http://pubmedsfakianakis.blogspot.com/2017/05/antibiotic-use-in-pregnancy-and.html
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
Παρασκευή 26 Μαΐου 2017
leven Broad-Spectrum Antibiotics Investigated Antibiotic Description Year of Initial FDA Approval Amoxicillin Semi-synthetic beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1974 Chloramphenicol Broad-spectrum antibiotic isolated from Streptomyces venezuela in 1947, now synthetically available. Binds to the 50S subunit of bacterial ribosomes, inhibiting peptide bond formation and protein synthesis. 1950 Ciprofloxacin Fluoroquinolone antibiotic. Exerts its bactericidal effect by disrupting DNA replication, transcription, recombination, and repair by inhibiting bacterial DNA gyrase. 1987 Clindamycin Antibiotic derived from lincomycin that has wide-ranging antimicrobial activity. Binds to the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. 1970 Doxycycline Broad-spectrum antibiotic that binds to the 30S bacterial ribosomal subunit. Blocks the binding of transfer-RNA to messenger-RNA, thereby disrupting prote
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
Reviews Antibiotic Use in Pregnancy and Lactation What Is and Is Not Known About Teratogenic and Toxic Risks Gerard G. Nahum, MD , CAPT Kathleen Uhl, USPHS, and CAPT Dianne L. Kennedy, USPHS OBJECTIVE: Over ten million women are either pregnant or lactating in the United States at any time. The risks of medication use for these women are unique. In addition to normal physiologic changes that alter the pharmaco- kinetics of drugs, there is the concern of possible terato- genic and toxic effects on the developing fetus and newborn. This article reviews the risks and pharmacoki- netic considerations for 11 broad-spectrum antibiotics that can be used to treat routine and life-threatening infections during pregnancy and lactation. DATA SOURCES: Information from the U.S. Food and Drug Administration (FDA) product labels, the Teratogen Information Service, REPROTOX, Shepard's Catalog of Teratogenic Agents, Clinical Pharmacology, and the peer- reviewed medical literature was reviewed concerning the use of 11 antibiotics in pregnant and lactating women. The PubMed search engine was used with the search terms "[antibiotic name] and pregnancy," "[antibiotic name] and lactation," and "[antibiotic name] and breast- feeding" from January 1940 to November 2005, as well as standard reference tracing. METHODS OF STUDY SELECTION: One hundred twen- ty-four references had sufficient information concerning numbers of subjects, methods, and findings to be in- cluded. TABULATION, INTEGRATION, AND RESULTS: The ter- atogenic potential in humans ranged from "none" (pen- icillin G and VK) to "unlikely" (amoxicillin, chloramphen- icol, ciprofloxacin, doxycycline, levofloxacin, and rifampin) to "undetermined" (clindamycin, gentamicin, and vancomycin). Assessments were based on "good data" (penicillin G and VK), "fair data" (amoxicillin, chlor- amphenicol, ciprofloxacin, doxycycline, levofloxacin, and rifampin), "limited data" (clindamycin and gentamicin), and "very limited data" (vancomycin). Significant phar- macokinetic changes occurred during pregnancy for the penicillins, fluoroquinolones and gentamicin, indicating that dosage adjustments for these drugs may be neces- sary. With the exception of chloramphenicol, all of these antibiotics are considered compatible with breastfeed- ing. CONCLUSION: Health care professionals should con- sider the teratogenic and toxic risk profiles of antibiotics to assist in making prescribing decisions for pregnant and lactating women. These may become especially impor- tant if anti-infective countermeasures are required to protect the health, safety, and survival of individuals exposed to pathogenic bacteriologic agents that may occur from bioterrorist acts. (Obstet Gynecol 2006;107:1120–38) A ntibiotics are among the most commonly pre- scribed prescription medications for pregnant and lactating women. 1 More than 10 million women are either pregnant or lactating in the United States at any one time, and they are administered antibiotics for many reasons. 2 Because of the special consider- ations associated with fetal and newborn develop- ment, these women constitute a uniquely vulnerable population for which the risks of medication use must be separately assessed. In addition to the pharmacokinetic and pharma- codynamic changes that may occur during pregnancy and lactation that can alter the effectiveness of drugs, 3 there is the added concern of the possible teratogenic and toxic effects that medications may have on the developing fetus and newborn. In general, there is a dearth of pharmacokinetic and pharmacodynamic information regarding the use and proper dosing of Food and Drug Administration (FDA)–approved From the Department of Obstetrics and Gynecology, Uniformed Services Uni- versity of the Health Sciences, Bethesda, Maryland; Office of Women's Health, U.S. Food and Drug Administration, Rockville, Maryland; FDA Center for Drug Evaluation and Research, Silver Spring, Maryland. Presented in part at the FDA Science Forum in Washington, DC, April 27–28, 2005. The views, opinions, interpretations, and conclusions expressed in this article are those of the authors only and do not reflect either the policies or positions of the Center for Drug Evaluation and Research, the U.S. Food and Drug Adminis- tration, or the U.S. Department of Health and Human Services. Corresponding author: Gerard G. Nahum, MD, FACOG, FACS, Box 2184, Rockville, MD 20847; e-mail: GNahum2003@yahoo.com. © 2006 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/06 1120 VOL. 107, NO. 5, MAY 2006 OBSTETRICS & GYNECOLOGY drugs in pregnant and lactating women, as well as limited data pertaining to the teratogenic potential and the fetal or neonatal toxicity of these marketed medications. Accordingly, sparse information must sometimes be assembled from diverse sources to address these issues. Recently, the threat of bioterrorism has expanded the context in which the potential use of antibiotic medications may be needed. 4 Although the possibility of a large-scale bioterrorist attack in the United States is unlikely, the potential for widespread antibiotic use in this situation emphasizes the need for health care professionals to be familiar with the risks and benefits of administering antibiotics to pregnant and lactating women. This article reviews the available information concerning the risks and special circumstances to be considered in pregnant and lactating women for a group of 11 broad-spectrum antibiotics (amoxicillin, chloramphenicol, ciprofloxacin, clindamycin, doxy- cycline, gentamicin, levofloxacin, penicillin G, peni- cillin VK, rifampin, and vancomycin). By using this information, better choices can be made for the treatment of different types of bacterial pathogens in these particularly vulnerable populations. DATA SOURCES AND METHODS OF STUDY SELECTION Information from FDA-approved product labels, the Teratogen Information Service, Shepard's Catalog of Teratogenic Agents, REPROTOX, Clinical Pharma- cology, and the peer-reviewed literature were re- viewed for information concerning the use of 11 antibiotics in pregnant and lactating women. The medical literature was queried with the PubMed search engine. Papers searched were published from January 1940 to November 2005, in any language. The search terms "[antibiotic name] and pregnancy," "[antibiotic name] and lactation,", and "[antibiotic name] and breastfeeding," were used, as was standard reference tracing. A total of 124 references were accessed through these sources that contained suffi- cient information concerning the numbers of subjects, methods of investigation, and findings to be useful for the purpose of drawing conclusions concerning phar- macokinetic parameters, teratogenic potential, and toxicity assessments of these drugs. All materials were restricted to information from nonproprietary sources that were available in the public domain. Addition- ally, information concerning the potential treatment options for exposures and diseases caused by possible agents of bioterrorism were obtained from materials published by the Centers for Disease Control and Prevention in Atlanta. RESULTS A description of the 11 broad-spectrum antibiotics and their general modes of action are provided in Table 1. All 11 antibiotics cross the placenta and enter the fetal compartment. For 5 of these, human umbilical cord blood levels are of the same order of magnitude as circulating maternal blood concentrations (chlor- amphenicol, clindamycin, gentamicin, rifampin, and vancomycin). For 4, the concentrations are of the same magnitude or higher in amniotic fluid as in maternal blood (ciprofloxacin, clindamycin, levo- floxacin, and vancomycin) (Table 2). All 11 antibiotics are excreted in human breast milk. Limited information concerning the amount in breast milk was available for 8 antibiotics (ciprofloxa- cin, clindamycin, doxycycline, gentamicin, levofloxa- cin, penicillin G, penicillin VK, and rifampin). No quantitative data concerning breast milk concentra- tions were available for 3 (amoxicillin, chloramphen- icol, and vancomycin) (Table 2). Using the Teratogen Information Service clas- sification system for teratogenic risk, 44 the terato- genic potential of the 11 antibiotics during human pregnancy ranged from "none" in 2 cases (penicil- lin G and VK) to "unlikely" in 6 (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levo- floxacin, and rifampin) to "undetermined" in 3 (clindamycin, gentamicin, and vancomycin). As- sessments were based on data that were "good" for 2 (penicillin G and VK) to "fair" for 6 (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levo- floxacin, and rifampin) to "limited" for 2 (clinda- mycin and gentamicin) to "very limited" for 1 (vancomycin). A summary of the human and ani- mal data contributing to these assessments is shown in Table 3. The Food and Drug Administration Pregnancy Category classifications for the 11 anti- biotics (as defined under 21 CFR [Code of Federal Regulations] 201.57 for the A, B, C, D, X Preg- nancy Category system) (Table 4) were "B" in 5 cases (amoxicillin, clindamycin, penicillin G, peni- cillin VK, and vancomycin), "C" in 5 cases (chlor- amphenicol, ciprofloxacin, gentamicin, levofloxa- cin, and rifampin), and "D" in 1 case (doxycycline) (Table 3). In addition to the published literature, proprietary data were used to establish the FDA pregnancy category for these drugs. Despite numerous concerns regarding the poten- tial for maternal and fetal or neonatal toxicity of these VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1121 11 drugs—including idiosyncratic and dose-related bone marrow suppression with chloramphenicol, ar- thropathies and bone and cartilage damage with ciprofloxacin and levofloxacin, dental staining and hepatic necrosis with doxycycline, and ototoxicity and nephrotoxicity with gentamicin and vancomy- cin—none of these toxicities has been documented in human mothers or offspring either during preg- nancy or breastfeeding with these antibiotics (Table 3). Very limited information was available pertain- ing to maternal pharmacokinetics in pregnancy for 8 antibiotics (amoxicillin, ciprofloxacin, clindamycin, gentamicin, levofloxacin, penicillin G, penicillin VK, and vancomycin), and none was available for 3 (chloramphenicol, doxycycline, and rifampin) (Table 2). For 4 antibiotics (amoxicillin, gentamicin, penicil- lin G, and penicillin VK), lower circulating drug concentrations were measured in pregnant women than nonpregnant, suggesting that a shorter dosing interval or increased maternal dose or both may be necessary to obtain similar circulating drug concen- trations as for women in the nonpregnant state. In the case of ciprofloxacin and levofloxacin, circulating concentrations were generally reduced in pregnant women, also suggesting that an increased maternal dose or a shorter dosing interval or both may be necessary. In 3 cases (chloramphenicol, gentamicin, and vancomycin), therapeutic drug monitoring of serum peak and trough levels is recommended to assess circulating drug levels. In 1 case (clindamycin), the standard pharmacokinetic parameters did not change appreciably during the first, second, or third trimester of pregnancy (Table 2). Very little pharma- Table 1. Description of the Eleven Broad-Spectrum Antibiotics Investigated Antibiotic Description Year of Initial FDA Approval Amoxicillin Semi-synthetic beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1974 Chloramphenicol Broad-spectrum antibiotic isolated from Streptomyces venezuela in 1947, now synthetically available. Binds to the 50S subunit of bacterial ribosomes, inhibiting peptide bond formation and protein synthesis. 