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Chapter 5. Use of the monographs on drugs

Chapter 5. Use of the monographs on drugs

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Use of the monographs on drugs



The dose is usually specified in milligrams (mg); in this case 100 mg. The frequency in this example is shown by, e.g. x 3/d, which indicates 3 doses daily. The

duration is shown by, e.g. x 14 d, which indicates 14 days. (A single dose is shown

as x 1/d x 1 d.). The route is shown as p.o., i.v., i.m. etc. The number of subjects

is shown as, e.g. n = 6 or n = 10, indicating that 6 or 10 subjects were studied. The

lactation stage is often shown by a question mark which implies that the stage of

lactation is unknown (many studies examined). It is presumed that this indicates

established lactation. In some cases colostrum or transitional milk was examined.



Concentrations

The concentration of drug in milk or plasma is shown as mg/1 in most cases

(occasionally/tg/1 or ng/1). A figure of <50/zg/1 indicates that the drug was not detectable at the sensitivity level of the assay (in this case 50/tg/1). If the assay sensitivity is not known the abbreviation n.d. (for not detected) is used. A figure in parentheses indicates a concentration of metabolite.



Milk to plasma ratio

The milk to plasma ratio (M/P) is calculated for paired samples or from the areas

under the respective concentration-time curves; in some cases a range is given

which reflects intersubject variation.



Dose

The assumption is made that the infant ingests milk at the rate of 150 ml/kg day.

The average dose is then calculated from the data shown in column 2 and expressed

as mg or mg/kg per day. The maximum dose is calculated from the maximum milk

concentration. The relative dose to the infant is then given both in terms of the maternal dose and of the paediatric therapeutic dose where this is available (see assumptions on page 70).

There follow comments on any observed effects or drug measurements in the infants. The section on each drug finishes with an assessment and recommendations,

and with references. The criteria used for the general recommendations are shown

in the discussion on assumptions on pages 69-74.

SELECTION AND REJECTION OF EVIDENCE

Readers may notice that certain references are missing from this book, and indeed

information on some drugs has been excluded altogether. In some cases no data

were available, and in other cases the data were inconclusive. Many of the early

studies in this field used spectrophotometric or colorimetric methods, or measured

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Use of the monographs on drugs



total radioactivity in breast milk after a radiolabelled dose of the drug. It is very

likely that many of these studies measured not only drug, but also metabolites. In

many cases very few subjects were studied: in some only one mother was examined. Unless the data were of particular interest, these studies have not been included.

Many studies examined only the situation after a single dose of the drug. It

should be realised that drug concentration in breast milk may be different in a multiple-dose regimen (the usual situation) to that seen after single dosing. In particular

the milk to plasma ratio, often quoted as an accurate assessment for any situation,

may vary not only from the single-dose to a multiple-dose regimen, but also during

a dosing interval (see Chapter 3). Even when the multiple-dose situation was studied, on some occasions the mothers were clearly not at steady state. Data are often

insufficient to evaluate unexpected accumulation in milk. In general comments on

these aspects of the quoted studies are included below the main table.

ASSUMPTIONS FOR CALCULATIONS AND INTERPRETATION OF DATA

a.



b.



c.



d.



e.



f.



A drug can accumulate in plasma (and in milk) during repeated dosing. This is

not considered when the daily 'dose to infant' calculations are made from single-dose data. In general no assumptions are made about conditions of chronic

dosing when only single-dose data are available.

Inter-individual variation occurs in both the maternal plasma drug concentrations and the milk concentrations. The data are often not sufficient to assess

this variation, and so the dose in the milk is calculated without this assessment.

Breast-feeding practices vary in different parts of the world. In some countries

the only alternative to breast milk may be an artificial feed which may harbour

bacteria. Thus the risk of a drug-contaminated milk must be weighed against

that of possibly infected milk. In most cases the recommendations assume a

suitable alternative source of milk.

Due to local circumstances or personal wishes, some women may wish to

breastfeed contrary to the recommendations of this book. It is advisable then:

(i) to use the lowest dose of drug necessary to achieve the therapeutic effect in

the mother, (ii) to monitor the drug plasma concentration in the infant, and (iii)

to observe the infant for drug effects.

