Medications in Pregnancy: Dispelling Myths and Ensuring Safety - PowerPoint PPT Presentation

Canadian Society of Internal Medicine Annual Meeting 2017 Toronto, ON Medications in Pregnancy: Dispelling Myths and Ensuring Safety Geena Joseph, MD, FRCPC Nephrology and Obstetrical Medicine Renfrew Victoria Hospital The University of Ottawa

CSIM Annual Meeting 2017 The following presentation represents the views of the speaker at the time of the presentation. This information is meant for educational purposes, and should not replace other sources of information or your medical judgment. Learning Objectives: • Describe the general principles of teratogenicity • Recite the new FDA Pregnancy and Lactation Labeling Rule (PLLR) • Describe an approach to counseling on the use of medications in pregnancy and lactation • Describe the particularities of using common medications in pregnant and lactating patients

CSIM Annual Meeting 2017 Conflict Disclosures Definition: A Conflict of Interest may occur in situations where the personal and professional interests of individuals may have actual, potential or apparent influence over their judgment and actions. “I have no conflicts to declare” Company/Organization Details Advisory Board or equivalent NONE Speakers bureau member NONE Payment from a commercial NONE organization. (including gifts or other consideration or ‘in kind’ compensation) Grant(s) or an honorarium NONE Patent for a product referred to or NONE marketed by a commercial organization. Investments in a pharmaceutical NONE organization, medical devices company or communications firm. Participating or participated in a NONE clinical trial

CSIM Annual Meeting 2017 Some of the drugs, devices, or treatment modalities mentioned in this presentation are: Off-label use I intend to make therapeutic recommendations for medications that have not received regulatory approval for use in pregnancy.

Polling during Presentation  Any cell phone with text messaging capabilities can be used to respond.  It is a standard rate text message, so it may be free to send, or up to 20 cents if you don’t have a text message plan. Your phone number won’t be recorded or used for anything else

Case 1: Nellie  33 yo G0P0 woman with Lupus Nephritis  Referred for pre-pregnancy consultation  PMH: 1. SLE x 10 years  Presentation: Rash, Arthritis, nephritis  Dx/ Class IV - Diffuse proliferative glomerulonephritis  Rx/ Prednisone, MMF  azathioprine Hypertension x 10 years 2.

Case 1: (Cont’d)  HPI:  Last flare 2 years ago, treated with high dose prednisone & mycophenolate. Switched to azathioprine 8 months ago. Titrating dose of prednisone.  Generally well, asymptomatic  Meds: Prednisone 10mg OD, Azathioprine 75mg OD, hydroxychloroquine 200mg BID, Nifedipine XL 60mg OD.  Exam: BP 125/75, HR 80bpm  CVS, Resp, Abdo: Normal  No rash or active joints

Case 1: (cont’d)  Investigations:  Hb 130  Cr 91, K=5.2  ANA 1/320, anti-DNA 186 (<50)  ESR, C3, C4, CH50 Normal  Anti-Ro positive, APLA negative  U/A: neg blood, 1+ protein  24hr Urine Collection :  Proteinuria 0.49g/d, Cr 9.2mmol/d  CrCl 1.09ml/s/1.73m 2 (65ml/min/1.73m 2 )  MALB/Cr = 34.8mg/mmol Cr

Would you give her the Green light to get pregnant? A. No, her disease is uncontrolled, unsafe pregnancy medications and the risk of pregnancy is too high B. Not yet, her disease and medications need to optimized C. Not yet, her disease is in remission, blood pressure stable, but we need to change some medications first D. Yes, her disease is in remission, blood pressure stable, pregnancy safe medications

Background  The use of medications in pregnancy and lactation presents a challenge to all health care providers.  In the US, there are 6 million pregnancies every year  50% of pregnant women report taking at least one medication  Pregnant women take an average of 2.6 medications during pregnancy  First trimester use of prescription medications has increased by more than 60% Mitchell AA, et al., Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol. 2011; 205(1):51

Medications in Pregnancy General Principles  Goal is to support the mother-to-be (medically & psychologically) while ensuring the lowest possible risk to fetus  Optimal use of medications to treat diseases during pregnancy can improve the mother ’ s quality of life, reduce maternal complications and any subsequent risk to fetus  Fundamental principle: Risk vs. Benefit of treatment