1950 Ciprofloxacin Fluoroquinolone antibiotic. Exerts its bactericidal effect by disrupting DNA replication, transcription, recombination, and repair by inhibiting bacterial DNA gyrase. 1987 Clindamycin Antibiotic derived from lincomycin that has wide-ranging antimicrobial activity. Binds to the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. 1970 Doxycycline Broad-spectrum antibiotic that binds to the 30S bacterial ribosomal subunit. Blocks the binding of transfer-RNA to messenger-RNA, thereby disrupting protein synthesis. 1967 Gentamicin Aminoglycoside antibiotic with broad-spectrum activity. Binds irreversibly to 30S bacterial ribosomal subunit, thereby inhibiting protein synthesis. 1966 Levofloxacin Fluoroquinolone antibiotic. L-isomer of ofloxacin, which provides its principal antibiotic effect. Inhibits bacterial DNA replication, transcription, recombination, and repair by inhibiting bacterial type II topoisomerases. 1996 Penicillin G Beta-lactam antibiotic that is primarily bactericidal. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1943 Penicillin V (phenoxymethyl penicillin) Naturally derived beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. Considered preferable to penicillin G for oral administration because of its superior gastric acid stability. 1956 Rifampin Rifamycin B derivative that inhibits bacterial and mycobacterial DNA-dependent RNA polymerase activity. Used primarily for the treatment of tuberculosis, with additional utility for the treatment of both leprosy and meningococcal carriers. 1971 Vancomycin Glycopolypeptide antibiotic. Binds to the precursor units of bacterial cell walls, inhibiting their synthesis and altering cell wall permeability while also inhibiting RNA synthesis. Because of its dual mechanism of action, bacterial resistance is rare. 1964 FDA, U.S. Food and Drug Administration. 1122 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Amoxicillin Gram-positive aerobes, most gram-positive anaerobes, gram- negative aerobes including some enteric bacilli, Helicobacter, spirochetes, actinomyces* Crosses the human placenta. 5–7 Penicillins transferred to the fetus and amniotic fluid reach therapeutic levels. 5 Excreted in human breast milk in small amounts. 8 Considered "usually compatible with breastfeeding." 9† Following therapeutic doses, mean human milk concentrations were 0.1–0.6 g/mL. 10 No adverse effects seen in nursing infants whose mothers have been treated with amoxicillin. Shorter dosing interval and/ or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillins are primarily renally excreted via tubular secretion and glomerular filtration. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 Chloramphenicol Gram positives, gram negatives, anaerobes, chlamydia, rickettsiae Crosses the human placenta readily. Umbilical cord serum concentrations 29–106% of maternal levels. 12 Excreted in human breast milk. 13–15 In 5 patients with minor obstetrical lacerations who receive d1gPOqDfor8 days, mean milk concentrations were 0.5–2.8 g/mL. In 5 patients receivin g2gPOqDfor8 days for mastitis, mean milk concentrations were 1.8–6.1 g/mL. 13 Human milk concentrations are 51–62% of blood levels. 14 Percentage of administered dose in human breast milk per day is 1.3%. 15 Effect on breastfed infants considered "unknown but may be of concern." 16 Unknown whether dose adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Serum concentrations can be monitored to keep peak and trough levels in the ranges of 10–20 and 5–10 g/mL, respectively. CBC monitored to detect bone marrow depression. Ciprofloxacin Gram-negative aerobes, some staphylococci Crosses the human placenta and concentrates in amniotic fluid (Product information Cipro, 2001). 17 In 20 women at 19–25 weeks of gestation who received two 200-mg IV doses q 12 hours, the mean amniotic fluid level 2–4 hours after dosing was 0.12 0.06 g/mL (n 7; amniotic fluid: maternal serum concentration [AF:MS ratio] 0.57), 0.13 0.07 g/mL at 6–8 hours (n 7; AF:MS ratio 1.44), and 0.10 0.04 g/mL at 10–12 hours (n 6; AF: MS ratio 10.00). 17 Excreted in human breast milk (Product information Cipro, 2001). 17 Considered usually compatible with breastfeeding." 9† In 10 women given 750 mg q12 hours PO, serum and milk concentrations were obtained 2, 4, 6, 9, 12, and 24 hours after the 3rd dose. Concentrations were 3.79 1.26, 2.26 0.75, 0.86 0.27, 0.51 0.18, 0.20 0.05, and 0.02 0.006 g/mL at these times and the ratios of breast milk: serum concentration were 1.84, 2.14, 1.60, 1.70, 1.67, and 0.85, respectively. 17 For breastfeeding infants consuming 150 mL/kg per day, the estimated maximum dose is 0.569 mg/kg per day or 2.8% the approved dose for infants of 20 mg/kg per day. 18 Circulating fluoroquinolone concentrations are lower in pregnant than in nonpregnant women, but no specific pharmacokinetic data is available regarding ciprofloxacin in pregnant women. 19 It is unknown whether dose adjustments during pregnancy are necessary. Approximately 50–70% of a dose is excreted in the urine and, if renal function is impaired, the serum half- life is slightly prolonged (Product information Cipro, 2001). ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1123 Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Clindamycin Gram-positive anaerobes, gram- negative anaerobes, aerobic gram-positive cocci, streptococci, Clostridia strains Crosses the human placenta readily. 44,20–23 In 54 women undergoing cesarean delivery who received 600 mg IV 30 minutes before surgery, umbilical cord blood concentrations were 46% of maternal serum levels. 20 After multiple oral doses prior to therapeutic abortion, fetal blood concentrations were 25% and amniotic fluid levels were 30% of maternal blood levels. 21 Excreted in human breast milk (Product information Clindamycin, 1970). Considered "usually compatible with breastfeeding." 9† At maternal doses of 150 mg orally to 600 mg IV, breast milk concentrations range from 0.7 to 3.8 g/mL (Product information Clindamycin, 1970). Pharmacokinetic parameters do not change during pregnancy in women studied during the 1st, 2nd, and 3rd trimesters of gestation. 20,24 There are no studies to indicate that dosing should be modified during pregnancy. C max and T max (after a single standard dose) and C ss (after multiple doses) do not change appreciably at any time during pregnancy. Doxycycline Gram-positives, gram- negatives, rickettsiae, chlamydiae, mycoplasma, spirochetes, actinomyces Crosses the placenta (Product information Vibramycin, 2001). Excreted in human breast milk. 25 Use for a short period (1 week) during breastfeeding is considered probably safe. 9,16 Breast milk concentrations are 30–40% of that found in maternal blood. 25 Unknown whether dose adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Enterohepatically recirculated. Excreted in urine and feces as unchanged drug. From 29% to 55.4% of a dose can be accounted for in the urine by 72 hours (Product information Vibramycin, 2001). Gentamicin Gram-negative aerobic rods, many streptococci, Staphylococcus aureus , mycobacteria Crosses the human placenta. 20,26–28 In 2 different studies, peak umbilical cord blood levels were 34% 26 and 42% 20 of associated maternal blood concentrations. Excreted in human breast milk. 29,30 Considered "usually compatible with breastfeeding." 9† Poorly absorbed from the GI tract. 29 Only half of nursing newborns had detectable serum levels, which were low and not likely to cause clinical effects. 29 No adverse signs or symptoms in nursing infants as a result of maternal treatment. 9 Increased dosage suggested due to decreased serum half-life in pregnancy and lower maternal serum levels. 20,31 In 54 women undergoing cesarean delivery, levels were lower than nonpregnant women. 20 Eliminated mainly by glomerular filtration (Product information Gentamicin, 1966). Clearance decreased in preeclamptic patients. 32 Dose/ dosing interval adjusted via peak and trough levels (Product information Gentamicin 1966). ( continued ) 1124 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Levofloxacin Gram-positives and gram-negatives Crosses the human placenta and concentrates in amniotic fluid (based on data for racemic ofloxacin) (Product information Levaquin, 1996). 17 In 20 women at 19–25 weeks of gestation receiving two IV 400-mg doses of ofloxacin q12 hours, mean amniotic fluid concentration 3–6 hours after dosing was 0.25 0.11 g/mL (n 6; amniotic fluid: maternal serum concentration [AF:MS ratio] 0.35), 0.15 0.11 g/mL at 6–10 hours (n 8; AF:MS ratio 0.67), and 0.13 0.11 g/mL at 11–12 hours (n 6; AF:MS ratio 2.57). 17 Excreted in human breast milk in high concentrations (based on data for racemic ofloxacin) (Product information Levaquin, 1996). 17 Considered "usually compatible with breastfeeding." 9† In 10 women given 400 mg of ofloxacin q12 hours PO, serum and milk concentrations were obtained 2, 4, 6, 9, 12, and 24 hours after the 3rd dose. Concentrations were 2.41 0.80, 1.91 0.64, 1.25 0.42, 0.64 0.21, 0.29 0.10, and 0.05 0.02 g/mL at these times, with breast milk: serum concentration ratios of 0.98, 1.30, 1.39, 1.25, 1.12, and 1.66, respectively. 17 For breastfed infants consuming 150 mL/kg per day, the estimated maximum infant dose of ofloxacin is 0.362 mg/kg per day. 18 Circulating fluoroquinolone concentrations are lower in pregnant than in nonpregnant women, but no specific pharmacokinetic data is available regarding levofloxacin in pregnant women. 19 There are no data to support dosing adjustments during pregnancy. Penicillin G Gram-positive aerobes including most streptococci/ enterococci, gram- positive anaerobes, spirochetes, actinomyces, some gram negatives* Crosses the human placenta. 5,33,34 Penicillins are transferred to the fetus and amniotic fluid reaching therapeutic levels. 5 Excreted in human breast milk in small amounts (Product information Bicillin, 2001; product information Penicillin V, 1997). 15 Considered "usually compatible with breastfeeding." 9† In women with serum concentrations of penicillin ranging from 6 to 120 g/dL, corresponding breast milk concentrations were 1.2–3.6 g/dL, and the amount of the maternal dose appearing in breast milk per day was estimated at 0.03%. 15 Shorter dosing interval and/ or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillins are primarily renally excreted via tubular secretion and glomerular filtration. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 Penicillin VK Gram-positive aerobes including most streptococci/ enterococci, gram- positive anaerobes, gram negatives Crosses the human placenta readily. 5,7,10,33,34,35 Penicillins are transferred to the fetus and amniotic fluid reaching therapeutic levels. 5 Excreted in human breast milk in small amounts (Product information Penicillin V, 1997). 15,36 Considered "usually compatible with breastfeeding." 9† In 18 women, penicillin V milk concentration depended on presence of mastitis, with peak levels 2.6–5.4 hours after a single PO 1,320-mg dose. 35 Peak concentration was 30–72 g/dL with mean concentration 26-37 g/dL. AUC over 8 hours after dosing was 2.1–3.0 mg-h/L. 35 Estimated dose of penicillin V ingested per day by breastfed infants is 40–60 g/kg, or 0.09– 0.14% of maternal dose per kg body weight. 35 Shorter dosing interval and/or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillin V is excreted renally, primarily via tubular secretion. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1125 Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Rifampin Mycobacteria, Neisseria meningitidis , S aureus , Haemophilus influenzae , Legionella pneumophila , Chlamydia Crosses the human placenta (Product information Rifampin, 1971). 37–39 Umbilical cord concentrations between 12% and 33% of maternal blood levels, with peak levels occurring concurrently after drug administration. 37–39 Excreted in human breast milk (Product information Rifampin, 1971). 15,40,41 Considered "usually compatible with breastfeeding." 9† After a single oral dose of 600 mg, a nursing infant would ingest approximately 0.05% of the maternal dose per day, or approximately 0.3 mg/day. 15,40,41 Unknown whether dosing adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Hepatically deacetylated to active metabolite. Parent compound and metabolites excreted via biliary elimination (60%). Enterohepatic re-circulation; plasma levels elevated in hepatic disease. Up to 30% excreted in urine; renal clearance is 12% of GFR. 38 Vancomycin Gram positives, S aureus , Staphylococcus epidermidis , streptococci, enterococci, Clostridium , Coryne- bacterium Crosses the human placenta (Product information Vancomycin, 1964). 42,43 Appears in umbilical cord blood after IV maternal treatment (Product information Vancomycin, 1964). 