1. NLM EXPRESS Drug Information Resources at the National Library of Medicine James E. Knoben, PharmD, MPH July 9, 2013

2. Disclaimer The views expressed in this presentation are those of the presenter and do not necessarily represent, and should not be attributed to NLM. Any reference to a particular medication by generic and/or brand name is for illustrative purposes only and does not represent endorsement of the commercial product.

3. Learning Objectives 1.State the names and main features of the five NLM electronic resources for drug information. 2.Describe the conceptual development of these databases and information needs that they fulfill. 3.Discuss navigational methods by which information is obtained from these resources.

4. National Library of Medicine

5. NLM Reading Room

6. World’s Largest Medical Library 19 million books, journals, manuscripts, audiovisuals MEDLINE/PubMed, 22 million journal citations PubMed Central, > 2.5 million full text articles ClinicalTrials.gov, > 140,000 clinical studies Leading global resource for genomic information

7. Drug Information Databases DailyMed Drug Information Portal LactMed LiverTox Dietary Supplement Label Database

8. Database Types Bibliographic – A list of literary citations, sources Evidence-Based – A systematic, critical review and summarization of literature and/or best clinical practices Portal – Multiple resource searching for specific content, and aggregation of results Repository [Factual] – Storage of data, documents, and/or images All involve selection, organization, and search capability.

9. Drug Information Databases by Type DatabaseType DailyMedDocument repository Drug Information PortalSearch portal LactMedEvidence-based data collection LiverTox Evidence-based data collection Case repository Dietary Supplement Label Database Document repository

10. DRUG INFORMATION DATABASES DailyMed DailyMed Drug Information Portal LactMed LiverTox Dietary Supplement Label Database

11. DailyMed A document repository of FDA drug labeling (package insert) and related information in the public domain http://dailymed.nlm.nih.gov/ http://dailymed.nlm.nih.gov/dailymed/mobile/

12. DailyMed Initiative Health Technology Partnership, 2005 –Food and Drug Administration* –National Library of Medicine* –Veterans Health Administration, Dept. of VA* –Agency for Healthcare Research and Quality –National Cancer Institute * Current Partnership

13. DailyMed Initiative (cont.) Coincides with Structured Product Labeling (SPL) regulations (November, 2005) Uses standardized format and terminology Uses eXtensible Markup Language (XML): –Encodes documents in a format that is human and machine readable; embeds computer tags to denote data sections Improves submission, review and archiving process, and enables searching for specific information

15. DailyMed Searching Search methods –Drug name: brand, generic/active ingredient –Pharmacologic class (FDA) –National Drug Code –Limits to human drugs or to animal drugs

16. DailyMed Features Email label information to yourself or others Download all labels or pharmacologic indexing Access SPL document archives Receive update notices about new label postings Preview SPL format (for use by label authors) Access a solid dose form identification system Link to FDA to report an adverse event (MedWatch) Mobile version also available

19. Sample Record

20. DailyMed Options Side Bar that appears with search result labeling

21. DailyMed Additional Resources With links (and “canned” searches*) –MedWatch –MedlinePlus* –ClinicalTrials.gov* –PubMed* –LactMed* –Medical Dictionary

23. Search PubMed Articles

24. DailyMed Database Stats –Over 50,000 drugs and 25,000 SPLs –Updated product labels posted within one day after FDA approval or submission to FDA (when no prior approval is needed) –SPL updates daily –Increasing percent of new labels each year

25. DRUG INFORMATION DATABASES Drug Information Portal DailyMed Drug Information Portal LactMed LiverTox Dietary Supplement Label Database

26. Drug Information Portal A search engine for Web-based drug information resources in the public domain from NLM and other Federal agencies http://druginfo.nlm.nih.gov/ http://druginfo.nlm.nih.gov/m.drugportal/

27. Resource Selection Criteria The proliferation of drug-related Websites requires objective review to identify credible information. –Authority – Owner/publisher/sponsor is a respected or responsible organization with documented expertise –Content – Information is reliable: accurate, current, unbiased; substantive (has value); data source is cited –Design – Good display, ease of use and navigability –Purpose – The primary purpose is educational and not commercial; financial support is disclosed (as appropriate) –Support – Site is consistently available; includes quality links, contact information, privacy policy, revision date

28. Drug Information Portal Features Covers drugs from clinical trials through FDA approval and marketing NLM resources, such as ClinicalTrials.gov, DailyMed Outside resources, such as AIDSinfo, Drugs@FDA Drugs with official generic name status, such as US Adopted Name, British Approved Name Drugs which have categories extracted from the NLM MeSH Pharmacological Action data

31. Search Results - Ibuprofen

32. Search Results – Ibuprofen (cont.)

34. MeSH Drug Category Descriptions

37. Resources by Audience/Class

39. Resources for Health Professionals

40. DRUG INFORMATION DATABASES LactMed DailyMed Drug Information Portal LactMed LiverTox Dietary Supplement Label Database

