1 The National Academies of Sciences, Engineering and Medicine Regulatory Strategies of address prescription opioidrelated harms 4 th of November, 2016 Washington DC Product Labeling to Communicate Benefits and Risks of Treatment for Opioid Use Disorder in Pregnant Women Hendrée E. Jones, PhD Executive Director, Horizons Program Professor, Department of Obstetrics and Gynecology School of Medicine, University of North Carolina at Chapel Hill
2 Outline 1) Review the historical and current context of drug labeling for pregnancy and lactation 2) Highlight challenges and opportunities with current safety labeling of opioid agonist medications to treat opioid use disorder during pregnancy and lactation
3 History of Drug Labels with Pregnancy Information 1960 s 1973 1979 1997 2013 2015 2016 Thalidomide FDA said all pregnant women on methadone should undergo a 21-day detoxification- it was later reversed FDA regulations include pregnancy information when labeling drugs FDA convenes a hearing to review A-D and X pregnancy categories Letter to FDA by National Association of Attorneys General about NAS; Opioid pain medication labeling - NOWS precautions added FDA Pregnancy and Lactation Labeling Rule in effect FDA requires methadone and buprenorphine safety labeling to include the risk of neonatal opioid withdrawal syndrome (NOWS) Zuspan et al. Am J Obstet Gynecol. 1975;122:43-46; Greene Seminars in Perinatology 2015: 520-523; U.S. Food and Drug Administration (FDA). Neonatal opioid withdrawal syndrome and medication-assisted treatment with methadone and buprenorphine. http://www.fda.gov/drugs/drugsafety/ucm503630.htm. Updated May 26, 2016. Accessed October 24, 2016.
4 Defining NAS (also known as NOWS) Neonatal Abstinence Syndrome (NAS) or Neonatal Opioid Withdrawal (NOWS) often results when a pregnant woman uses opioids (e.g., heroin, oxycodone) during pregnancy. Defined by alterations in the: Central nervous system high-pitched crying, irritability exaggerated reflexes, tremors and tight muscles sleep disturbances Autonomic nervous system sweating, fever, yawning, and sneezing Gastrointestinal distress poor feeding, vomiting and loose stools Signs of respiratory distress nasal stuffiness and rapid breathing There are risks and benefits with using NOWS over NAS There are multiple factors that drive NAS/NOWS severity NAS and treatment are not known to have long-term effects; interactions between the caregiver and child can impact resiliency/risk with potential long-term effects in some cases. Finnegan et al., Addict Dis, 1975; Desmond & Wilson, Addict Dis, 1975; Jones & Fielder, Preventive Medicine, 2015.
5 Previous Opioid Agonist Labels: Pregnancy Information ROXANE LABORATORIES, INC. Columbus, OH 43216 DOLOPHINE HYDROCHLORIDE CII (Methadone Hydrochloride Tablets, USP) 5 mg, 10 mg Rx Only Pharmacokinetics in Special Populations Pregnancy The disposition of oral methadone has been studied in approximately 30 pregnant patients in 2nd and 3rd trimesters. Elimination of methadone was significantly changed in pregnancy. Total body clearance of methadone was increased in pregnant patients compared to the same patients postpartum or to non-pregnant opioid-dependent women. The terminal half-life of methadone is decreased during 2nd and 3rd trimesters. The decrease in plasma half-life and increased clearance of methadone resulting in lower methadone trough levels during pregnancy can lead to withdrawal symptoms in some pregnant patients. The dosage may need to be increased or the dosing interval decreased in pregnant patients receiving methadone. (See PRECAUTIONS: Pregnancy, Labor and Delivery, and DOSAGE AND ADMINISTRATION.) Infants born to mothers physically dependent on opioids may also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see PRECAUTIONS; Pregnancy, Labor and Delivery). http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/006134s028lbl.pdf
6 History of Drug Labels with Pregnancy Information 2013 Letter to FDA by National Association of Attorneys General about NAS; Opioid pain medication labeling - NOWS precautions added http://ag.ky.gov/pdf_news/nas_warning_label_letter.pdf