42,43 Amniotic fluid and umbilical cord blood concentrations during the early 3rd trimester comparable to maternal blood levels (fetal-maternal serum concentration ratio of 0.76). 43 Excreted in human breast milk when administered IV (Product information Vancomycin, 1964). 42 When administered orally, vancomycin is poorly absorbed from the GI tract (Product information Vancomycin, 1964). It is, therefore, not likely to cause adverse effects in nursing infants. There are no studies to indicate that vancomycin dosing should be modified during pregnancy. Volume of distribution and plasma clearance both increased, but half-life similar to that for nonpregnant women (4.55 versus 4–6 hours) in a woman administered IV vancomycin twice daily from 26–28 weeks of pregnancy. 43 CBC, complete blood count; AF, amniotic fluid; MS, maternal serum; GI, gastrointestinal; AUC, area under the curve; GFR, glomerular filtration rate . * Listed in the product label and the clinical pharmacology monograph as active against most strains; bacterial resistance occurs commonly in some sp ecies of otherwise susceptible bacteria due to beta-lactamase production. † Based on assessment by the American Academy of Pediatrics. 1126 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data Antibiotic Human Data: Teratogenic and Toxic Effects Animal Data: Teratogenic and Toxic Fetal Effects Magnitude of Human Teratogenic Fetal Risk (Based on TERIS Assessment) 44 FDA Pregnancy Category* Amoxicillin OR for major congenital anomalies 1.4 (95% CI 0.9–2.0) for women using amoxicillin clavulanic acid during pregnancy in a case-control study of 6,935 malformed infants (no increased risk). 45 OR (adjusted) for congenital anomalies 1.16 (95% CI 0.54– 2.50) in a Danish study (1991–2000) of 401 primiparous women who filled prescriptions for amoxicillin during pregnancy (rate 4.0%) compared with 10,237 controls who did not redeem any prescription drug (rate 4.1%). 46 No increased rate of congenital malformations among 147 women who received prescriptions for amoxicillin during the 1st trimester. 46 No increased rate of congenital anomalies among 284 infants whose mothers were administered amoxicillin or ampicillin during the 1st trimester, or in 1,060 infants whose mothers were treated at any time during pregnancy. 47 No significantly increased rate of major or minor anomalies in the children of 14 women treated with amoxicillin and probenecid during the first 14 weeks of gestation or among 57 women treated after the 14th week in a controlled clinical trial on the treatment of gonorrhea during pregnancy. 48 No adverse effects in offspring exposed to amoxicillin during the 2nd and 3rd trimesters in 3 controlled clinical trials of antibiotic treatment for premature preterm rupture of membranes. 49–51 An association of necrotizing enterocolitis in newborns and maternal amoxicillin and clavulanic acid treatment during the 3rd trimester was observed in a randomized controlled trial including 4,826 pregnant patients. 52,53 No increased congenital malformations in mice treated with 3–7 times the maximum human therapeutic dose of amoxicillin. 54 No adverse reproductive effects in rats given amoxicillin- clavulanic acid at doses of 400 and 1,200 mg/day prior to fertilization and during the first 7 days of gestation (Product information Amoxil, 2001). 55 No adverse fetal effects in pigs given amoxicillin with clavulanic acid at doses of 600 mg/kg on days 12–42. 56 Increased frequency of embryonic death in mice treated with amoxicillin at 6–7 times the maximum therapeutic human dose. 54 Increased risk of teratogenicity is "unlikely," based on "fair" data. B Chloramphenicol OR for major congenital anomalies 1.7 (95% CI 1.2–2.6) for oral administration at any time during pregnancy in a case- control study of 22,865 malformed infants (risk marginally increased). 57 RR for congenital malformations 1.19 (95% CI 0.52–2.31) in 348 offspring born to women who took chloramphenicol at any time during pregnancy (no statistically increased risk). 58 Potential for both dose-related and idiosyncratic bone marrow toxicity. Caution should be used near term, during labor, and while breastfeeding due to the possibility of inducing "gray-baby" syndrome. 59 No increased congenital anomalies in monkeys. 60 No teratogenicity in mice or rabbits at 10–40 times the recommended human dose. 61 No teratogenicity in rats at 2–4 times the usual human dose, 62 but various fetal anomalies at 10–40 times the human dose. 61,63 Increased fetal death and decreased fetal weight in mice, rats, and rabbits. 61–63 Increased risk of teratogenicity is "unlikely," based on "fair" data. "Therapeutic doses of chloramphenicol are unlikely to pose a substantial teratogenic risk." C ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1127
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Reviews Antibiotic Use in Pregnancy and Lactation What Is and Is Not Known About Teratogenic and Toxic Risks Gerard G. Nahum, MD , CAPT Kathleen Uhl, USPHS, and CAPT Dianne L. Kennedy, USPHS OBJECTIVE: Over ten million women are either pregnant or lactating in the United States at any time. The risks of medication use for these women are unique. In addition to normal physiologic changes that alter the pharmaco- kinetics of drugs, there is the concern of possible terato- genic and toxic effects on the developing fetus and newborn. This article reviews the risks and pharmacoki- netic considerations for 11 broad-spectrum antibiotics that can be used to treat routine and life-threatening infections during pregnancy and lactation. DATA SOURCES: Information from the U.S. Food and Drug Administration (FDA) product labels, the Teratogen Information Service, REPROTOX, Shepard's Catalog of Teratogenic Agents, Clinical Pharmacology, and the peer- reviewed medical literature was reviewed concerning the use of 11 antibiotics in pregnant and lactating women. The PubMed search engine was used with the search terms "[antibiotic name] and pregnancy," "[antibiotic name] and lactation," and "[antibiotic name] and breast- feeding" from January 1940 to November 2005, as well as standard reference tracing. METHODS OF STUDY SELECTION: One hundred twen- ty-four references had sufficient information concerning numbers of subjects, methods, and findings to be in- cluded. TABULATION, INTEGRATION, AND RESULTS: The ter- atogenic potential in humans ranged from "none" (pen- icillin G and VK) to "unlikely" (amoxicillin, chloramphen- icol, ciprofloxacin, doxycycline, levofloxacin, and rifampin) to "undetermined" (clindamycin, gentamicin, and vancomycin). Assessments were based on "good data" (penicillin G and VK), "fair data" (amoxicillin, chlor- amphenicol, ciprofloxacin, doxycycline, levofloxacin, and rifampin), "limited data" (clindamycin and gentamicin), and "very limited data" (vancomycin). Significant phar- macokinetic changes occurred during pregnancy for the penicillins, fluoroquinolones and gentamicin, indicating that dosage adjustments for these drugs may be neces- sary. With the exception of chloramphenicol, all of these antibiotics are considered compatible with breastfeed- ing. CONCLUSION: Health care professionals should con- sider the teratogenic and toxic risk profiles of antibiotics to assist in making prescribing decisions for pregnant and lactating women. These may become especially impor- tant if anti-infective countermeasures are required to protect the health, safety, and survival of individuals exposed to pathogenic bacteriologic agents that may occur from bioterrorist acts. (Obstet Gynecol 2006;107:1120–38) A ntibiotics are among the most commonly pre- scribed prescription medications for pregnant and lactating women. 1 More than 10 million women are either pregnant or lactating in the United States at any one time, and they are administered antibiotics for many reasons. 2 Because of the special consider- ations associated with fetal and newborn develop- ment, these women constitute a uniquely vulnerable population for which the risks of medication use must be separately assessed. In addition to the pharmacokinetic and pharma- codynamic changes that may occur during pregnancy and lactation that can alter the effectiveness of drugs, 3 there is the added concern of the possible teratogenic and toxic effects that medications may have on the developing fetus and newborn. In general, there is a dearth of pharmacokinetic and pharmacodynamic information regarding the use and proper dosing of Food and Drug Administration (FDA)–approved From the Department of Obstetrics and Gynecology, Uniformed Services Uni- versity of the Health Sciences, Bethesda, Maryland; Office of Women's Health, U.S. Food and Drug Administration, Rockville, Maryland; FDA Center for Drug Evaluation and Research, Silver Spring, Maryland. Presented in part at the FDA Science Forum in Washington, DC, April 27–28, 2005. The views, opinions, interpretations, and conclusions expressed in this article are those of the authors only and do not reflect either the policies or positions of the Center for Drug Evaluation and Research, the U.S. Food and Drug Adminis- tration, or the U.S. Department of Health and Human Services. Corresponding author: Gerard G. Nahum, MD, FACOG, FACS, Box 2184, Rockville, MD 20847; e-mail: GNahum2003@yahoo.com. © 2006 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/06 1120 VOL. 107, NO. 5, MAY 2006 OBSTETRICS & GYNECOLOGY drugs in pregnant and lactating women, as well as limited data pertaining to the teratogenic potential and the fetal or neonatal toxicity of these marketed medications. Accordingly, sparse information must sometimes be assembled from diverse sources to address these issues. Recently, the threat of bioterrorism has expanded the context in which the potential use of antibiotic medications may be needed. 4 Although the possibility of a large-scale bioterrorist attack in the United States is unlikely, the potential for widespread antibiotic use in this situation emphasizes the need for health care professionals to be familiar with the risks and benefits of administering antibiotics to pregnant and lactating women. This article reviews the available information concerning the risks and special circumstances to be considered in pregnant and lactating women for a group of 11 broad-spectrum antibiotics (amoxicillin, chloramphenicol, ciprofloxacin, clindamycin, doxy- cycline, gentamicin, levofloxacin, penicillin G, peni- cillin VK, rifampin, and vancomycin). By using this information, better choices can be made for the treatment of different types of bacterial pathogens in these particularly vulnerable populations. DATA SOURCES AND METHODS OF STUDY SELECTION Information from FDA-approved product labels, the Teratogen Information Service, Shepard's Catalog of Teratogenic Agents, REPROTOX, Clinical Pharma- cology, and the peer-reviewed literature were re- viewed for information concerning the use of 11 antibiotics in pregnant and lactating women. The medical literature was queried with the PubMed search engine. Papers searched were published from January 1940 to November 2005, in any language. The search terms "[antibiotic name] and pregnancy," "[antibiotic name] and lactation,", and "[antibiotic name] and breastfeeding," were used, as was standard reference tracing. A total of 124 references were accessed through these sources that contained suffi- cient information concerning the numbers of subjects, methods of investigation, and findings to be useful for the purpose of drawing conclusions concerning phar- macokinetic parameters, teratogenic potential, and toxicity assessments of these drugs. All materials were restricted to information from nonproprietary sources that were available in the public domain. Addition- ally, information concerning the potential treatment options for exposures and diseases caused by possible agents of bioterrorism were obtained from materials published by the Centers for Disease Control and Prevention in Atlanta. RESULTS A description of the 11 broad-spectrum antibiotics and their general modes of action are provided in Table 1. All 11 antibiotics cross the placenta and enter the fetal compartment. For 5 of these, human umbilical cord blood levels are of the same order of magnitude as circulating maternal blood concentrations (chlor- amphenicol, clindamycin, gentamicin, rifampin, and vancomycin). For 4, the concentrations are of the same magnitude or higher in amniotic fluid as in maternal blood (ciprofloxacin, clindamycin, levo- floxacin, and vancomycin) (Table 2). All 11 antibiotics are excreted in human breast milk. Limited information concerning the amount in breast milk was available for 8 antibiotics (ciprofloxa- cin, clindamycin, doxycycline, gentamicin, levofloxa- cin, penicillin G, penicillin VK, and rifampin). No quantitative data