How To Read Drug Entries
Drug Name and Generic Name
Each monograph begins with the generic name (capitalized in index)of the drug. Several of the most common USA trade names are provided under the Trade section.
Most, but not all, of the most common trade names used in Canada, Australia, and the United Kingdom are provided.
This lists the general use of the medication, such as penicillin antibiotic, or antiemetic, or analgesic, etc. Remember, many drugs have multiple uses in many syndromes. I have only listed the most common use.
This entry lists the new recommendations provided by the American Academy of Pediatrics as published in their document. The transfer of drugs and other chemicals into human milk (Pediatrics. 2001 Sep;108(3):77689.). Drugs are listed in tables according to the following recommendations: Cytotoxic drugs that may interfere with cellular metabolism of the nursing infant; Drugs of abuse for which adverse effects on the infant during breastfeeding have been reported; Radioactive compounds that require temporary cessation of breastfeeding; Drugs for which the effect on nursing infants is unknown but may be of concern; Drugs that have been associated with significant effects on some nursing infants and should be given to nursing mothers with caution; Maternal medication usually compatible with breastfeeding.
In this book, the AAP recommendations have been paraphrased to reflect these recommendations. Because the AAP recommendations do not cover all drugs, "Not Reviewed" simply implies that the drug has not yet been reviewed by this committee. The author recommends that each user review these recommendations for further detail.
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. I have reported only what the references have documented.
Pregnancy Risk Category
Pregnancy risk categories have been assigned to almost all medications by their manufacturers and are based on the level of risk the drug poses to the fetus during gestation. They are not useful in assigning risk via breastfeeding. The FDA has provided these five categories to indicate the risk associated with the induction of birth defects. Unfortunately, they do not indicate the importance of when during gestation the medication is used, since some drugs are more dangerous during certain trimesters of pregnancy. The definitions provided below are, however, a useful tool in determining the possible risks associated with using the medication during pregnancy. Some newer medications may not yet have pregnancy classifications and are therefore not provided herein.
Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters) and the possibility of fetal harm appears remote.
Either animal-reproduction studies have not demonstrated a fetal risk, but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).
Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal, or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (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).
Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
Lactation Risk Category
L1 - No Data-Compatible
L1 - Limited Data-Compatible
L1 - Extensive Data-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 - No Data-Probably Compatible
L2 - Limited Data-Probably Compatible
L2 - Significant Data-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 - No Data-Probably Compatible
L3 - Limited Data-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 - No Data-Possibly Hazardous
L4 - Limited Data-Possibly Hazardous
L4 - Significant Data-Possibly Hazardous
There is positive evidence of risk to a breastfed infant or to breastmilk 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 - No Data-Hazardous
L5 - Limited Data-Hazardous
L5 - Significant Data-Hazardous
L5 - Limited Data-Hazardous if Maternal HIV Infection
L5 - No Data-Hazardous if Maternal HIV Infection
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.
Theoretic Infant Dose
This is an estimate (hence the term "Theoretic") of the maximum likely dose per kilogram per day that an infant would ingest via milk. Because the literature is highly variable, I used several methods to calculate this estimate. First, if the authors provided milk AUC information or clear estimates of the average amount in milk during the day, I used this data to estimate the dose to the infant as it is much more accurate. But more commonly, the only data provided was the peak milk level, also called Cmax. In these cases I used this data to derive the theoretic infant dose. For determining dose I used the standard milk intake of 150 mL/kg/day multiplied times the concentration of medication in milk (Cmax/Liter X 0.150 mL/kg/day= TID). Please remember, this is generally the maximum concentration that would be transferred. Most often the actual dose to the infant would be much lower. If you know the maternal dose, calculate the Relative Infant Dose using the formula below. It may prove very useful.
Relative Infant Dose
The relative infant dose (RID) is calculated by dividing the infants dose via milk (Theoretic Infant Dose) in mg/kg/day by the maternal dose in mg/kg/day (see box above). This weight-normalizing method gives one a feeling for just how much of the ?maternal dose? the infant is receiving. Many authors now use this preferred method because it gives the reader a better idea of the relative dose transferred to the infant. These same authors also suggest that anything less than 10% of the maternal dose is probably safe. This is usually correct. However, some drugs (metronidazole, fluconazole) 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, I chose the data I felt was best and this often included larger studies with AUC calculations of mean concentrations in milk. I also chose an average body weight of 70 kg for an adult. Thus the RIDs herein are calculated assuming a maternal average weight of 70 kg, and a daily intake of 150 mL/kg/day in the infant. Please note, many authors fail to normalize their data for weight. Others provide a RID for each feeding, not a daily average. Therefore, my values may vary slightly from others due simply to differences in the method of calculation.
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% of the time. Side effects vary from one patient to another and should not be overemphasized, since most patients do not experience untoward effects.
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. They are not the effects that would result from direct administration to the infant. In some sections, I have added comments that may not have been reported in the literature, but are well known attributes of this medication and are useful information to provide the mother so that she can better care for her infant (Observe for weakness, apnea).
Drug interactions generally indicate which medications, when taken together, may produce higher or lower plasma levels of other medications, or they may decrease or increase the effect of another medication. These effects may vary widely from minimal to dangerous. Because some medications have hundreds of interactions, and because I had limited room to provide this information, I have listed only those that may be highly significant. Therefore please be advised that this section may not be complete. In several references, I have suggested that due to the large number of interactions the reader consult a more complete drug interaction reference. Please remember that the drugs administered to a mother could interact with those being administered concurrently to an infant. Example: Maternal fluconazole and pediatric cisapride.
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 alternates listed are only suggestions and may not be at all proper 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.
This is the usual adult oral dose provided in the package insert. While these are highly variable, I chose the dose for the most common use of the medication.
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), then find a similar medication with a shorter half-life (compare ibuprofen with Naproxen).
This lists the most commonly recorded pediatric half-life of the medication. Medications with extremely long half-lives (>12 hours) in pediatric patients may accumulate to high levels in the infant?s plasma. Pediatric half-lives are difficult to find due to the paucity of studies.
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 to 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.
Tmax ( formerly PK )
This lists the time interval from administration of the drug, until it reaches the highest level in the mother?s plasma (Cmax), which we call the peak or time to max , hence Tmax. The peak is when you do not want the mother to breastfeed her infant, rather, wait until the peak is subsiding or has at least dropped significantly. Remember, drugs enter breastmilk as a function of the maternal plasma concentration. 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 it is at Cmax.
This lists the percentage of maternal protein binding. Most drugs circulate in the blood bound to plasma albumin. If a drug is highly protein bound it cannot exit the plasma compartment as well. 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 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, or they 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, I have included these terms when no data is available on the exact amount (percentage) absorbed.
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. For instance, digoxin enters the blood compartment and then rapidly leaves to enter the heart and skeletal muscle. Most of the drug is sequestered in these remote compartments (100 fold). Therefore, drugs with high volumes of distribution (1-20 liter/kg ) generally require much longer to clear from the body than drugs with smaller volumes (0.1 liter/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) which has a huge volume of distribution. In addition, 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. For a complete description of Vd, please consult a good pharmacology reference. In this text, the units of measure for Vd are liters/kg.
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, they become 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.
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) 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 lipid bilayer, 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, Insulin), which have enormous molecular weights, transfer at much lower concentrations and are virtually excluded from human breastmilk. Therefore, when possible, choose drugs with higher molecular weights to reduce their entry into milk.