7 Stakeholder Concern: Potential Negative Impact of Labeling Changes June 2013 letter from American Society of Addiction Medicine September 2013 letter from American College of Obstetrics and Gynecology October 2013 Citizen Petitions from National Advocates for Pregnant Women Could reduce number of pregnant women with opioid use disorder who are recommended to or maintained on opioid agonist treatment Discontinuation of treatment likely to result in relapse to nonmedical use of opioids, which will increase risk to pregnant women and their babies Labeling could be used to justify punitive and counterproductive child welfare interventions Could lead pregnant women with opioid use disorder to avoid seeking treatment and/or prenatal care
8 Current Opioid Agonist Labels: Pregnancy Information Current NOWS Labeling in ER/LA Opioid Analgesics (approved 4/16/14) Boxed Warning: Prolonged use of TRADENAME during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Warnings and Precautions 5.3 Neonatal Opioid Withdrawal Syndrome: Prolonged use of TRADENAME during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. 8.1 Pregnancy: Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms http://www.fda.gov/safety/medwatch/safetyinformation/ucm396503.htm
9 History of Drug Labels with Pregnancy Information 1960 s 1973 1979 1997 2013 2015 2016 Thalidomide FDA said all pregnant women on methadone should undergo a 21-day detoxification- it was later reversed FDA regulations include pregnancy information when labeling drugs FDA convenes a hearing to review A-D pregnancy categories Letter to FDA by National Association of Attorneys General about NAS; Opioid pain medication labeling - NOWS precautions added FDA Pregnancy and Lactation Labeling Rule in effect FDA requires methadone and buprenorphine safety labeling to include the risk of neonatal opioid withdrawal syndrome (NOWS) Zuspan et al. Am J Obstet Gynecol. 1975;122:43-46; Greene Seminars in Perinatology 2015: 520-523; U.S. Food and Drug Administration (FDA). Neonatal opioid withdrawal syndrome and medication-assisted treatment with methadone and buprenorphine. http://www.fda.gov/drugs/drugsafety/ucm503630.htm. Updated May 26, 2016. Accessed October 24, 2016.
10 Response to Current Opioid Agonist Labels: Pregnancy Practice Advisory: FDA Boxed Warning on Immediate- Release Opioid Medications and All Prescription Opioids March 24, 2016 On March 22nd, 2016, the U. S. Food and Drug Administration (FDA) announced required, class-wide safety labeling changes for immediate-release opioid pain medications. As part of these changes, the FDA is now requiring a new boxed warning ( black box warning) about the serious risks of misuse, abuse, addiction, overdose, and death on all prescription opioids. The boxed warning will also include a precaution that chronic maternal opioid use during pregnancy can result in neonatal abstinence syndrome (NAS, referred to in the FDA warning as neonatal opioid withdrawal syndrome or NOWS ), described as a condition that may be life-threatening if not recognized and treated using protocols developed by neonatology experts. The FDA has included messaging that treatment should not be abruptly stopped in a physically dependent patient, although this is not specifically stated in regards to a pregnant patient, nor is this messaging in the boxed warning. https://www.acog.org/about-acog/news-room/practice-advisories/practice-advisory-fda-opioid-warning
11 Current Opioid Agonist Labels: Unintended Consequences NAS/NOWS The FDA warning emphasizes the potential greater risk if NAS is unexpected or unrecognized - no data that support the distinction between recognized and unrecognized nor opioid use and subsequent neonatal death. Concerns related to unexpected or unrecognized NAS are related to the process of identifying women using chronic opioids and are not a direct result of the medication or drug itself. Opioid use clearly contributes to the clinical spectrum of NAS, the identification of women who use opioids chronically is a separate issue. Opposite to the intended effect of FDA s new labeling rules, this identification may become more challenging with the universal implementation of a boxed warning on opioids. http://www.acog.org/about-acog/news-room/practice-advisories/practice-advisory-fda-opioid-warning