concerning breast milk concentra- tions were available for 3 (amoxicillin, chloramphen- icol, and vancomycin) (Table 2). Using the Teratogen Information Service clas- sification system for teratogenic risk, 44 the terato- genic potential of the 11 antibiotics during human pregnancy ranged from "none" in 2 cases (penicil- lin G and VK) to "unlikely" in 6 (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levo- floxacin, and rifampin) to "undetermined" in 3 (clindamycin, gentamicin, and vancomycin). As- sessments were based on data that were "good" for 2 (penicillin G and VK) to "fair" for 6 (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levo- floxacin, and rifampin) to "limited" for 2 (clinda- mycin and gentamicin) to "very limited" for 1 (vancomycin). A summary of the human and ani- mal data contributing to these assessments is shown in Table 3. The Food and Drug Administration Pregnancy Category classifications for the 11 anti- biotics (as defined under 21 CFR [Code of Federal Regulations] 201.57 for the A, B, C, D, X Preg- nancy Category system) (Table 4) were "B" in 5 cases (amoxicillin, clindamycin, penicillin G, peni- cillin VK, and vancomycin), "C" in 5 cases (chlor- amphenicol, ciprofloxacin, gentamicin, levofloxa- cin, and rifampin), and "D" in 1 case (doxycycline) (Table 3). In addition to the published literature, proprietary data were used to establish the FDA pregnancy category for these drugs. Despite numerous concerns regarding the poten- tial for maternal and fetal or neonatal toxicity of these VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1121 11 drugs—including idiosyncratic and dose-related bone marrow suppression with chloramphenicol, ar- thropathies and bone and cartilage damage with ciprofloxacin and levofloxacin, dental staining and hepatic necrosis with doxycycline, and ototoxicity and nephrotoxicity with gentamicin and vancomy- cin—none of these toxicities has been documented in human mothers or offspring either during preg- nancy or breastfeeding with these antibiotics (Table 3). Very limited information was available pertain- ing to maternal pharmacokinetics in pregnancy for 8 antibiotics (amoxicillin, ciprofloxacin, clindamycin, gentamicin, levofloxacin, penicillin G, penicillin VK, and vancomycin), and none was available for 3 (chloramphenicol, doxycycline, and rifampin) (Table 2). For 4 antibiotics (amoxicillin, gentamicin, penicil- lin G, and penicillin VK), lower circulating drug concentrations were measured in pregnant women than nonpregnant, suggesting that a shorter dosing interval or increased maternal dose or both may be necessary to obtain similar circulating drug concen- trations as for women in the nonpregnant state. In the case of ciprofloxacin and levofloxacin, circulating concentrations were generally reduced in pregnant women, also suggesting that an increased maternal dose or a shorter dosing interval or both may be necessary. In 3 cases (chloramphenicol, gentamicin, and vancomycin), therapeutic drug monitoring of serum peak and trough levels is recommended to assess circulating drug levels. In 1 case (clindamycin), the standard pharmacokinetic parameters did not change appreciably during the first, second, or third trimester of pregnancy (Table 2). Very little pharma- Table 1. Description of the Eleven Broad-Spectrum Antibiotics Investigated Antibiotic Description Year of Initial FDA Approval Amoxicillin Semi-synthetic beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1974 Chloramphenicol Broad-spectrum antibiotic isolated from Streptomyces venezuela in 1947, now synthetically available. Binds to the 50S subunit of bacterial ribosomes, inhibiting peptide bond formation and protein synthesis. 1950 Ciprofloxacin Fluoroquinolone antibiotic. Exerts its bactericidal effect by disrupting DNA replication, transcription, recombination, and repair by inhibiting bacterial DNA gyrase. 1987 Clindamycin Antibiotic derived from lincomycin that has wide-ranging antimicrobial activity. Binds to the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. 1970 Doxycycline Broad-spectrum antibiotic that binds to the 30S bacterial ribosomal subunit. Blocks the binding of transfer-RNA to messenger-RNA, thereby disrupting protein synthesis. 1967 Gentamicin Aminoglycoside antibiotic with broad-spectrum activity. Binds irreversibly to 30S bacterial ribosomal subunit, thereby inhibiting protein synthesis. 1966 Levofloxacin Fluoroquinolone antibiotic. L-isomer of ofloxacin, which provides its principal antibiotic effect. Inhibits bacterial DNA replication, transcription, recombination, and repair by inhibiting bacterial type II topoisomerases. 1996 Penicillin G Beta-lactam antibiotic that is primarily bactericidal. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1943 Penicillin V (phenoxymethyl penicillin) Naturally derived beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. Considered preferable to penicillin G for oral administration because of its superior gastric acid stability. 1956 Rifampin Rifamycin B derivative that inhibits bacterial and mycobacterial DNA-dependent RNA polymerase activity. Used primarily for the treatment of tuberculosis, with additional utility for the treatment of both leprosy and meningococcal carriers. 1971 Vancomycin Glycopolypeptide antibiotic. Binds to the precursor units of bacterial cell walls, inhibiting their synthesis and altering cell wall permeability while also inhibiting RNA synthesis. Because of its dual mechanism of action, bacterial resistance is rare. 1964 FDA, U.S. Food and Drug Administration. 1122 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Amoxicillin Gram-positive aerobes, most gram-positive anaerobes, gram- negative aerobes including some enteric bacilli, Helicobacter, spirochetes, actinomyces* Crosses the human placenta. 5–7 Penicillins transferred to the fetus and amniotic fluid reach therapeutic levels. 5 Excreted in human breast milk in small amounts. 8 Considered "usually compatible with breastfeeding." 9† Following therapeutic doses, mean human milk concentrations were 0.1–0.6 g/mL. 10 No adverse effects seen in nursing infants whose mothers have been treated with amoxicillin. Shorter dosing interval and/ or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillins are primarily renally excreted via tubular secretion and glomerular filtration. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 Chloramphenicol Gram positives, gram negatives, anaerobes, chlamydia, rickettsiae Crosses the human placenta readily. Umbilical cord serum concentrations 29–106% of maternal levels. 12 Excreted in human breast milk. 13–15 In 5 patients with minor obstetrical lacerations who receive d1gPOqDfor8 days, mean milk concentrations were 0.5–2.8 g/mL. In 5 patients receivin g2gPOqDfor8 days for mastitis, mean milk concentrations were 1.8–6.1 g/mL. 13 Human milk concentrations are 51–62% of blood levels. 14 Percentage of administered dose in human breast milk per day is 1.3%. 15 Effect on breastfed infants considered "unknown but may be of concern." 16 Unknown whether dose adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Serum concentrations can be monitored to keep peak and trough levels in the ranges of 10–20 and 5–10 g/mL, respectively. CBC monitored to detect bone marrow depression. Ciprofloxacin Gram-negative aerobes, some staphylococci Crosses the human placenta and concentrates in amniotic fluid (Product information Cipro, 2001). 17 In 20 women at 19–25 weeks of gestation who received two 200-mg IV doses q 12 hours, the mean amniotic fluid level 2–4 hours after dosing was 0.12 0.06 g/mL (n 7; amniotic fluid: maternal serum concentration [AF:MS ratio] 0.57), 0.13 0.07 g/mL at 6–8 hours (n 7; AF:MS ratio 1.44), and 0.10 0.04 g/mL at 10–12 hours (n 6; AF: MS ratio 10.00). 17 Excreted in human breast milk (Product information Cipro, 2001). 17 Considered usually compatible with breastfeeding." 9† In 10 women given 750 mg q12 hours PO, serum and milk concentrations were obtained 2, 4, 6, 9, 12, and 24 hours after the 3rd dose. Concentrations were 3.79 1.26, 2.26 0.75, 0.86 0.27, 0.51 0.18, 0.20 0.05, and 0.02 0.006 g/mL at these times and the ratios of breast milk: serum concentration were 1.84, 2.14, 1.60, 1.70, 1.67, and 0.85, respectively. 17 For breastfeeding infants consuming 150 mL/kg per day, the estimated maximum dose is 0.569 mg/kg per day or 2.8% the approved dose for infants of 20 mg/kg per day. 18 Circulating fluoroquinolone concentrations are lower in pregnant than in nonpregnant women, but no specific pharmacokinetic data is available regarding ciprofloxacin in pregnant women. 19 It is unknown whether dose adjustments during pregnancy are necessary. Approximately 50–70% of a dose is excreted in the urine and, if renal function is impaired, the serum half- life is slightly prolonged (Product information Cipro, 2001). ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1123 Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Clindamycin Gram-positive anaerobes, gram- negative anaerobes, aerobic gram-positive cocci, streptococci, Clostridia strains Crosses the human placenta readily. 44,20–23 In 54 women undergoing cesarean delivery who received 600 mg IV 30 minutes before surgery, umbilical cord blood concentrations were 46% of maternal serum levels. 20 After multiple oral doses prior to therapeutic abortion, fetal blood concentrations were 25% and amniotic fluid levels were 30% of maternal blood levels. 21 Excreted in human breast milk (Product information Clindamycin, 1970). Considered "usually compatible with breastfeeding." 9† At maternal doses of 150 mg orally to 600 mg IV, breast milk concentrations range from 0.7 to 3.8 g/mL (Product information Clindamycin, 1970). Pharmacokinetic parameters do not change during pregnancy in women studied during the 1st, 2nd, and 3rd trimesters of gestation. 20,24 There are no studies to indicate that dosing should be modified during pregnancy. C max and T max (after a single standard dose) and C ss (after multiple doses) do not change appreciably at any time during pregnancy. Doxycycline Gram-positives, gram- negatives, rickettsiae, chlamydiae, mycoplasma, spirochetes, actinomyces Crosses the placenta (Product information Vibramycin, 2001). Excreted in human breast milk. 25 Use for a short period (1 week) during breastfeeding is considered probably safe. 9,16 Breast milk concentrations are 30–40% of that found in maternal blood. 25 Unknown whether dose adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Enterohepatically recirculated. Excreted in urine and feces as unchanged drug. From 29% to 55.4% of a dose can be accounted for in the urine by 72 hours (Product information Vibramycin, 2001). Gentamicin Gram-negative aerobic rods, many streptococci, Staphylococcus aureus , mycobacteria Crosses the human placenta. 20,26–28 In 2 different studies, peak umbilical cord blood levels were 34% 26 and 42% 20 of associated maternal blood concentrations. Excreted in human breast milk. 29,30 Considered "usually compatible with breastfeeding." 9† Poorly absorbed from the GI tract. 29 Only half of nursing newborns had detectable serum levels, which were low and not likely to cause clinical effects. 29 No adverse signs or symptoms in nursing infants as a result of maternal treatment. 9 Increased dosage suggested due to decreased serum half-life in pregnancy and lower maternal serum levels. 20,31 In 54 women undergoing cesarean delivery, levels were lower than nonpregnant women. 20 Eliminated mainly by glomerular filtration (Product information Gentamicin, 1966). Clearance decreased in preeclamptic patients. 32 Dose/ dosing interval adjusted via peak and trough levels (Product information Gentamicin 1966). ( continued ) 1124 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Levofloxacin Gram-positives and gram-negatives Crosses the human placenta and concentrates in amniotic fluid (based on data for racemic ofloxacin) (Product information Levaquin, 1996). 17 In 20 women at 19–25 weeks of gestation receiving two IV 400-mg doses of ofloxacin q12 hours, mean amniotic fluid concentration 3–6 hours after dosing was 0.25 0.11 g/mL (n 6; amniotic fluid: maternal serum concentration [AF:MS ratio] 0.35), 0.15 0.11 g/mL at 6–10 hours (n 8; AF:MS ratio 0.67), and 0.13 0.11 g/mL at 11–12 hours (n 6; AF:MS ratio 2.57). 17 Excreted in human breast milk in high concentrations (based on data for racemic ofloxacin) (Product information Levaquin, 1996). 17 Considered "usually compatible with breastfeeding." 9† In 10 women given 400 mg of ofloxacin q12 hours PO, serum and milk concentrations were obtained 2, 4, 6, 9, 12, and 24 hours after the 3rd dose. Concentrations were 2.41 0.80, 1.91 0.64, 1.25 0.42, 0.64 0.21, 0.29 0.10, and 0.05 0.02 g/mL at these times, with breast milk: serum concentration ratios of 0.98, 1.30, 1.39, 1.25, 1.12, and 1.66, respectively. 