41. LactMed An evidence-based information resource on drugs and chemicals to which breastfeeding mothers may be exposed, and the effects of those agents on nursing infants and lactation http://lactmed.nlm.nih.gov/ http://toxnet.nlm.nih.gov/help/lactmedapp.htm

42. LactMed (cont.) Responds to 2005 “urgent call” to action by the Centers for Disease Control and Prevention for accurate, current, and accessible information on medication use during lactation Endorsed by the American Academy of Pediatrics [AAP] as “The most comprehensive, up-to-date source of information regarding the safety of maternal medications when the mother is breastfeeding is LactMed….” Supportive of policy positions of the AAP, American Academy of Family Physicians, Healthy People 2010/2020, UNICEF, WHO, and breast feeding advocacy groups Is one of the most accessed databases in the TOXNET suite of databases at the National Library of Medicine

43. Breastfeeding Breastfeeding and human milk are the reference normative standards for infant feeding and nutrition Recommendation: exclusive breastfeeding for six months, with continuation of breastfeeding for one year or longer [ American Academy of Pediatrics ] Goal: increase breastfeeding to 75% during early infancy [ Healthy People 2010 ] Prevalence of breastfeeding is increasing in the US and worldwide

44. Human Milk Human milk is the most complete form of infant nutrition, rich in nutrients and antibodies For most infants, particularly premature babies, breast milk is easier to digest than formula Human milk helps protect infants against a number of diseases such as otitis media, atopic disease, respiratory and gastrointestinal tract infections Provides immunologic and other benefits that may last into childhood, adolescence and adulthood, including reduction in asthma, type 2 diabetes, and obesity rates

45. Drug Exposure Factors Drugs are excreted in breast milk to varying degrees, and environmental chemicals may be possible contaminants Drug and chemical exposure has potential risk with respect to nursing infants Absent adequate safety information about a drug, the decision is whether to not breastfeed, or breastfeed with uncertainty, or discontinue a medication Mothers often discontinue breastfeeding unnecessarily Health professionals and mothers have little reliable information, and most information is inaccurate

46. LactMed Features 1,000 drug, herbal, and dietary supplement records Data are derived from the world’s scientific literature, and fully referenced to source documents Information prepared by a drug information pharmacist, and quality reviewed by pediatric physician specialists Other features include PubMed citation links, cross-file searching capability with other TOXNET databases, links to reliable breastfeeding Websites, glossary Apps for iPhone/iPod Touch and Android also available

48. LactMed Information Categories Summary of pertinent information regarding recommendations for use of the medication during lactation Drug concentrations measured in the breast milk of lactating women Drug concentrations measured in breastfed infants Adverse effects reported in breastfed infants Possible effects of the drug on lactation Alternative medications that have similar therapeutic effect that may be used during breastfeeding

49. Content by Category

50. LactMed Sample Record 1 Summary of Use Drug Levels Maternal and Infant Effects in Breastfed Infants Effects on Lactation Alternate Drugs

51. Sample Record: Drug Levels

52. Possible Effects on Lactation

54. DRUG INFORMATION DATABASES LiverTox DailyMed Drug Information Portal LactMed LiverTox Dietary Supplement Label Database

55. LiverTox An international resource of evidence-based information and clinical case registry on drug induced liver injury http://livertox.nih.gov/

56. LiverTox Description A database that provides an array of medical information in one site on the diagnosis, cause, frequency, patterns, and management of liver injury attributed to prescription and nonprescription medications, herbals, and dietary supplements

57. An Information Resource LiverTox serves as a… –Clinical resource for clinical pharmacists, general practitioners, specialists and their patients –Research resource for specialists and investigators in liver disease and toxicology –Teaching resource and virtual textbook

58. Medical, Regulatory, Research Interest Drug induced liver injury is… –The cause of 5% of new onset acute liver disease leading to hospitalization –The leading cause of acute liver failure in the United States (Acetaminophen and Prescription Drugs) *Lee WM. Recent developments in acute liver failure. Best Pract Res Clin Gastroenterol 2012; 26: 3-16. F ACTOID : 30% fatality rate in drug induced acute liver failure, absent transplantation. Surgery cost: $250,000+, and $20,000/year for immuno- suppressive drugs.

59. Medical, Regulatory, Research Interest (cont.) Drug induced liver injury is… –The most common reason for failure of new drugs in clinical trials –Until 2000, the leading cause of medications being withdrawn from the market (Cardiovascular events now prevail) F ACTOID : R & D costs are variably estimated to be $100 million to > $1 billion, over 10 years, to bring a new drug to market.

