Drug Name and Generic Name:

Each monograph begins with the generic name of the drug. The most common trade names are provided under the Trade section. With some pharmaceuticals, there may be more than one drug added to the product. In this case we have added a table called “Combination Drugs” in the appendix where all the drugs present in that specific pharmaceutical are listed and you can then look up the individual products.

Other Trades:

This book is used all over the world. Thus many other trade names from other countries are now included in this section.

Category:

This lists the class or “family of drugs” that the medication belongs to and gives a general idea of the pharmacology, mechanism of action, and probable use of the drug.

Drug Monograph:

The drug monograph lists what we currently understand about the drug, its ability to enter milk, the concentration in milk at set time intervals, and other parameters that are important to a clinical consultant. We have attempted at great length to report only what the references have documented.

L1 Compatible:

Drug which has been taken by a large number of breastfeeding mothers without any observed increase in adverse effects in the infant. Controlled studies in breastfeeding women fail to demonstrate a risk to the infant and the possibility of harm to the breastfeeding infant is remote; or the product is not orally bioavailable in an infant.

L2 Probably Compatible:

Drug which has been studied in a limited number of breastfeeding women without an increase in adverse effects in the infant. And/or, the evidence of a demonstrated risk which is likely to follow use of this medication in a breastfeeding woman is remote.

L3 Probably Compatible:

There are no controlled studies in breastfeeding women; however, the risk of untoward effects to a breastfed infant is possible, or controlled studies show only minimal non threatening adverse effects. Drugs should be given only if the potential benefit justifies the potential risk to the infant. (New medications that have absolutely no published data are automatically categorized in this category, regardless of how safe they may be.)

L4 Potentially Hazardous:

There is positive evidence of risk to a breastfed infant or to breast-milk production, but the benefits from use in breastfeeding mothers may be acceptable despite the risk to the infant (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective.)

L5 Hazardous:

Studies in breastfeeding mothers have demonstrated that there is significant and documented risk to the infant based on human experience, or it is a medication that has a high risk of causing significant damage to an infant. The risk of using the drug in breastfeeding women clearly outweighs any possible benefit from breastfeeding. The drug is contraindicated in women who are breastfeeding an infant.

Adult Concerns:

This section lists the most prevalent undesired or bothersome side effects listed for adults. As with most medications, the occurrence of these is often quite rare, generally less than 1%-10%. Side effects vary from one patient to another, with most patients not experiencing untoward effects.

Pediatric Concerns:

This section lists the side effects noted in the published literature as associated with medications transferred via human milk. Pediatric concerns are those effects that were noted by investigators as being associated with drug transfer via milk. In some sections, we have added comments that may not have been reported in the literature, but are well known attributes of this medication.

Infant Monitoring:

This section provides advice to the clinician regarding potential side effects that may occur in the infant from exposure to a medication in breast milk. The infant monitoring parameters can be used by the clinician to educate the mother about potential side effects that could occur in the infant.

Relative Infant Dose:

The Relative Infant Dose (RID) is calculated by dividing the infant’s dose via milk in “mg/kg/day” by the maternal dose in “mg/kg/day” (see page 9). This weight-normalizing method indicates approximately how much of the “maternal dose” the infant is receiving. Many authors now use this calculation because it gives a better indication of the relative dose transferred to the infant. We report RID ranges, as this gives the reader an estimate of all the Relative Infant Doses published by the various authors.

Please understand, however, that many authors use different methods for calculating RID. Some are not weight-normalized. In these cases, their estimates may differ slightly from this book. While we often place the authors’ estimates of Relative Infant Dose in the text, the RID range that we calculate is weight-normalized in all instances when the maternal weight is provided. So RID may be slightly different according to how it is calculated.

Many researchers now suggest that anything less than 10% of the maternal dose is probably safe. This is usually correct. However, some drugs (metronidazole, acetaminophen) actually have much higher Relative Infant Doses, but because they are quite non-toxic, they do not often bother an infant. To calculate this dose, we chose the data we felt was best, and this often included larger studies with AUC calculations of mean concentrations in milk. When maternal weights are not published, we choose an average body weight of 70 kg for an adult. Thus, most of the RIDs herein are calculated assuming a maternal average weight of 70 kg and a daily milk intake of 150 mL/kg/day in the infant.

Adult Dosage:

This is the usual adult oral dose provided in the package insert. While these are highly variable, wechose the dose for the most common use of the medication.

Alternatives:

Drugs listed in this section may be suitable alternate choices for the medication listed above. In many instances, if the patient cannot take the medication or it is a poor choice due to high milk concentrations, these alternates may be suitable candidates. WARNING: The alternatives listed are only suggestions and may not be at all appropriate for the syndrome in question. Only the clinician can make this judgment. For instance, nifedipine is a calcium channel blocker with good antihypertensive qualities, but poor antiarrhythmic qualities. In this case, verapamil would be a better choice.

T½=

This lists the most commonly recorded adult half-life of the medication. It is very important to remember that short half-life drugs are preferred. Use this parameter to determine if the mother can successfully breastfeed around the medication by nursing the infant, then taking the medication. If the half-life is short enough (1-3 hours), then the drug level in the maternal plasma will be declining when the infant feeds again. This is ideal. If the half-life is significantly long (12-24 hours) and if your physician is open to suggestions, then find a similar medication with a shorter half-life (compare ibuprofen with naproxen). However, in todays world, longer-half life drugs are preferred and we simply have to accomodate these and rely on published data.

Vd=

The volume of distribution is a useful kinetic term that describes how widely the medication is distributed in the body. Drugs with high volumes of distribution (Vd) are distributed in higher concentrations in remote compartments of the body and may not stay in the blood. Marijuana is a classic example.