17 For breastfed infants consuming 150 mL/kg per day, the estimated maximum infant dose of ofloxacin is 0.362 mg/kg per day. 18 Circulating fluoroquinolone concentrations are lower in pregnant than in nonpregnant women, but no specific pharmacokinetic data is available regarding levofloxacin in pregnant women. 19 There are no data to support dosing adjustments during pregnancy. Penicillin G Gram-positive aerobes including most streptococci/ enterococci, gram- positive anaerobes, spirochetes, actinomyces, some gram negatives* Crosses the human placenta. 5,33,34 Penicillins are transferred to the fetus and amniotic fluid reaching therapeutic levels. 5 Excreted in human breast milk in small amounts (Product information Bicillin, 2001; product information Penicillin V, 1997). 15 Considered "usually compatible with breastfeeding." 9† In women with serum concentrations of penicillin ranging from 6 to 120 g/dL, corresponding breast milk concentrations were 1.2–3.6 g/dL, and the amount of the maternal dose appearing in breast milk per day was estimated at 0.03%. 15 Shorter dosing interval and/ or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillins are primarily renally excreted via tubular secretion and glomerular filtration. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 Penicillin VK Gram-positive aerobes including most streptococci/ enterococci, gram- positive anaerobes, gram negatives Crosses the human placenta readily. 5,7,10,33,34,35 Penicillins are transferred to the fetus and amniotic fluid reaching therapeutic levels. 5 Excreted in human breast milk in small amounts (Product information Penicillin V, 1997). 15,36 Considered "usually compatible with breastfeeding." 9† In 18 women, penicillin V milk concentration depended on presence of mastitis, with peak levels 2.6–5.4 hours after a single PO 1,320-mg dose. 35 Peak concentration was 30–72 g/dL with mean concentration 26-37 g/dL. AUC over 8 hours after dosing was 2.1–3.0 mg-h/L. 35 Estimated dose of penicillin V ingested per day by breastfed infants is 40–60 g/kg, or 0.09– 0.14% of maternal dose per kg body weight. 35 Shorter dosing interval and/or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillin V is excreted renally, primarily via tubular secretion. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1125 Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Rifampin Mycobacteria, Neisseria meningitidis , S aureus , Haemophilus influenzae , Legionella pneumophila , Chlamydia Crosses the human placenta (Product information Rifampin, 1971). 37–39 Umbilical cord concentrations between 12% and 33% of maternal blood levels, with peak levels occurring concurrently after drug administration. 37–39 Excreted in human breast milk (Product information Rifampin, 1971). 15,40,41 Considered "usually compatible with breastfeeding." 9† After a single oral dose of 600 mg, a nursing infant would ingest approximately 0.05% of the maternal dose per day, or approximately 0.3 mg/day. 15,40,41 Unknown whether dosing adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Hepatically deacetylated to active metabolite. Parent compound and metabolites excreted via biliary elimination (60%). Enterohepatic re-circulation; plasma levels elevated in hepatic disease. Up to 30% excreted in urine; renal clearance is 12% of GFR. 38 Vancomycin Gram positives, S aureus , Staphylococcus epidermidis , streptococci, enterococci, Clostridium , Coryne- bacterium Crosses the human placenta (Product information Vancomycin, 1964). 42,43 Appears in umbilical cord blood after IV maternal treatment (Product information Vancomycin, 1964). 42,43 Amniotic fluid and umbilical cord blood concentrations during the early 3rd trimester comparable to maternal blood levels (fetal-maternal serum concentration ratio of 0.76). 43 Excreted in human breast milk when administered IV (Product information Vancomycin, 1964). 42 When administered orally, vancomycin is poorly absorbed from the GI tract (Product information Vancomycin, 1964). It is, therefore, not likely to cause adverse effects in nursing infants. There are no studies to indicate that vancomycin dosing should be modified during pregnancy. Volume of distribution and plasma clearance both increased, but half-life similar to that for nonpregnant women (4.55 versus 4–6 hours) in a woman administered IV vancomycin twice daily from 26–28 weeks of pregnancy. 43 CBC, complete blood count; AF, amniotic fluid; MS, maternal serum; GI, gastrointestinal; AUC, area under the curve; GFR, glomerular filtration rate . * Listed in the product label and the clinical pharmacology monograph as active against most strains; bacterial resistance occurs commonly in some sp ecies of otherwise susceptible bacteria due to beta-lactamase production. † Based on assessment by the American Academy of Pediatrics. 1126 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data Antibiotic Human Data: Teratogenic and Toxic Effects Animal Data: Teratogenic and Toxic Fetal Effects Magnitude of Human Teratogenic Fetal Risk (Based on TERIS Assessment) 44 FDA Pregnancy Category* Amoxicillin OR for major congenital anomalies 1.4 (95% CI 0.9–2.0) for women using amoxicillin clavulanic acid during pregnancy in a case-control study of 6,935 malformed infants (no increased risk). 45 OR (adjusted) for congenital anomalies 1.16 (95% CI 0.54– 2.50) in a Danish study (1991–2000) of 401 primiparous women who filled prescriptions for amoxicillin during pregnancy (rate 4.0%) compared with 10,237 controls who did not redeem any prescription drug (rate 4.1%). 46 No increased rate of congenital malformations among 147 women who received prescriptions for amoxicillin during the 1st trimester. 46 No increased rate of congenital anomalies among 284 infants whose mothers were administered amoxicillin or ampicillin during the 1st trimester, or in 1,060 infants whose mothers were treated at any time during pregnancy. 47 No significantly increased rate of major or minor anomalies in the children of 14 women treated with amoxicillin and probenecid during the first 14 weeks of gestation or among 57 women treated after the 14th week in a controlled clinical trial on the treatment of gonorrhea during pregnancy. 48 No adverse effects in offspring exposed to amoxicillin during the 2nd and 3rd trimesters in 3 controlled clinical trials of antibiotic treatment for premature preterm rupture of membranes. 49–51 An association of necrotizing enterocolitis in newborns and maternal amoxicillin and clavulanic acid treatment during the 3rd trimester was observed in a randomized controlled trial including 4,826 pregnant patients. 52,53 No increased congenital malformations in mice treated with 3–7 times the maximum human therapeutic dose of amoxicillin. 54 No adverse reproductive effects in rats given amoxicillin- clavulanic acid at doses of 400 and 1,200 mg/day prior to fertilization and during the first 7 days of gestation (Product information Amoxil, 2001). 55 No adverse fetal effects in pigs given amoxicillin with clavulanic acid at doses of 600 mg/kg on days 12–42. 56 Increased frequency of embryonic death in mice treated with amoxicillin at 6–7 times the maximum therapeutic human dose. 54 Increased risk of teratogenicity is "unlikely," based on "fair" data. B Chloramphenicol OR for major congenital anomalies 1.7 (95% CI 1.2–2.6) for oral administration at any time during pregnancy in a case- control study of 22,865 malformed infants (risk marginally increased). 57 RR for congenital malformations 1.19 (95% CI 0.52–2.31) in 348 offspring born to women who took chloramphenicol at any time during pregnancy (no statistically increased risk). 58 Potential for both dose-related and idiosyncratic bone marrow toxicity. Caution should be used near term, during labor, and while breastfeeding due to the possibility of inducing "gray-baby" syndrome. 59 No increased congenital anomalies in monkeys. 60 No teratogenicity in mice or rabbits at 10–40 times the recommended human dose. 61 No teratogenicity in rats at 2–4 times the usual human dose, 62 but various fetal anomalies at 10–40 times the human dose. 61,63 Increased fetal death and decreased fetal weight in mice, rats, and rabbits. 61–63 Increased risk of teratogenicity is "unlikely," based on "fair" data. "Therapeutic doses of chloramphenicol are unlikely to pose a substantial teratogenic risk." C ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1127
https://pdfs.semanticscholar.org/6dc9/a1ef535442351b406ebcfce85c43f66fec03.pdf
Safe lists for medications in pregnancy
medications and pregnancy/pregnant','prescriptiondrugs and pregnancy','medications and pregnancyand safe','medications safe to take during preg-nancy','prescription drugs safe during pregnancy',and'prescription drugs ok to take while pregnant'. Medication names were abstracted and compared across sites. Vitamins, herbals, intravenous medications, and topical cutaneous medications were excluded from the analysis, and equivalent medications (e.g., acyclovir and valacyclovir) were combined. Components of over-the-counter (OTC) and prescription medications listed as ' safe ' by any source were searched in the Teratogen Information System (TERIS), 5 and frequencies were tabulated by risk rating. TERIS is a database housing expert assessments of the terato- genic risk of medications in human pregnancy after exposure under usual conditions. The magnitude of risk is categorized as none, unlikely, minimal, small, moderate, high, or undetermined (http://depts. washington.edu/terisweb/teris/). Published clinical, experimental, and epidemiologic literature is used to determine the risk rating, and a data quality and quantity score ranging from none to excellent is also assigned. Given that this study was conducted solely using Internet sources and an electronic database, the study was deemed not to constitute human subjects research. RESULTS The environmental scan identi fi ed ' safe medication ' lists from 28 sources. Of these, 26 were still available in September 2011; upon further veri fi ca- tion of website data in August 2012 at the journal ' s request, one additional site was excluded as the current information was inconsistent with that gath- ered in the initial search. Analyses were restricted to this subset of 25, which included three medical, one professional organization, four pregnancy infor- mation, and 17 clinical practice sources (Table 1). Only three lists displayed references, and only one of these (Netdoctor) provided references from peer-reviewed scienti fi c literature. From the 25 lists (none of which were identical), a total of 245 med- ication products were identi fi ed as ' safe ' for use by pregnant women. Eight of the 25 lists offered some type of safety de fi nition, two of which de fi ned it in the context of the medication not having been shown to cause birth defects, and two others de- fi ned safety based on the Food and Drug Adminis- tration use in pregnancy labels (categories A – X). 