The effect of the stage of lactation on the dose delivered to the infant is not

considered, i.e. for the purposes of dose calculation it is assumed that maximum drug concentration in milk does not change as a function of stage

(duration) of lactation, unless stated otherwise.

The calculations for the doses of drug received by infants are based on the milk

concentrations and on maternal doses used in the studies quoted. Caution

should be exercised when advice is given to mothers who receive doses in excess of those studied.

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Use of the monographs on drugs



g.



Whenever possible advice is given on the basis of the information available,

but as a general principle, if recommendations are based on data from less than

6 women at only one stage of lactation, then it is considered that further studies

are needed to validate or to refute the recommendations. In such a situation the

mother should be appropriately monitored until more data are available.

h. Milk to plasma (M/P) ratio estimates. The M/P ratio is expressed in two ways.

(i) The area under the concentration-time curve in milk relative to that in

plasma; when a range is quoted, this refers to the variation within or between mothers and does not indicate the variation between doses and during repeated dosing.

(ii) The concentration in milk relative to that in plasma; when a range is

quoted, this may indicate the variation for all paired data points in all cases

or it may indicate the variation between average M/P ratios for all cases in

the study.

No assumption is made that the time-course profile of drug concentration in

milk is concurrent with that in plasma. Accordingly, the M/P ratio is usually

calculated when the data are sufficient to show the extent of its variation within

a dose interval.

The M/P ratio derived from a single dose may not necessarily be that observed after multiple doses if a drug accumulates in milk more than in plasma.

Calculations of the M/P ratio are based on the conditions of each study.

j. Pharmacokinetic parameters are quoted for adults (often healthy males) and the

assumption has been made these parameters also apply to lactating females

unless otherwise specified.

k. Relative dose in milk. The chemical form in which a drug is administered, e.g.

salt or ester, may differ from the form measured in plasma or milk, e.g. free

base. Where the chemical form of a drug is not specified the total maternal

dose is assumed to reflect the parent drug for the purpose of calculating infant

dose as a percentage of maternal dose. When an active metabolite(s) of a drug

was measured in milk, the values for drug and metabolite(s) were added together (i.e. the metabolite(s) were assumed to have equal biological activity to

the parent drug).

The dose of drug that an infant received in breast milk has been expressed as a

dose in mg/kg rather than as dose per square metre of body surface area as follows:



Relationship to maternal dose

The dose in breast milk is expressed relative to the maternal dose and a linear relationship between age and weight-adjusted dose requirements is assumed. The maternal dose is weight-adjusted using a reference female weight of 60 kg. An infant

milk consumption of 150 ml/kg per day is assumed. The average and maximum

concentrations in the following calculations are quoted in mg/1.

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Use of the monographs on drugs



Single dose administration

Many studies report results of single doses of drags to mothers. For these the

maximum milk concentration (either mean or single maximum concentrations as is

judged appropriate in the individual study) is taken, and it is assumed that the child

will suckle once at this maximum milk concentration (Cmax). It is further assumed

that the infant will suckle 5 times per day and thus will ingest a milk volume of

30 ml/kg (0.03 1/kg) in that feed. The data can then be expressed (in percent) as the

dose received in a feed relative to the weight-adjusted maternal single dose. The

calculation is:

0.03 • 60

Cma x • 180

• 100=

=%

Maternal single dose

Maternal single dose

Cma x x



Multiple-dose administration

In some studies breast-milk concentrations were measured during multiple dosing.

Here, the achievement of steady state is assumed unless the conditions of the study

suggest otherwise. The infant daily dose is expressed as a percentage of the weightadjusted maternal daily dose. The dose is expressed both as an average figure using

the average milk concentration (Cave) and/or as a maximum figure using the maximum milk concentration Cmax, (mean or single value as is judged appropriate in the

individual study). The calculations are, for averag e doses:

Cav e x



0.15 • 60



Maternal daily dose



x 100=



900

=%

Maternal daily dose

Cav e x



and for maximum doses:

0.15 • 60

Cma x • 900

• 100=

=%

Maternal daily dose

Maternal daily dose

Cma x x



where 0.15 is the daily milk intake of the infant in 1/kg and 60 is the reference

maternal weight in kg. The daily maternal dose is the dose used in the particular

study.

