activity, which can be observed in children taking phenobarbital. With therapeuti-
cally monitored medications, the standard adult therapeutic range is typically used
because age-specific, concentration-effect information is scarce. Because of pro-

tein binding differences, infants might respond to lower total drug concentrations
than those used in adults for certain medications (eg, phenytoin, theophylline).
One of the problems facing the clinician and caregiver of small children is
the administration of medications. Dosage forms are usually designed with the
adult population in mind, and the dosage cannot easily be individualized in small
patients. This is especially true for most sustained-release products. Most young
children cannot swallow tablets and capsules; thus, liquid preparations are gener-
ally preferred in this age group. For many drugs, liquid forms are not commer-
cially available and must be extemporaneously compounded. Stability of these
preparations is often unknown or of limited duration. Even when appropriate
dosage forms suitable for young children are available, palatability, resistance to
taking medications, and compliance issues can hinder optimal therapy.
■ PHARMACOKINETICS
ABSORPTION
At birth, gastric pH is neutral but falls to values of 1–3 in the first day of life. Sub-
sequently, gastric pH returns toward neutrality because gastric acid secretion is
low in the first several weeks to months. Adult values are usually achieved after
the age of 2 yr.
1,2
Medications that require gastric acidity for absorption can have
poor bioavailability in this age group, rendering them ineffective or requiring
much higher doses than normal for therapeutic serum concentrations to be
reached. Examples of medications in this group are phenytoin, ketoconazole, and
itraconazole.
1,3
Alternative agents might have to be used if adequate serum levels
cannot be documented when these drugs are administered orally. Certain medica-
tions that are acid labile actually might have increased bioavailability in infants,
and these are antibiotics such as penicillin G and ampicillin.
4

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Gastric emptying time can be delayed in infants, especially premature in-
fants.
1,3,5
Peak drug concentrations can occur much later in infants than in older
children and adults. Other factors that can influence overall bioavailability of a
particular medication in infants are the relatively high frequencies of gastro-
esophageal reflux, which can cause the dose to be spit up or vomited, and acute
gastroenteritis (diarrhea), which can considerably shorten intestinal transit time.
The oral route must be used with caution in these instances, especially in critically
ill patients.
Other routes of administration can pose difficulties in the pediatric pop-
ulation. Overall muscle mass is decreased, and intramuscular administration
might not be practical and certainly is not appreciated by most children. Most
adults still remember their first injections in the doctor’s office when they were
children. Also, the dose of drug to be administered might require multiple in-
jections.
Rectal administration may be used in situations where the oral route is not
practical or available; however, absorption might be incomplete and/or erratic.
Topical administration of medications can lead to undesired systemic absorption,
especially in infants in whom the skin thickness is less and the total skin surface
area is proportionally greater than in adults.
1,2,4

DISTRIBUTION
Rapid changes in body composition can dramatically alter the V
d
for many med-
ications during the first several months of life. Newborns have a higher percentage
of total body water and extracellular fluid than older children and adults.
1,3,6
Hy-
drophilic drugs such as the aminoglycosides have a much larger V
d
in newborns;
this gradually decreases over the first year of life to approach adult values.
Total body fat in newborns (especially premature infants) is much lower
than in older children and adults.
6
Medications that are lipophilic might have a
lower weight-adjusted V
d
in the very young.
Protein binding is an important determinant of the V
d
for drugs that are
bound by albumin and other plasma proteins. In the neonatal period, the binding
affinity of albumin is decreased compared with that in older children and adults
(because of the persistence of fetal albumin).
1–3
Highly protein-bound drugs such
as phenytoin have higher free fractions in neonates, and there might be an in-
creased pharmacodynamic response at lower concentrations of total drug. The V
d

of these drugs is inversely related to the degree of protein binding.
In addition, the clinician must be aware of the potential for highly protein-
bound substances to displace bilirubin from binding sites on albumin, particularly
in the newborn.
1–3,7
The blood–brain barrier in newborns is more permeable than
in older patients, and free bilirubin can readily cross into the CNS and cause ker-
nicterus.
Tissue binding for many medications is unknown but can differ dramatically
from that in adults. One example is digoxin, which binds to erythrocytes in pedi-
atric patients to a much greater extent than in adult patients.
2,4
Digoxin has a much
larger V
d
in pediatric patients, and recommended loading doses in this age group
are much larger on a mg/kg basis than in adult patients. In general, drug distribu-
tion volumes are larger in neonates and gradually approach adult values (in L/kg)
by the first year of life.
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METABOLISM
Metabolic processes show dramatic changes in the first weeks to months of life.