6 There was a mean of 34 medication products per list. Twenty-two (9%) of the products listed as safe byoneormoresiteswerestatednottobesafeby one or more of the other sites (Table 2). The active components from each product were identi fi ed, and duplicate components (e.g., acetaminophen from multiple acetaminophen-containing products) were removed, resulting in 164 unique components that were included in the analysis. After applying the exclusion criteria noted in the methods, TERIS was searched for the remaining 114 components, of which 103 (90%) had existing evaluations. None had a small, moderate, or high risk rating (Figure 1). Seven components (7%) of 103 were rated as having no risk; three (3%) had a ' none to minimal ' risk rating; one (1%) was rated as posing a minimal risk (pseudoephedrine); 49 (48%) were rated as unlikely to pose a risk; and 43 (42%) were of undetermined risk. Regardless of risk rating, 42 components were given a data quality and quantity score of none to limited, 40 (95%) of which corresponded with ' un- determined ' risk ratings (data not shown). At the other end of the scale, only 7% of the components had data quality and quantity scores ranging from good to excellent. Of interest, among the four med- ication components with TERIS risk ratings of either ' none to minimal ' or ' minimal ' (erythromycin, metronidazole, phenylephrine, and pseudoephedrine), all had data quality and quantity scores ranging only from fair to good. Only 13 (52%) of the websites encouraged consulta- tion with a healthcare provider before stopping or starting a medication during pregnancy, and less than half (40%) recommended taking medications during pregnancy only when necessary. DISCUSSION This report identi fi es inconsistencies in publicly available information on the safety of medications during pregnancy and shows that a large proportion of currently available information for products fre- quently used in pregnancy lacks data to support safety claims. Although it is reassuring that no medications from any identi fi ed ' safe ' lists had evi- dence suggesting a moderate or high teratogenic risk, it was often the case that these medications had an as yet undetermined teratogenic risk; there- fore, caution is advised in interpreting the majority of these medications as ' safe ' for use during preg- nancy. The existence of lists purporting safety might encourage use of medications during preg- nancy even when they are not necessary. s. l. peters et al. Copyright © 2013 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety , (2013) DOI: 10.1002/pds Only three of the 25 sites surveyed provided references or source material to support their claims of safety, and only half of the included websites encouraged consulta- tion with a healthcare provid er about medication use during pregnancy. This means many websites lack a critical message that should be paramount in any website that provides information t o pregnant women. However, given the limited availability of human data on the terato- genic risks associated with most medications, 4 healthcare providers frequently also do not have the information needed to provide informed guidance to their patients. The proportion of women who take medication dur- ing pregnancy has increased by 60% since the 1970s, as has the average number of medications pregnant women take. 3 These trends can be accounted for, at least inpart,byincreasingmaternalage 7 and concomitant comorbidities that often require treatment. Both OTC and prescription use is high (70 – 80% of women report taking at least one medication) during the fi rst trimester of pregnancy, 3 a critical period for embryonic develop- ment during which the potential for teratogenic risk may be of greatest concern. The prevalence of unintended pregnancy (nearly 50%) in the USA 8 also contributes to inadvertent medication exposures in the critical time period before pregnancy recognition. This analysis excluded herbal/dietary supplements because these products often have an uncertain safety pro fi le given the absence of data. Use of herbal products is relatively common, with nearly 10% of women reporting exposures at some point Table 1. Evaluated lists grouped by website type and including number of medications listed as ' safe ' for use during pregnancy — Active, August 2012 Website type Source name URL Medication products* ( N ) Medical site Livestrong http://www.livestrong.com/article/26729-list-safe-otc-medications-pregnancy/ 8 Netdoctor http://www.netdoctor.co.uk/health_advice/facts/medicinesinpregnancy.html 15 OBFocus http://www.obfocus.com/high-risk/medsprint.htm 51 Professional organization American College of Nurse – Midwives http://www.midwife.org/documents/TakingMedicineDuringPregnancy52-5.pdf 16 Pregnancy information BabyCenter http://www.babycenter.com/0_chart-over-the-counter-medications-during- pregnancy_1486462.bc 54 Dr. Lera http://drlera.com/health_beauty/healthy_baby/Medications_for_Pregnant_Women. htm 39 She Knows, Pregnancy & Baby http://www.pregnancyandbaby.com/pregnancy/articles/945667/medications- during-pregnancy-list-of-safe-and-unsafe-drugs 7 Pregnancy etc. http://www.pregnancyetc.com/what-are-some-safe-medications-to-take-during- pregnancy.htm 37 Clinical practice Bend OBGYN http://www.bendobgyn.net/Safe_Medications_When_Pregnant.htm?m=45&s=39 30 Boojum OBGYN http://www.drkells.com/Medication.pdf 35 Budge Clinic OBGYN http://intermountainhealthcare.org/services/medicalgroup/clinics/physicianclinics/ budgeobgyn/Documents/Medications_While_Pregnant.pdf 21 Diamond Women ' s Center http://www.diamondobgyn.com/Groups/1000050633/Diamond_Womens_Center/ Early_Life_Services/Pregnancy_Info/General_Medication_Use/ General_Medication_Use.aspx 34 Fayetteville Woman ' s Care http://www.fwc.net/expecting-mothers/safe-meds-during-pregnancy 40 Kristin Miller OBGYN http://www.kristinmillermd.com/forms/obMedications.pdf 43 Mercy OBGYN http://mercyobgyn.com/docs/medicationapprovedduringpregnancy.pdf 20 Midtown OBGYN http://www.mymidtownobgyn.com/PDFDocuments/SAFEMedicationList.pdf 68 Oakwood Women ' s Center http://www.oakwoodwomens.com/ fi les/safe_meds_list.pdf 25 OBGYN Centers for Family Health http://drmsg.com/new_page_2.htm 18 Paci fi c Regional Medical Army Medical Center OBGYN http://www.tamc.amedd.army.mil/of fi ces/obgyn/PregnancyMedications.htm 18 Providence Health and Services http://www.providence.org/Oregon/health_resource_centers/Pregnancy_Center/ Medication.htm 23 Seasons Healthcare for Women http://www.seasonshealthcare4women.com/docs/SafeMedicationsInPregnancy.pdf 34 Women ' s Health Specialists of Fremont http://www.womenshealthfremont.com/webdocuments/medications-in-pregnancy.pdf 77 OBGYN Women ' s Physicians Assoc. http://www.womendoctor.com/pdf/preg_meds.pdf 65 Obstetrical Associates, Inc. http://oba-ma.com/Medications.html 27 Women ' s Health Consultants http://www.whcobgyn.com/Medication_List.pdf 44 *The total number of medication products is at least that listed in the table — some sites listed a group of similar products as ' safe ' , such as, Tylenol W products. web safe lists for medications in pregnancy Copyright © 2013 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety , (2013) DOI: 10.1002/pds during pregnancy. 9 Substances marketed as natural products can be incorrectly perceived as harmless to both a pregnant woman and her developing fetus, even though no evidence of safety (or risk) exists. 10 In fact, herbal and dietary products are less studied than prescription medications prior to marketing. Under the Dietary Supplement Health and Education Act, the Food and Drug Administration can take regulatory action against a supplement only if the agency can prove that a marketed supplement is unsafe, and post-marketing safety concerns have emerged for sev- eral products. 9,11 Similarly, a product ' s availability as OTC does not necessarily mean that it is ' safe ' for use during pregnancy. However, one of the factors considered prior to designation of (or switch to) OTC status is the potential for risk if taken during pregnancy (or taken by women of reproductive potential). Furthermore, these products tend to have multiple active ingredients, which complicate the character- ization of risks associated with their use. This environmental scan evaluated all Internet sources that could be identi fi ed during the period November 2010 – September 2011 and that could be veri fi ed as of August 2012. The analysis used an existing independent re source to evaluate the evidence base for the medications deemed to be ' safe ' for use during pregnancy. Assumptions had to be made about the exact nature of some of the medications because of the unclear terminology used in the ' safe ' lists. In addition, for most medications, these websites did not specify dosage, routes, or timing of exposure in pregnancy, which can be critical factors in assessing safety. 12 The fi ndings in this report are subject to several limitations. First, while no two lists were identical, some lists might have borrowed from other existing lists. Thus, the sources are not likely to be com- pletely independent. Second, because only English language sources were evaluated, this environmental scan probably underestimates the diversity of avail- able Internet sources on this topic and may underes- timate the inconsistency that exists. Third, this environmental scan did not include paper lists that may be distributed by prenatal care providers or other non-Internet sources. Finally, the investigators were unable to determine the frequency of use of the included websites. The implications of inaccu- rate guidance probably depend on which sites are most frequently visited. Women or healthcare providers relying on Inter- net sources of information on ' safe ' medications for use in pregnancy may be inappropriately reassured because many medications listed as ' safe ' lack evidence that actually demonstrates safety. The wide availability of ' safe ' medication lists suggests Table 2. Medications listed as ' safe ' for use in pregnancy by one or more websites and ' unsafe ' by one or more other sites Cold/ fl u/allergy Actifed W (chlorpheniramine and phenylephrine) Afrin W (oxymetazoline) Claritin-D W (loratadine and pseudoephedrine) Chlor-Trimeton W (chlorpheniramine) Dimetapp W (brompheniramine and pseudoephedrine) Diphenhydramine Loratadine Phenylephrine Pseudoephedrine Thera fl u W (acetaminophen, pheniramine, and phenylephrine) Zyrtec-D W (cetirizine and pseudoephedrine) Pain relief Acetaminophen (extra strength) Codeine Constipation Dulcolax W (bisacodyl) Surfak W (docusate calcium) Vaginal yeast infection Gyne-Lotrimin W (clotrimazole) Heartburn Rolaids W (calcium carbonate and magnesium hydroxide) Upset stomach/nausea Bismuth subsalicylate Insomnia Unisom W (SleepTabs: doxylamine; SleepGels/SleepMelts: diphenhydramine) Anticholinergic Scopolamine Antidiarrheal Loperamide Antifungal Lamisil W (terbina fi ne) Trade/generic names are listed as provided by the websites, with generic components provided in parentheses for completeness. Figure 1. Frequency distribution of Teratogen Information System (TERIS) risk ratings for 103 medications listed as safe for use in pregnancy by one or more of the websites s. l. peters et al. Copyright © 2013 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety , (2013) DOI: 10.1002/pds
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
Drug Safety and Availability.Medication Guides are paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. FDA requires that Medication Guides be issued with certain prescribed drugs and biological products when the Agency determines that: certain information is necessary to prevent serious adverse effects patient decision-making should be informed by information about a known serious side effect with a product, or patient adherence to directions for the use of a product are essential to its effectiveness. Information Update (3/2017) Medication Guides are updated as they appear in new drug labeling. Please note that we link directly into the drug label to the first page of the medication guide. Medication Guides may or may not be at the end of the label. Before printing check the number of pages of the Medi
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
Medication Guides are available for these products:
https://www.fda.gov/Drugs/DrugSafety/ucm085729.htm
*biologic or drug/biologic combination
- Abilify (aripiprazole) [8/2016 version]
- Abilify Maintena (aripiprazole) [1/2016 version]
- Absorica (isotrentinoin) [2014 version]
- Abstral (fentanyl) [2016 version]
- Aciphex (rabeprazole sodium) [4/2016 version]
- Aciphex DR (rabeprazole sodium) [4/2016 version]
- Accutane (isotretinoin) [2010 version]
- Actemra (tocilizumab) [5/2017 version]
- Actiq (fentanyl citrate) [2016 version]
- Actonel (risedronate sodium) [2015 version]
- Actonel with Calcium (risedronate sodium and calcium carbonate) [2015 version]
- Actoplus Met (metformin hydrochloride and pioglitazone hydrochloride) [2014 version]
- Actoplus Met XR (metformin hydrochloride and pioglitazone hydrochloride) [2016 version]
- Actos (pioglitazone hydrchloride) [2016 version]
- Adasuve (loxapine) [2016 version]
- Adderall (Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets) [2015 version]
- Adderall XR (dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate) [2015 version]
- Addyi (flibanserin) [2015 version]
- Adempas (riociguat) [2017 version]
- Adlyxin (lixisenatide) {2016 version]
- Advair Diskus (fluticasone propionate and salmeterol xinafoate) [4/2016 version]
- Advair HFA (fluticasone propionate and salmeterol xinafoate) [2/2017 version]
- Afrezza (insulin human) [2015 version]
- Ambien (zolpidem tartrate) [2014 version]
- Ambien CR (zolpidem tartrate) [2014 version]
- Amevive* (alefacept) [2012 version]
- Amjevita (adalimumab-atto) [9/2016 version]
- Ampyra (dalfampridine) [2016 version]
- Anafranil (clomipramine hydrochloride) [2014 version]
- Anaprox (naproxen sodium) [8/2016 version]
- Androgel (1%) (testosterone) [2014 version]
- Androgel (1.62%) (testosterone) [2015 version]
- Anoro Ellipta (Umeclidinium; Vilanterol) [3/2017 version]
- Ansaid (flurbiprofen) [5/2016 version]
- Aplenzin (bupropion hydrobromide [5/2017 version]
- Aptryxol( desvenlafaxine ) extended Release Tablets [2017 version]
- Aranesp* (darbepoetin alfa) [4/2017 version)
Arcapta (indacaterol maleate) [2012 version]
Aristada (aripiprazole lauroxil) [10/2015 version]
- Arthrotec (diclofenac sodium) [5/2016 version]
- Arymo ER (morphine sulfate) [2017 version]