12 Current Opioid Agonist Labels: Unintended Consequences Impact on Care of Pregnant Women Patients may be denied access to medically indicated opioid prescriptions (either for pain management or opioid-assisted therapy), potentially resulting in an abrupt discontinuation of opioids. Boxed warning was specifically assigned to immediate-release formulations. Immediate-release formulations may be abused, but there are clearly appropriate indications for the use of opioids May negatively impact the appropriate use of opioids in acute pain management for pregnant women, further limiting appropriate pain management options. http://www.acog.org/about-acog/news-room/practice-advisories/practice-advisory-fda-opioid-warning
13 Current Opioid Agonist Labels: Unintended Consequences Impact on Mothers and Children Boxed warning may be used to show mother harmed child prenatally May be used as evidence to support termination of parental rights
14 New Rule: Drug Labels with Pregnancy Information New label has four sub-headings Pregnancy exposure registry Risk Summary Clinical Considerations Data Note: Pregnancy A-D categories has been removed Greene Seminars in Perinatology 2015: 520-523
15 Current Concern: Opioid Use during Pregnancy Examined whether maternal opioid treatment between 1 month before pregnancy and the first trimester was associated with birth with at least 200 case infants or at least 4 exposed case infants using data from National Birth Defects Prevention Study for the period1997 through 2005. Therapeutic opioid use was reported by 2.6% of 17,449 case mothers and 2.0% of 6,701 control mothers Opioid treatment was statistically significantly associated with conoventricular septal defects atrioventricular septal defects hypoplastic left heart syndrome spina bifida gastroschisis Modest absolute increase in risk above the baseline birth defects risk. For example, the estimated birth prevalence of hypoplastic left heart syndrome in the United States is 2.4/10,000 live births Findings suggest a potentially 2.4-fold increased risk for a hypoplastic left heart syndrome-affected pregnancy in a woman taking opioid analgesics periconceptionally Would suggest up to a 5.8 in 10,000 (0.06%) chance of that woman having an infant with hypoplastic left heart syndrome Broussard et al., Am J Obstet Gynecol. 2011
16 Current Concern: Opioid Use during Pregnancy Three concerns severely limit the future research and clinical usefulness of these findings: 1. There is an important difference between relative risk and absolute risk 2. Drug use data are collected retrospectively between 6 weeks and 2 years post delivery 3. Measuring tobacco use as periconceptional smoking status (no-smoking from 1 month before to 1 month postconception, smoking at least once in the same period) equates mothers smoking 1 cigarette once to mothers smoking 2 packs daily. These 2 measurement lapses seriously threaten the study's statistical conclusion validity. 3. Respondents (66%) reported common prescription opioid use reasons were surgical procedures (41%), infections (34%), chronic diseases (20%), and injuries (18%). The extent that these issues are independently related to the birth defects described is unknown. Also unknown is whether or not the cases and controls differed in their respective prevalence of these events. These are stressful events, and stress can influence fetal and neonatal outcomes Omitting the measurement and statistical control of stressful events potentially biases the results The potential relationship between birth defects and other medications (e.g., acetaminophen) that are present in opioid analgesic medications was not addressed Jones et al., Am J Obstet Gynecol. 2011.
17 Summary Boxed warning overemphasizes the risks of NAS without appropriately acknowledging that there are even greater risks associated with abrupt cessation of opioids in the population most effected Labels need to be more easily updated and provide userfriendly data summaries of emerging risk and benefit data Research needs to answer questions about unintended consequences of boxed warnings and the language used to convey warnings
18 Acknowledgements Contact Michael Greene MD Hendrée E Jones, PhD Executive Director, UNC Horizons Professor, Department of Obstetrics and Gynecology School of Medicine University of North Carolina at Chapel Hill 127 Kingston Drive Chapel Hill, NC 27514 USA Hendree_Jones@med.unc.edu Direct Line: 1-919-445-0501 Main Office: 1-919-966-9803 Fax: 1-919-966-9169