Relationship to paediatric dose



The dose received by the infant from breast milk is also expressed as a percentage

of the relevant infant therapeutic dose. Where the drag is not given to infants (e.g.

sex steroids) or the paediatric dose applies to older children (e.g. antidepressants)

no such relative dose is given.

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Use of the monographs on drugs

Single-dose administration

When the mother is given a single dose, the maximum milk concentration is taken

(Cmax in mg/1) and it is assumed that the child suckles once at this maximum milk

concentration. It is further assumed that the infant ingests a milk volume of 30 ml/

kg (0.03 1/kg) in that feed. The infant single dose is normally quoted as a weightadjusted dose (mg/kg). The calculation is:



Cmax X 0.03

Cmax X3

xl00=

=%

Infant single dose

Infant single dose

(weight- adjusted)

(weight- adjusted)



Multiple-dose administration

The dose received by the infant in the breast milk is calculated using both average

and/or maximum concentrations (in mg/1) in milk (mean or single maximum values

as is judged appropriate in the individual study). The dose referred to is the lowest

daily therapeutic dose (in mg/kg) as currently recommended. The amount of milk

ingested is taken as 0.15 1/kg/day. The calculation for average daily intake of drag

from breast milk, expressed as a percentage of daily therapeutic dose, is:



0.15

Cave x 15

• 100=

=%

Infant single dose

Infant single dose

(weight - adjusted)

(weight - adjusted)

Cav e x



The calculation for maximum daily intake of drug from breast milk, expressed as a

percentage of daily infant therapeutic dose, is:

0.15

Cma x X 15

xl00=

-'%

Infant daily dose

Infant daily dose

(weight- adjusted)

(weight- adjusted)

Cma x •



k.



In order to assign a level of risk to the infant for drugs received in breast milk,

the following criteria are used:

- If the inherent pharmacological action of the drug suggests that a toxic effect may occur in the immediate or longer term, regardless of the amount

of drug in milk, then the conclusion about the drug is appropriately qualified. Usually breast-feeding is not advisable, e.g. for most cytotoxic drugs.

If there are observed effects in breast-fed infants which suggest that the

drug may not be safe during breast-feeding, then the appropriate recommendation is made if the study results are supported by the calculated



-



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Use of the monographs on drugs



amount of the drug in the milk or observed concentrations in the infant's

plasma. Usually breast-feeding is not advisable.

If the relative dose in milk calculation reveals that either: (i) during multiple dosing to the mother there is an average or maximum daily dose in milk

greater than 10% of the weight-adjusted maternal or paediatric daily dose,

or (ii) after a single dose to the mother there is a maximum dose in each

milk feed that is greater than 10% of the weight-adjusted maternal or paediatric dose, then the drug will usually be unacceptable for breast-feeding

mothers on the basis of the dose of drug in milk alone. In some cases qualifying statements are made, and knowledge about infant pharmacokinetic

parameters may modify the recommendation. Thus it is assumed that a

dose that is less than 10% of the lowest paediatric dose, or less than 10% of

the weight-adjusted maternal dose, is most unlikely to create a risk of adverse effects that exceeds the risk which an infant would run by receiving

the drug for therapeutic purposes.

Under expected steady state conditions in the infant, if the plasma concentration of a drug in the suckling infant is greater than 25% of the lower end

of the therapeutic concentration range, then the drug is taken to be unacceptable for breast-feeding women, on the basis of the dose of drug in

milk.

Adverse effects to the infant are considered as: (i) toxicity related to the dose of a

drug or chemical taken in milk, i.e. when a dose-response relationship appears to

exist and the consequence is either an exaggerated therapeutic effect or an adverse

effect (such events tend to be recognised and reported) and (ii) toxicity unrelated to

the dose, i.e. when an idiosyncratic response occurs (much of this data is dependent

on case reports).