- Astagraf XL (tacrolimus) [2014 version]
- Atelvia (risedronate sodium) [2015 version]
- Ativan (lorazepam) [2016 version]
- Aubagio (teriflunomide) [2016 version]
- Austedo (deutetrabenazine ) [4/2017 version]
- Avandamet (metformin hydrochloride and rosiglitazone maleate) [4/2017 version]
- Avandaryl (glimepiride and rosiglitazone maleate) [3/2015 version]
- Avandia (rosiglitazone maleate) [5/2014 version]
- Aveed (testosterone undecanoate) [5/2015 version]
- Avelox (moxifloxacin) [7/2016 version]
- Avinza (morphine sulfate) [2014 version]
- Avonex* (interferon beta-1a) [2014 version]
- Axiron (testosterone) [2017 version]
- Banzel (rufinamide) [2015 version]
- Bavencio (avelumab) [5/2017 version]
- Belbuca (buprenorphine) [12/2016 version]
- Belsomra (suvorexant) [2014 version]
- Benlysta (belimumab) [2016 version]
- Betaseron*(interferon beta-1b) [2016 version]
- Bevespi Aerosphere (glycopyrrolate and formoterol fumarate) [4/2016 version]
- Binosto (alendronate sodium) [2/2015 version]
- Blincyto (blinatumomab) injection [5/2017 version]
- Boniva (ibandronate sodium) Injection [2016 version]
- Boniva (ibandronate sodium) Tablets [2016 version]
- Botox* (onabotulinumtoxinA) [1/2016 version]
- Breo Ellipta (fluticasone furoate and vilanterol) [5/2017 version]
- Brilinta (ticagrelor) [9/2016 version]
- Brintellix (vortioxetine) [2014 version]
- Brisdelle (paroxetine) [4/2017 version]
- Briviact ((brivaracetam) [2/2016 version]
- Brovana (arformoterol tartrate) [2014 version]
- Bunavail (Buprenorphine and naloxone) Buccal Film (2016)
- Butrans (buprenorphine) [2016 version]
- Bydureon (exenatide) [32015 version]
- Byetta (exenatide) [2/2015 version]
- Cambia (diclofenac) [3/2017 version]
- Caprelsa (vandetanib) [3/2014 version]
- Carbatrol (carbamazepine) [2013 version]
- Cataflam (diclofenac potassium) [5/2016 version]
- Celebrex (celecoxib) [5/2016 version]
- Celexa (citalopram hydrobromide) [2017version]
- Cellcept (mycophenolate mofetil) [2013 version]
- Celontin (methsuximide) [2010 version]
- Cerdelga (eliglustat) [2014 version]
- Chantix (varenicline tartrate) [2016 version]
- Cimzia* (certolizumab pegol) [2016 version]
- Cipro (ciprofloxacin) [2016 version]
- Clinoril (sulindac) [2010 version]
- Codeine Sulfate oral solution [2016 version]
- Codeine Sulfate tablets [2016 version]
- Colcrys (colchicine) [2012 version]
- Combunox (oxycodone hydrochloride and ibuprofen) [2010 version]
- Concerta (methylphenidate hydrochloride) [2013 version]
- Contrave(naltrexone HCl and bupropion HCl) ER [5/2017 version]
- Copegus (ribavirin) [2015 version]
- Cordarone (amiodarone hydrochloride) [3/2015 version]
- Corlanor (ivabradine) [2017 version]
- Cosentyx (secukinumab) [2015 version]
- Coumadin (warfarin sodium) [2016 version]
- Creon (pancrelipase) [2012 version]
- Cymbalta (duloxetine hydrochloride) [2017 version)]
Daliresp (roflumilast) [2015 version]
- Dalmane (flurazepam hydrochloride) [2009 version]
- Darvocet (acetaminophen and propoxyphene napsylate) [2009 version]
- Darvon (propoxyphene hydrochloride) [2009 version]
- Daypro (oxaprozin potassium) [5/2016 version]
- Daypro Alta (oxaprozin potassium) [5/2016 version]
- Daytrana (methylphenidate) [2017 version]
- Depakene (valproic acid) [3/2017 version]
- Depakote ER(divalproex sodium) [3/2017 version]
- Desoxyn (methamphetamine hydrochloride) [2015 version]
- Desvenlafaxine Extended Release Tablet(desvenlafaxine fumarate) [2017version]
- Dexedrine (dextroamphetamine sulfate) [2013 version]
- Dexilant (dexlansoprazole) [2016 version]
- Dilantin (phenytoin) Chewable/ER [2015 version]
- Dilantin-125 (phenytoin) [2016 version]
- Dolophine (methadone hydrochloride) [2016 version]
- Doral (quazepam) [2016 version]
- Duetact (glimepiride and pioglitazone) [3/2015 version]
- Duexis (ibuprofen and famotidine) [5/2016 version]
- Dulera (mometasone furoate and formoterol fumarate) [4/2015 version]
- Duragesic (fentanyl) [2016 version]
- Dyanavel XR (amphetamine) [5/2017 version]
- Dysport* (abobotulinumtoxinA) [2016 version]
- EC-Naprosyn (naproxen) [8/2016 version]
- Edluar (zolpidem tartrate) [2013 version]
- Effexor (venlafaxine hydrochloride) [2012 version]
- Effexor XR (venlafaxine hydrochloride) [1/2017 version
- Effient (prasugrel) [1/2016 version]
- Elidel Cream (pimecrolimus) [3/2014 version]
- Eliquis (apixaban) [6/2015 version]
- Embeda (morphine sulfate and naltrexone hydrochloride) [2014 version]
- Emsam (selegeline transdermal system) [2007 version]
- Enbrel* (etanercept) [2013 version]
- Entyvio (vedolizumab) [2014 version]
- Epogen* (epoetin alfa) [2012 version]
- Epzicom (abacavir sulfate and lamivudine) [3/2017 version]
- Equetro (carbamazepine) [9/2016 version]
- Erivedge (vismodegib) [2016 version]
- Estazolam [2008 version]
- Evista (raloxifene hydrochloride) [2007 version]
- Exalgo (hydromorphone hydrochloride) [2014 version]
- Extavia (interferon beta-1b) [2016 version]
- Extraneal (icodextrin) [2010 version]
- Exubera (insulin recombinant human) [2008 version]
- Factive (gemifloxacin) [2016 version]
- Farxiga (dapagliflozin) [8/2016 version]
- Farydak (panobinostat) [2/2015 version]
Felbatol (felbamate) [2011 version]
- Feldene (piroxicam) [5/2016 version]
- Fentora (fentanyl citrate) [12/2016 version]
- Ferriprox (deferiprone) [2012 version]
- Fetzima (levomilnacipran) [2017 version]
- FIORINAL with CODEINE (Butalbital, Aspirin, Caffeine, and Codeine Phosphate) [12/2016 version]
- Flector (diclofenac epolamine) [5/2016 version]
- Floxin (ofloxacin) [2011 version]
- Fluoxetine (Fluoxetine) [2017 version]
- Fluvoxamine (Fluvoxamine Maleate) [2014 version]
- Focalin (dexmethylphenidate hydrochloride) [2017 version]
- Focalin XR (dexmethylphenidate hydrochloride) [2017 version]
- Foradil Aerolizer (formoterol fumarate inhalation powder) [2012 version]
- Foradil Certihaler (formoterol fumarate inhalation powder) [2010 version]
- Forfivo XL (bupropion hydrochloride) [5/2017 version]
- Forteo (teriparatide) [2013 version]
- Fortesta (testosterone) [5/2015 version]
- Fosamax (alendronate sodium) [2013 version]
- Fosamax Plus D (alendronate sodium and cholecalciferol) [2013 version]
- Fosrenol (lanthanum carbonate) [9/2014 version]
- Fycompa (perampanel) [4/2016 version]
- Gabitril (tiagabine) [11/2015 version]
- Gattex (teduglutide [rDNA origin]) [2012 version]
- Gilenya (fingolimid) [2/2016 version]
- Glyxambi (empagliflozin and linagliptin) Tablets [3/2017 version]
- GoLytely (polyethylene glycol 3500, potassium chloride, sodium bicarbonate, sodium chloride, and sodium sulfate anhydrous) [2013 version]
- Gralise (gabapentin) [2012 version]
- Halcion (triazolam) [2016 version]
- HalfLytely and Bisacodyl Bowel Prep Kit (bisacodyl, polyethylene glycol 3500, potassium chloride, sodium bicarbonate, and sodium chloride) [2010 version]
- Horizant (gabapentin enacarbil) [2013 version]
- H.P. Acthar Gel (repository corticotropin) [2010 version]
- Humira (adalimumab) [4/2017 version]
- Hycodan ( hydrocodone bitartrate and homatropine methylbromide) [2017 version]
- Hydromorphone Hydrochloride ER [2014 version]
- Hysingla ER (Hydrocodone, Bitartrate) [2016 version]
- Iclusig (ponatinib) [2016 version]
- Ilaris* (canakinumab) [7/2016 version]
- Imfinzi (durvalumab) [4/2017 version]
- Impavido (miltefosine) [2014 version]
- Incivek (telaprevir) [2013 version]
- Indocin (indomethacin) [5/2016 version]
- Indocin SR (indomethacin) [5/2016 version]
- Inflectra (Infliximab-dyyb) [4/2016 version]
- Infergen* (interferon alfacon-1) [2013 version]
- Intermezzo (zolpidem tartrate) [2013 version]
- Intron A* (interferon alfa-2b) [4/2014 version]
- Invirase (saquinavir mesylate) [12/2016 version]
- Invokamet (canagliflozin and metformin hydrochloride) [2017]
- Invokamet XR (canagliflozin and metformin hydrochloride extended-release) [2016 version]
- Invokana (canagliflozin) [2016 version]
- Janumet (metformin hydrochloride and sitagliptin phosphate) [2013 version]
- Janumet XR (sitagliptin and metformin hydrochloride) [2014 version]
- Januvia (sitagliptin phosphate) [2013 version]
- Jentadueto (linagliptin and metformin hydrochloride) [3/2017 version]
- Jentadueto XR (linagliptin and metformin hydrochloride) [7/2017 version]
- Juvisync (sitagliptin and simvastatin) [2014 version]
- Juxtapid (lomitapide) [5/2016 version]
- Kadian (morphine sulfate) [12/2016 version]
- Kalbitor* (ecallantide) [3/2014 version]
- Kaletra Capsules (lopinavir and ritonavir) [2013 version]
- Kaletra Tablets and Oral Solution (lopinavir and ritonavir) [11/2016 version]
- Kazano (alogliptin and metformin hydrochloride) [4/2016 version]
- Keppra (levetiracetam) [4/2017 version]
- Keppra XR (levetiracetam) [4/2017 version
- Ketek (telithromycin) [2010 version]
- Keytruda (pembrolizumab) [5/2017 version]
- Khedezla (desvenlafaxine) [2016 version]
- Klonopin (clonazepam) [2016 version]
- Kombiglyze XR (metformin hydrochloride and saxagliptin) [2/2017 version]
- Korlym (mifepristone) [5/2017 version]
- Krystexxa* (pegloticase) [12/2014 version]
- Kynamro (mipomersen sodium) [5/2016 version]
- Lacosamide Tablets (lacosamide) [4/2016 version]
- Lacosamide Tablets CV (lacosamide) [4/2016 version]
- Lacosamide Oral Solution (lacosamide) [3/2016 version]
- Lamictal (lamotrigine) [2013 version]
- Lamictal XR (lamotrigine) [2013 version]
- Lamisil (terbinafine hydrochloride) [8/2016 version]
- Lariam (mefloquine hydrochloride) [2009 version]
- Latuda (lurasidone hydrochloride) [2017 version]
- Lazanda (fentanyl citrate) [2016 version]
- Lemtrada (alemtuzumab) Injection [11/2014 version]
- Letairis (ambrisentan) [10/2015 version]
- Levaquin (levofloxacin) [2016 version]
- Lexapro (escitalopram oxalate) [2017 version]
- Librax ( chlordiazepoxide HCl and clidinium bromide ) [2017 version]
- Librium(chlordiazepoxide) [2016 version]
- Limbitrol (chlordiazepoxide and amitriptyline) [2016 version]
- Lindane Lotion (lindane) [2007 version]
- Lindane Shampoo (lindane) [2007 version]
- Linzess (linaclotide) [3/2017 version]
- Lotronex (alosetron hydrochloride) [/2016 version]
- Lunesta (eszopiclone) [2014 version]
- Lupron Injection (leuprolide acetate) [5/2017 version]
- Lupron Depot-Ped (leuprolide acetate for depot suspension) [5/2017 version]
- Luvox (fluvoxamine maleate) [2014 version] See: Fluvoxamine
- Luvox CR (fluvoxamine maleate) [2014 version]
- Lynparza (olaparib) [2014 version]
- Lyrica (pregabalin) [2013 version]
- Marplan (isocarboxazid) [2008 version]
- Mekinist (trametinib) [2015 version]
- Meridia (sibutramine hydrochloride) [2010 version]
- Metadate CD (methylphenidate hydrochloride) [2014 version]
- Methylin (methylphenidate)
- chewable tablets [2013 version]
- oral solution [2013 version]
- Metoclopramide Oral Solution [2009 version]
- Metozolv ODT (metoclopramide hydrochloride) [2011 version]
- Mifeprex (mifepristone) [2016 version]
- Mircera* (methoxy polyethylene glycol-epoetin beta) [4/2016 version]
- Mitigare (Colchicine) [9/2014 version]
- Mobic (meloxicam) [5/2016 version]
- Morphabond (morphine sulfate)extended release tablets [12/2016]
- Morphine Sulfate (morphine sulfate oral solution) [2011 version]
- Motrin (ibuprofen) [2007 version]
Moviprep (polyethylene glycol 3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid) [2013 version]
Moxifloxacin (moxifloxacin) [7/2016 version]
MS Contin (morphine sulfate) [2014 version]
- Multaq (dronedarone) [2014 version]
- Myalept (Metreleptin) [2015 version]
- Myfortic (mycophenolic acid) [2013 version]
- Myobloc* (rimabotulinumtoxinB) [2009 version]
- Mysoline (primidone) [2010 version]
- Nalfon (fenoprofen calcium) [5/2016 version]
- Naprelan (naproxen sodium) [2011 version]
- Naprosyn (naproxen) [3/2017 version]
- Nardil (phenelzine sulfate) [2007 version]
- Natpara (parathyroid hormone) for injection [12/2015 version]
- Nesina (alogliptin) [4/2016 version]
- Neurontin (gabapentin) [9/2015 version]
- Nexium (esomeprazole magnesium) [3/2014 version]
- Nizoral (ketoconazole) [2014 version]
- Noctiva (desmopressin acetate) [3/2017 version]
- Nolvadex (tamoxifen) [2006 version]
- Noroxin (norfloxacin) [2016 version]
- Norpramin (desipramine hydrochloride) [2014 version]
- Novantrone (mitoXantrone) [2012 version]
- Nplate* (romiplostim) [4/2016 version]
- NSAID (Nonsteroidal Anti-inflammatory Drugs) [8/2016 version]
- Nucynta (tapentadol hydrochloride) [11/2016 version]
- Nucynta ER (tapentadol) [2014 version]
- Nulojix (belatacept) [2014 version]
- NuLytely (polyethylene glycol 3500, potassium chloride, sodium bicarbonate, and sodium chloride) [2013 version]
- Nuvigil (armodafinil) [4/2015 version]
- Ocrevus (ocrelizumab) [3/2017 version]
- Obredon (hydrocodone bitartrate and guaifenesin) [2017 version]
- Odomzo (sonidegib) [2015]
- Oleptro (trazodone hydrochloride) [2014 version]
- Omontys (peginesatide) [2012 version]
- Onfi (clobazam) [2016 version]