General Principles of Teratogencity  Teratology: the scientific study of congenital abnormalities and abnormal formations due to different factors (eg/genetics, maternal disease, maternal exposures)  Baseline Risk:  Risk in the general population for major birth defects is 2-4%and for miscarriage is 15-20%  Critical Time period:  Teratogens produce specific abnormalities at specific, susceptible periods during gestation

General Principles of Teratogencity  Types of Teratogencity 1. Pregnancy loss (miscarriage, stillbirth) 2. Congenital malformations Major –Structural or functional defect that requires  intervention or can impair future lifestyle Minor –Unusual morphologic traits of no serious  consequence to the child 3. Neurobehavioral abnormalities (eg/ impaired IQ) 4. Growth Restriction (IUGR) 5. Carcinogenicity

Critical Time Period Moore KL et al. The developing human: clinically oriented embryology. 2003:520

Different Periods of Teratogenicity  First 2 weeks (conception to implantation)  “ All or nothing ” period  First Trimester (Embryogenesis)  Structural malformations  Second & third Trimester (Fetal period)  Growth Restriction & neurodevelopment abnormalities

Causes for Congenital Malformations  65% Unknown  Multifactorial, spontaneous errors of development  25% Genetic  Inherited genetic disorders, new mutations, chromosomal abnormalities  10% Environmental  4% Maternal Disease (eg/ DM, Obesity)  3% Maternal Infection (eg/rubella, CMV)  1-2% Mechanical deformities  < 1% Drugs, radiation, chemical, hyperthermia Brent RL. Addressing environmentally caused human birth defects. Pediatr Rev 2001; 22:153-165

Original FDA Pregnancy Categories

Problems with the Original FDA Classification  The letter classification was overly simplistic and did not provide meaningful clinical information about drug exposure  The category system allowed drugs with evidence of risk and those without evidence of risk to be assigned the same category  Majority of medications classified as Category C  Misinterpreted as a grading system  Drug category could not be changed or updated unless better evidence such as controlled studies were completed which is very challenging to do in pregnancy

History of Pregnancy and Lactation Labeling Rule (PLLR) www.fda.gov

Phased Implementation  After June 2015, all new drugs approved by the FDA will have the new labels  By June 2018, all drugs approved after June 2001 will have the new labels. Pernia, S & DeMaagd G. The New Pregnancy and Lactation Labeling Rule. P&T November 2016; 41(11):713.

Labeling Changes www.fda.gov

8.1 Pregnancy  Pregnancy Exposure Registry  Included if a registry exists for the product and will include information about how to enroll in the registry  Risk Summary  Presented as a narrative and summarizes any human, animal, and pharmacological risk data available  Clinical Considerations  Details disease associated maternal and fetal risk, relevant dose adjustments, maternal and fetal adverse reactions, and labor and delivery information  Data  Describes the information used for the “Risk Summary” and “Clinical Considerations”

Examples:

8.1 Pregnancy  Pregnancy Exposure Registry  Included if a registry exists for the product and will include information about how to enroll in the registry  Risk Summary  Presented as a narrative and summarizes any human, animal, and pharmacological risk data available  Clinical Considerations  Details disease associated maternal and fetal risk, relevant dose adjustments, maternal and fetal adverse reactions, and labor and delivery information  Data  Describes the information used for the “Risk Summary” and “Clinical Considerations”

Zepatier (elbasvir and grazoprevir) Product Monograph

8.2 Lactation • Risk Summary • Describes the presence of the drug in human milk and the effects on milk production and the breastfed child, and contains a statement on the risk–benefit ratio related to use • Clinical Considerations • Includes information on minimizing exposure and monitoring for adverse reactions • Data • Describes the information used for the “Risk Summary” and “Clinical Considerations”

8.3 Female and Males of Reproductive Potential  Recommendations or requirements for pregnancy testing and/or contraception before, during, or after drug therapy OR  Human and/or animal data suggesting drug- associated effects on fertility and/or preimplantation loss effects  Subheadings:  Pregnancy Testing  Contraception  Infertility