Another such drug, digoxin enters the blood compartment and then rapidly leaves to enter the heart and skeletal muscles. Most of the drug is sequestered in these remote compartments (100-fold). Therefore, drugs with high volumes of distribution (1-20 L/kg) generally require much longer to clear from the body than drugs with smaller volumes (<1 L/kg). For instance, whereas it may only require a few hours to totally clear gentamycin (Vd = 0.28 L/kg), it may require weeks to clear amitriptyline (Vd = 10 L/kg). Further, some drugs may have one half-life for the plasma compartment, but may have a totally different half-life for the peripheral compartment, as half-life is a function of volume of distribution. We have found that drugs with high Vd generally produce lower milk levels. For a complete description of Vd, please consult a good pharmacology reference. In this text, the units of measure for Vd are L/kg.

T_max=

This lists the time interval from administration of the drug until it reaches the highest level in the mother’s plasma (C_max), which we call the peak or “time to max”, hence T_max. Occasionally, you may be able to avoid nursing the baby when the medication is at the peak. Rather, wait until the peak is subsiding or has at least dropped significantly. Remember, drugs enter breast milk as a function of the maternal plasma concentration. In general, the higher the mother’s plasma level, the greater the entry of the drug into her milk. If possible, choose drugs that have short peak intervals, and suggest mom not breastfeed when the drug is at C_max.

MW=

The molecular weight of a medication is a significant determinant as to the entry of that medication into human milk. Medications with small molecular weights (<200 Da) can easily pass into milk by traversing small pores in the cell walls of the mammary epithelium (see ethanol). Drugs with higher molecular weights must traverse the membrane by dissolving in the cells’ lipid membranes, which may significantly reduce milk levels. As such, the smaller the molecular weight, the higher the relative transfer of that drug into milk. Protein medications (e.g., heparin), which have enormous molecular weights, transfer at much lower concentrations and are virtually excluded from human breast milk. Therefore, when possible, choose drugs with higher molecular weights to reduce their entry into milk. A new class of drugs has risen in popularity in the last decade. These are the monoclonal antibodies. These very selective antibodies mostly derived from human IgG1-4, are used to treat a number of severe diseases, such as Crohn’s disease, multiple sclerosis, rheumatoid conditions, migraine headache, etc. Interesly, IgG molecules are enormous in molecular weight (around 160,000 Da) and thus enter the milk compartment poorly. Further, they are largely destroyed by proteases in the GI tract of the infant if presented in milk. At this point, we do not think much, if any, of these monoclonals enter milk, or survive the GI tract of the infant. Thus far, all studies of these antibodies in human milk thus far, suggest levels in milk are far less than 1.0%, and virtually none of this would survive the GI tract of the infant. However, the use of these drugs in pregnant women in the last trimester, may produce significant plasma levels in the fetus, and thus the newborn infant. Thus some infants could be susceptible to problems associated with the fetal exposure to these drugs (immunosuppressed). Current data thus far does not suggest significant transfer of these products into human milk.

M/P=

This lists the milk/plasma ratio. This is the ratio of the concentration of drug in the mother’s milk divided by the concentration in the mother’s plasma. If high (>1-5), it is useful as an indicator of drugs that may sequester in milk in high levels. If low (<1), it is a good indicator that only minimal levels of the drug are transferred into milk (this is preferred). While it is best to try to choose drugs with LOW milk/plasma ratios, the amount of drug which transfers into human milk is largely determined by the level of drug in the mother’s plasma compartment. Even with high M/P ratios and LOW maternal plasma levels, the amount of drug that transfers is still low. Therefore, the higher M/P ratios often provide an erroneous impression that large amounts of drug are going to transfer into milk. This simply may not be true.

PB=

This lists the percentage of maternal protein binding. Most drugs circulate in the blood bound to plasma albumin and other proteins. If a drug is highly protein bound, it cannot enter the milk compartment as easily. The higher the percentage of binding, the less likely the drug is to enter the maternal milk. Try to choose drugs that have high protein binding in order to reduce the infant’s exposure to the medication. Good protein binding is typically greater than 90%.

Oral=

Oral bioavailability refers to the ability of a drug to reach the systemic circulation after oral administration. It is generally a good indication of the amount of medication that is absorbed into the blood stream of the patient. Drugs with low oral bioavailability are generally either poorly absorbed in the gastrointestinal tract, are destroyed in the gut, or are sequestered by the liver prior to entering the plasma compartment. The oral bioavailability listed in this text is the adult value; almost none have been published for children or neonates. Recognizing this, these values are still useful in estimating if a mother or perhaps an infant will actually absorb enough drug to provide clinically significant levels in the plasma compartment of the individual. The value listed estimates the percent of an oral dose that would be found in the plasma compartment of the individual after oral administration. In many cases, the oral bioavailability of some medications is not listed by manufacturers, but instead terms such as “Complete,” “Nil,” or “Poor” are used. For lack of better data, we have included these terms when no data are available on the exact amount (percentage) absorbed.

pKa=

The pKa of a drug is the pH at which the drug is equally ionic and nonionic. The more ionic a drug is, the less capable it is of transferring from the milk compartment to the maternal plasma compartment. Hence, the drug becomes trapped in milk (ion-trapping). This term is useful because drugs that have a pKa higher than 7.2 may be sequestered to a slightly higher degree than one with a lower pKa. Drugs with higher pKa generally have higher milk/plasma ratios. Hence, choose drugs with a lower pKa.

With many drugs, the pharmacokinetics have not been described or published. In this case we leave this entry blank.