- Onglyza (saxagliptin hydrochloride) [2/2017 version]
- Onsolis (fentanyl buccal soluble film) [2016 version]
- Opana ER (oxymorphone hydrochloride) [2016 version]
- Opdivo (nivolumab) [4/2017 version]
- Opsumit (macitentan) [3/2017 version]
- Oseni (alogliptin and pioglitazone) [12/2016 version]
- Osmoprep (sodium phosphate dibasic anhydrous and sodium phosphate monobasic monohydrate) [2012 version]
- OXAYDO (oxycodone HCl) [2016 version]
- Oxtellar XR (oxcarbazepine) [2012 version]
- Oxycodone Hydrochloride Capsules [2016 version]
- Oxycodone Hydrochloride Oral Solution [2013 version]
- OxyContin (oxycodone hydrochloride) [2015 version]
- Oxymorphone Hydrochloride [1/2015 version]
- Pacerone (amiodarone hydrochloride) [2008 version]
- Palladone (hydromorphone hydrochloride) [2004 version]
- Pamelor (nortriptyline hydrochloride) [2012 version]
- Pancreaze (pancrelipase) [2014 version]
- Parnate (tranylcypromine sulfate) [2008 version]
- Paxil (paroxetine hydrochloride) [2014 version]
- Paxil CR (paroxetine hydrochloride) [2014 version]
- Peganone (ethotoin) [2010 version]
- Pegasys* (peginterferon alfa-2a) [2014 version]
- Pegintron* (peginterferon alfa-2b) [2013 version]
- PegIntron*/Rebetol Combo Pack (peginterferon alfa-2b and ribavirin) [2008 version]
- Pennsaid (diclofenac sodium) [5/2016 version]
- Percodan (ASPIRIN; OXYCODONE HYDROCHLORIDE; OXYCODONE TEREPHTHALATE) [2016 version]
- Perforomist (formoterol fumarate) [2012 version]
- Pertzye (pancrelipase) [2012 version]
- Pexeva (paroxetine mesylate) [2017 version]
- Plavix (clopidogrel bisulfate) [9/2016 version]
- Plegridy (peginterferon beta-1a) [7/2016 version]
- Pomalyst (pomalidomide) [4/2015 version]
- Ponstel (mefenamic acid) [5/2016 version]
- Potiga (ezogabine) [5/2016 version]
- Pradaxa (dabigatran etexilate mesylate) [2015 version]
- Prepopik (sodium picosulfate, magnesium oxide and citric acid) [2012 version]
- Prevacid (lansoprazole [12/2015 version]
- Prevacid NapraPac (lansoprazole and naproxen) [5/2019 version]
- Priftin (rifapentine) Tablets [11/2014 version]
- Prilosec (omeprazole [2016 version]
- Pristiq (desvenlafaxine succinate) [2017 version]
- Procrit (epoetin alfa) [4/2017 version]
- Prolia* (denosumab) [2/2015 version]
- Promethazine HCl and Codeine Phosphate (2017 version)
- Promethazine Hydrochloride, Phenylephrine Hydrochloride and Codeine Phosphate (2017 version)
- Propylthiouracil [2010 version]
- Promacta (eltrombopag) [3/2017version]
- Propulsid (cisapride) [2006 version]
- Proquin XR (ciprofloxacin hydrochloride) [2011 version]
- Protonix (pantoprazole sodium) [2013 version]
- Protopic Ointment (tacrolimus) [2011 version]
- Provigil (modafinil) [2015 version]
- Prozac (fluoxetine hydrochloride) [2017 version]
- Qsymia (phentermine and topiramate) [9/2014 version]
- Qtern (dapagliflozin and saxagliptin) [2/2017 version]
- Qualaquin (quinine sulfate) [2014 version]
- Qudexy XR (topiramate) [2017? version]
- QuilliChew ER (methylphenidate Hydorchloride) [3/2017 version]
- Quillivant XR (methylphenidate) [2015 version]
- Rapamune (sirolimus) [5/2015 version]
- Ravicti (glycerol phenylbutyrate) [4/2017 version]
- Rebetol (ribavirin) [2013 version]
- Rebif* (interferon beta-1a) [4/2014 version]
- Reclast (zoledronic acid) [1/2015 version]
- Reglan (metoclopramide hydrochloride) injection [2009 version]
- Reglan (metoclopramide hydrochloride) tablets [2011 version]
- Reglan ODT (metoclopramide hydrochloride) [2011 version]
- Relistor (methylnaltrexone bromide) [9/2014 version]
- Remeron (mirtazapine) [2014 version]
- Remeron SolTab (mirtazapine) [2014 version]
- Remicade* (infliximab) [10/2015 version]
- Renflexis (infliximab-abda) [4/2017 version]
- Restoril (temazepam) [2016 version]
- Revlimid (lenalidomide) [2017 version]
- Rexulti (brexpiprazole) [8/2015 version]
- Rezira ( hydrocodone bitartrate and pseudoephedrine hydrochloride) [2017 version]
- Ribasphere (ribavirin) [2008 version]
- Ritalin (methylphenidate hydrochloride) [2015 version]
- Ritalin LA (methylphenidate hydrochloride) [2017version]
- Ritalin-SR (methylphenidate hydrochloride) [2017 version]
- Rituxan* (rituximab) [2013 version]
- Roferon-A* (interferon alfa-2a recombinant) [2008 version]
- Roxocodone (oxycodone hydrochloride ) [12/2016 version]
- Roxybond (oxycodone hydrochloride) [4/2017 version]
- Rozerem (ramelteon) [2010 version]
- Sabril (vigabatrin) [4/2017 version]
- Samsca (tolvaptan) [2014 version]
- Sarafem (fluoxetine hydrochloride) [2017 version]
- Savaysa (edoxaban) tablets [2015 version]
- Savella (milnacipran hydrochloride) [8/2016 version]
- Saxenda (liraglutide) injection [9/2016 version]
- Selzentry (maraviroc) [3/2014 version]
- Serevent Diskus (salmeterol xinafoate) [4/2014 version]
- Seroquel (quetiapine fumarate) [2013 version]
- Seroquel XR (quetiapine fumarate) [2013 version]
- Signifor (pasireotide diaspartate) [3/2015 version]
- Silenor (doxepin) [2010 version]
- Siliq (brodalumab) [2017version]
- Simponi (golimumab) [2016 version]
- Simponi Aria (golimumab) [2016 version]
- Sinequan (doxepin hydrochloride) [2007 version]
- Sirturo (bedaquiline) [2013 version]
- Sodium Oxybate [2016 version]
- Solaraze (diclofenac sodium) Gel, 3% [5/2016 version]
- Soliqua (insulin glargine and lixisenatide) [2016 version]
- Soliris* (eculizumab) [2017 version]
- Soltamox (tamoxifen citrate) [2005 version]
- Sonata (zaleplon) [2013 version]
- Soriatane (acitretin) [2014 version]
- Sotret (isotretinoin) [2006 version]
- SPRIX (ketorolac tromethamine) Nasal Spray [5/2016 version]
- Spritam (levetiracetam) tablets [2/2016 version]
- Stavzor (valproic acid) [2013 version]
- Stelara* (ustekinumab) [9/2016 version]
- Stiolto Respimat (tiotropium bromide and olodaterol) [2016 version]
- Strattera (atomoxetine hydrochloride) [2014 version]
- Striverdi respimat (olodaterol) [2016 version]
- Suboxone (buprenorphine and naloxone) [12/2016 version]
- Subsys (fentanyl) [2016 version]
- Subutex (buprenorphine) [2016 version]
- Suclear (sodium sulfate, potassium sulfate, magnesium sulfate, sodium chloride, sodium bicarbonate, and potassium chloride) [2013 version]
- Suprep (sodium sulfate, potassium sulfate and magnesium sulfate) [2010 version]
- Supprelin LA (histrelin acetate) [5/2017 version]
- Surmontil (trimipramine) [2014 version]
- Sustol ( granisetron) [8/2016 version]
- Sutent (sunitimib malate) [2013 version]
- Sylatron (peginterferon alfa-2b) [5/2015 version]
- Symbicort (budesonide and formoterol fumarate dihydrate) [2017 version]
- Symbyax (fluoxetine hydrochloride and olanzapine) [2017 version]
- Symlin (pramlintide acetate) [2007 version]
- Synalgos-DC (aspirin, caffeine, and dihydrocodeine bitartrate) [2016 version]
- Synarel (nafarelin acetate) [2017 version]
- Synjardy (empagliflozin and metformin hydrochloride) [2016]
- Synjardy XR (empagliflozin and metformin Hydrochloride Extended Release) [2016 version]
- Synribo (omacetaxine mepesuccinate) [4/2014 version]
- Tafinlar (dabrafenib) [2013 version]
- Taltz (ixekizumab) [3/2016]
- Tanzeum (albiglutide) [3/2015 version]
- Tapentadol see Nucynta
- Targiniq ER (oxycodone hydrochloride and naloxone hydrochloride extended-release tablets) [2016 version]
- Tasigna (nilotinib) [2/2017 version]
- Tecentriq (atezolizumab) [4/2017version]
- Technivie (ombitasvir, paritaprevir and ritonavir tablets) [3/2017 version]
- Tegretol and Tegretol XR (carbamazepine) [2014 version]
- Testim (testosterone) [5/2015 version]
- Testosterone Gel (Perrigo) [5/2015 version]
- Testosterone Gel (Teva) [5/2015 version]
- Thalomid (thalidomide) [2017 version]
- Tikosyn (dofetilide) [2013 version]
- Tivorbex (indomethacin) [5/2016 version]
- Tofranil (imipramine hydrochloride) [2007 version]
- Tofranil-PM (imipramine pamoate) [2012 version]
- Tolectin (tolmetin sodium) [2008 version]
- Topamax (topiramate) [3/2014 version]
- Toradol (ketorolac tromethamine) [2013 version]
- Tracleer (bosentan) [12/2015 version]
- Tradjenta (linagliptin) [3/2017 version]
- Tranxene (clorazepate dipotassium) [2016 version]
- Trazodone (Trazodone Hydrochloride) [2014 version]
- Treximet (naproxen sodium and sumatriptan succinate) [5/2016 version]
- Tridione (trimethadione) [2012 version]
- Trileptal (oxcarbazepine) [2011 version]
- Trilipix (choline fenofibrate) [2012 version]
- Trintellix (vortioxetine) [4/2017 version]
- Triumeq (abacavir, dolutegravir, and lamivudine) tablets [3/2017version]
- Trizivir (abacavir sulfate, lamivudine and zidovudine) [3/2017 version]
- Troxyca (oxycodone hydrochloride and naltrexone hydrochloride) [2016 version]
- Trokendi XR (topiramate) [4/2017 version]
- Trulicity (dulaglutide) [2017 version]
- Truvada (emtricitabine and tenofovir disoproxil fumarate) [4/2017 version]
- Tussionex (hydrocodone polistirex and chlorpheniramine polistirex) [2017 version]
- Tuxarin ER ( codeine phosphate and chlorpheniramine maleate ) [2017 verion]
- Tuzistra XR (codeine polistirex and chlorpheniramine polistirex) [2017 version]
- Tysabri (natalizumab) [5/2015 version]
- Tyzeka (telbivudine) [2013 version]
- Ultracet ( tramadol hydrochloride/acetaminophen) [2016 version]
- Ultresa (pancrelipase) [2012 version]
- Ultram(tramadol hydrochloride) 2[016 version]
- Ultram ER (tramadol hydrochloride extended-release tablets [2016 version]
- Valchlor (mechlorethamine) [2013 version]
- Valium (diazepam) [2016 version]
- Vandetanib see Caprelsa
- Vantrela ER ( hydrocodone bitartrate) [2017 version]
- Venclexta (venetoclax) [4/2016 version]
- Venlafaxine HCl ER (venlafaxine hydrochloride) [2017 version]
- Vibativ (telavancin) [12/2014 version]
- Viberzi (eluxadoline) [4/2017 version]
- Vicoprofen (hydrocodone bitartrate and ibuprofen) [2016 version]
- Victoza (liraglutide) [5/2016 version]
- Victrelis (boceprevir) [2014 version]
- Videx (didanosine) [2011 version]
- Videx EC (didanosine) [2011 version]
- Viekira Pak ((ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) [3/2017 version]
- Viekira XR (dasabuvir, ombitasvir, paritaprevir, and ritonavir) [3/2017 version]
- Viibryd (vilazodone hydrochloride) [2017 version]
- Vimovo (esomeprazole magnesium and naproxen) [5/2016 version]
- Vimpat (lacosamide) [8/2014 version]
- Viokace (pancrelipase) [2012 version]
- Viramune and Viramune XR (nevirapine) [3/2017 version]
- Visicol (sodium phosphate dybasic anhydrous and sodium phosphate monobasic monohydrate) [2013 version]
- Vituz ( hydrocodone bitartrate and chlorpheniramine maleate) [2017 version]
- Vivactil (protriptyline hydrochloride) [2007 version]
- Vivitrol (naltrexone) [2013 version]
- Vogelxo (testosterone) gel [5/2015 version]
- Voltaren (diclofenac sodium) [5/2016 version]
- Voltaren XR (diclofenac sodium) [5/2016 version]
- Votrient (pazopanib hydrochloride) [5/2016 version]
- Vyvanse (lisdexamfetamine dimesylate) [2017 version]
- Wellbutrin (bupropion hydrochloride) [5/2017 version]
- Wellbutrin SR (bupropion hydrochloride) [5/2017 version]
- Wellbutrin XL (buproprion hydrochloride) [5/2017 version]
- Xanax (alprazolam) [2016 version]
- Xanax XR (alprazolam) [2016 version]
- Xarelto (rivaroxaban) [5/ 2016 version]
- Xartemis XR (oxycodone hydrochloride and acetaminophen) [12/2016 version]
- Xeljanz (tofacitinib) [3/2014 version]
- Xenazine (tetrabenazine) [6/2015 version]
- Xeomin* (incobotulinumtoxinA) [2011 version]
- Xiaflex* (collagenase clostridium histolyticum) [8/2016 version]
- Xigduo XR ( Depagliflozin and Metformin HCL extended release ) [8/2016 version]
- Xolair* (omalizumab) [7/2016 version]
- Xtampza ER (oxycodone) [2016 version]
- Xultophy (insulin degludec and liraglutide injection) [11/2016 version]
- Xyrem (sodium oxybate) [2015 version]
- Yervoy* (ipilimumab) [12/2013 version]
- Yosprala (aspirin and omeprazole) [ 9/2016 version ]
- Zarontin (ethosuximide) [2012 version]
- Zegerid (omeprazole and sodium bicarbonate) [2014 version]
- Zelboraf (vemurafenib) [8/2016 version]
- Zenpep (pancrelipase) [2014 version]
- Zerit (stavudine) [2011 version]
- Ziagen (abacavir sulfate) [3/2017 version]
- Zinbryta (daclizumab) [2016 version]
- Zipsor (diclofenac potassium) [5/2016 version]
- Zohydro ER (hydrocodone bitartrate) [2016 version]
- Zoloft (sertraline hydrochloride) [2016 version]
- Zolpidem (zolpidem tartrate) [2008 version]
- Zolpimist (zolpidem tartrate) [2008 version]
- Zonegran (zonisamide) [4/2016 version]
- Zontivity (vorapaxar) [2013 version]
- Zortress (everolimus) [2013 version]
- Zorvolex (diclofenac) [5/2016 version]
- Zubsolv (buprenorphine and naloxone) [2013 version]
- Zurampic (lesinurad) [2016 version]
- Zutripro ((hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride ) [2017 version]
- Zyban (bupropion hydrochloride) [5/2017 version]
- Zydelig ( idelalisib) [9/2016 version]
- Zyprexa (olanzapine) [2013 version]
- Zyprexa Relprevv (olanzapine) [2012 version]
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