The rationale underlying assignment of risks to the infant includes ethical and

practical considerations. From an ethical point of view, the child's inability to give

informed consent might require that drugs be given to children only for therapeutic

indications. If this principle were to be accepted for drug exposure through breast

milk, then even drugs with undetectable concentrations in milk would be unacceptable for breast-feeding women as idiosyncratic adverse response may be provoked

by minute amounts of drug. This approach is obviously impractical. Therefore, a

pragmatic approach is adopted whereby some exposure to drug in milk is accepted

but the risk is minimised by using the guidelines (above) for the percent of dose or

plasma concentration to which an infant may be exposed. While these guidelines do

not guarantee safety in all infants (hypersensitivity may occur at very low doses),

they are set to offer a practical margin of safety without unduly compromising drug

therapy in women who wish their infants to receive the benefits of breast-feeding.

1. It is generally assumed that no conditions coexist with the state of lactation or

the state of infancy to alter either drug disposition, in mother or infant, or the

pharmacological effect in the infant. Examples of such conditions include renal

-



-



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Use of the monographs on drugs



or hepatic disease, or combination drug therapy. Unless stated otherwise, the

interpretation of data, assessment and recommendations assumes absence of

such coexisting conditions.

m. In general, animal data have been excluded from an assessment of the risk.



74



Drugs and Human Lactation

P.N. Bennett, editor

9 Elsevier Science Publishers B.V., 1996



6. Monographs on individual drugs

P. Bennett, L Matheson, L.J. Notarianni, A. Rane and D. Reinhardt



ACICLOVIR

GENERAL

Aciclovir (acyclovir) is a synthetic analogue of guanine used in the treatment and

prophylaxis of infections due to herpes simplex or varicella-zoster viruses. Some

15-30% of an oral dose is absorbed from the gastrointestinal tract, 15% is bound to

plasma proteins and the 80% is cleared unchanged by the kidney. The plasma halflife is 2 h.

E V A L U A T I O N OF DATA



Passage of aciclovir into human milk has been reported as follows:

Treatment conditions

Dose x Frequency x

Duration; Route; No.

of patients; Lactation

stage

200 mg x 5/d x 5 d;

p.o.; 1, 12 months

900 mg/d x 5 d; i.v.;

1; 6 weeks



Concentration

(mg/l)



Milk/

plasma

ratio



Maximum

observed

milk conc.

(mg/l)



Absolute dose

to infant (mg/kg/day)

Ave



Max



Ref.



Milk



Plasma



0.78-1.26



0.16--0.92



3.24



1.45



0.16



0.22



(1)



7.3 (max.)

4.88 (ave.)



6.5



1.12



7.3



0.73



1.10



(2)



Five paired samples of milk and plasma were taken once daily during the 5-day course of aciclovir (1). The figures in (2) refer to collections taken every 6 h starting after the final aciclovir infusion on the 5th day of treatment.

Steady-state conditions of dosing are assumed to apply.



RELATIVE DOSE IN MILK

The amount of aciclovir that a suckling infant would ingest in a day is on average

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Antimicrobial drugs, pp. 75-203



1.0% (1.06 x 900/1000)* and a maximum of 1.3% (1.45 x 900/1000)* of the

weight-adjusted maternal daily oral dose (1). Alternatively, a suckling infant would

ingest in a feed at maximum 1.5% (7.3 x 180/900)* and on average 4.9% (4.88 x

900/900)* of the weight-adjusted maternal daily i.v. dose (2).

DATA ON THE INFANT

No data are available.

ASSESSMENT AND RECOMMENDATIONS

Data from two mothers suggests that the risk to the suckling infant of administering

aciclovir to its mother is low on the basis that the quantity of drug that passes into

milk is small. Breast feeding can probably be regarded as safe.

REFERENCES

1. Myer LJ, de Miranda P, Sheth N, Spruance S (1988) Acyclovir in human breast milk. Am. J.

Obstet. Gynecol., 158, 586-588.

2. Bork K, Benes (1995) Concentration and kinetic studies of intravenous acyclovir in serum and

breast milk of a patient with eczema herpeticum. J. Am. Acad. Derm., 32, 1053-1055.



* An explanation of the calculation (s) appears on pp. 71-72.



76



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