At birth, most hepatic enzymes are immature and drug metabolizing capacity is
greatly reduced. Phase I reactions (ie, oxidation) are controlled largely by the
mixed-function oxidase system, of which the cytochrome P450 enzymes are the
major determinant. These enzymes are largely undeveloped in newborns, espe-
cially premature infants, but maturation can take place quickly in the first weeks
to months of life. Phase II reactions (ie, conjugation) include glucuronidation, sul-
fation, and acetylation. These reactions also are immature at birth, and drug toxic-
ity has resulted (eg, with chloramphenicol) because of the absence of knowledge
about reduced dosage requirements in newborns.
1–3,6
The liver size relative to body weight in newborns is much larger than that in
adults.
1
Rapid weight gain, with subsequent increases in liver size and metabolic ca-
pacity, might require many dosage adjustments to prevent newborns from growing
out of their dosages for many medications. When full metabolic capacity is reached
in the pediatric patient, the hepatic clearance can greatly exceed that observed in
adult patients on a weight-adjusted basis. Pediatric dosages of many medications on a
mg/kg basis are often much greater than adult dosages. Figure 2–2 illustrates the
change in clearance with age for theophylline.
6
Most medications have similar curves
but can be shifted to the left or have different relative peaks compared with adult val-
ues. A decrease in hepatic clearance relative to body weight typically begins after a
child weighs approximately 30 kg.
8
Thereafter, the increase in total body weight in
proportion to liver size becomes greater. Thus, in adolescence, drug dosages typically
begin to approach adult values. Drug toxicity can be observed in the adolescent pa-
tient if drug dosages on a mg/kg basis (designed for younger patients) are used.

RENAL ELIMINATION
The kidneys are the major route of drug elimination for many drugs. The kidneys
are functionally immature at birth with regard to glomerular filtration and tubular
secretion. Glomerular filtration at birth adjusted for body surface area is only
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Figure 2–2. Maturation of theophylline metabolism.
ch12.qxd 8/13/2001 3:11 PM Page 945
30 to 40% of values in older infants and healthy young adults.
1–3
Premature infants
often have even lower values during the first few weeks of life. Dosages of many
medications (eg, aminoglycosides, vancomycin) that are eliminated largely by
glomerular filtration must be decreased on the basis of the relative immaturity of
the kidneys at birth. Maturation of glomerular filtration occurs over the first several
weeks to months of life. The dosages of most medications are similar to those in
older children by age 4–6 months. Although the frequency of renal disease in chil-
dren is much lower than in the adult population, factors that can alter renal func-
tion, such as shock, nonsteroidal anti-inflammatory drugs, or hypoxia, must be con-
sidered when evaluating dosage regimens. Serum creatinine, the usual marker for
renal function, is usually lower in young children than in adults because of chil-
dren’s lower muscle mass. Thus, a serum creatinine that indicates normal renal
function in an adult might indicate renal impairment in a young child.
Tubular secretion also is diminished in the newborn. Drugs that have a com-
ponent of tubular secretion (eg, penicillin) are typically administered at reduced

dosages in the newborn. Maturation of tubular secretion occurs somewhat more
slowly than glomerular filtration, but approaches adult values by age 8–12
months.
1–3
EVALUATING DRUG DATA IN CHILDREN
With the numerous maturational changes observed in children from birth through
adolescence, results of pediatric drug studies must be used with caution in children
whose ages differ from those in the study. Dosages extrapolated only on a weight
basis have the potential to underdose or overdose other age groups, depending on
the population studied. Body surface area might correlate better than body weight
with total body water and extracellular water and can be useful in certain instances
in calculating dosage regimens. With the exception of cancer chemotherapeutic
agents, information on drug dosage is more widely available in mg/kg than by body
surface area.
5
Medications with narrow therapeutic ranges should have serum con-
centrations measured to aid in individualizing drug therapy, especially in critically
ill children or those with known decreased renal or hepatic function.
Pharmacodynamic changes are poorly studied in the pediatric population,
and responses to specific drug concentrations might be much different from those
in the adult population. Diseases of childhood often differ from those in adults.
Medications tolerated by adult patients might be inappropriate for the pediatric
population (eg, aspirin for fever).
Caution must be used in the interpretation of drug levels because there might
be much greater fluctuation in serum concentrations because of shorter drug half-
lives in children than in adults. Further, the total volume of blood needed for drug
level monitoring in small children can limit monitoring.
Detailed information on specific drugs can be found in the Pediatric Dosage
sections of the individual drug monographs.
■ REFERENCES

1. Stewart CF, Hampton EM. Effect of maturation on drug disposition in pediatric patients. Clin Pharm
1987;6:548–64.
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