60. DILI Characteristics Can resemble many forms of acute and chronic liver disease, such as acute viral hepatitis, biliary obstruction, chronic hepatitis, fatty liver disease A diagnosis of exclusion Usually idiosyncratic; varying mechanisms Categorized into 12 clinical presentations/phenotypes Caused by at least 500 drugs and numerous herbals

61. Drugs Most Causative of DILI Antibiotics (eg, amoxicillin/clavulanate, ciprofloxacin, minocycline, nitrofurantoin, sulfonamides, telithromycin) Anticonvulsants (eg, carbamazepine, phenytoin, valproate) Antidepressants/antipsychotics (eg, atomoxetine, bupropion, duloxetine, olanzepine) Antifungals (eg, ketoconazole, terbinafine) Antituberculars (eg, isoniazid, pyrazinamide) Analgesics (eg, diclofenac, indomethacin, sulindac) Rheumatologics (eg, allopurinol, infliximab, interferon beta)

62. Herbals/Supplements Most Causative of DILI A rising proportion of cases are due to herbals and dietary supplements, and mixtures thereof; examples include… –Anabolic steroids –Chaparral –Ephedra –Green tea extracts –Usnic acid –Valerian

66. LiverTox Components Four major components: Clinical-Diagnostic Overview Drug Records Case Report Registry Information Resources

67. LiverTox Side Bar – Components

68. LiverTox – Overview Clinical-Diagnostic Overview –Clinical course and diagnosis –Phenotypes (clinical signatures) –Causality assessment –Severity grading –Likelihood of drug association

70. LiverTox – Drug Records Drug Records, including –Drug/Medication Classes Incorporates individual drugs within classes –Herbals, Dietary Supplements –Candidate agents include those that… Cause definite DILI Cause possible DILI Lack scientific evidence of DILI

71. Drug Record Sections SectionsDescription Overview Introduction, background, hepatotoxicity presentation, mechanism, outcome and management Case Examples From Drug-induced Liver Injury Network, published literature, NIH clinical center Histology From the national cancer institute and other clinical/scientific sources Product Information Molecular formula, chemical structure, trade name(s), product labeling References From literature, annotated, PubMed link

73. Case Report

74. Histology (Acute Hepatitis)

75. References Reference list of books and journals. Includes hepatologist- written annotations and PubMed citation links.

76. Product Information

77. Other Reference Links

78. LiverTox – Case Report Registry Case Report Registry (http://livertox.niddk.nih.gov/)http://livertox.niddk.nih.gov/ –Allows the user to submit a clinical case –Provides structured format for data entry –Generates printable case summary –Automated submission to FDA MedWatch –Cumulative registry allows future analysis (drug use trends, demographics…)

82. LiverTox – Information Resources Information Resources –Clinical alerts, news, listserv –Conference proceedings –Information resources –Research data from other programs –Abbreviations, glossary

83. LiverTox Status Livertox Status –700 drug records completed, with 15,000 references with annotations –Goal of 1,000 drug, herbal and supplement records –Currently gaining a worldwide audience –Content maintained by NIDDK and other specialists

84. DRUG INFORMATION DATABASES Dietary Supplement Label Database DailyMed Drug Information Portal LactMed LiverTox Dietary Supplement Label Database

85. A document repository derived from dietary supplement product labels, as provided by the manufacturers, for products marketed in the U.S. http://dsld.nlm.nih.gov/

86. Dietary Supplement An oral product intended to supplement the diet, containing one or more dietary ingredients, including vitamins, minerals, herbs or other botanicals, amino acids and other substances, or their constituents. The product is not intended to diagnose, treat, cure, or prevent any disease. FDA does not preapprove dietary supplement products for safety and effectiveness (unlike drugs); for ingredients sold after 1994, the manufacturer must verify that there is reasonable evidence regarding the safety of its use. The product must be properly labeled with specific information: product name, content quantities, mfr. information, directions for use, Supplement Facts panel (eg, serving size, ingredient list, amount per serving by weight, components of blend)

87. Label Database Background A joint project of the Office of Dietary Supplements (ODS) and the National Library of Medicine Results from a collaboration that involved representatives from most NIH components and numerous other agencies, such as the FDA, CDC, Agency for Healthcare Research and Quality, Consumer Product Safety Commission, Dept. of Agriculture Initial release provides label ingredients on 17,000 products; with regular updates, will eventually include most of the 55,000 dietary supplements in the U.S. market Will also serve as a research resource for studies on dietary supplement availability and formulation trends

88. Label Database Features Provides label information for products that are currently on the U.S. market and those discontinued/no longer available on the U.S. market Provides complete information from dietary supplement product labels, and images of the product labels Provides both quick and advanced search options Searchable by ingredient, product name, specific label text, manufacturer or distributor Advanced search allows combining search terms

90. Advanced Search

91. Advanced Search (cont.)

92. Search Page: Dietary Ingredients

93. Search Page: Products

94. Search Page: Contacts

95. Record: Product Information

96. Record: Dietary Supplement Facts

97. Record: Label Statements

98. Record: Images

99. Drug Information at NLM CONTACT INFORMATION Specialized Information Services, NLM Toxicology and Environmental Health Information Program (TEHIP), NLM tehip@teh.nlm.nih.gov Thank you!