[Federal Register Volume 85, Number 125 (Monday, June 29, 2020)]
[Notices]
[Pages 38901-38905]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-13974]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-N-1046]


Use of Codeine-Containing Analgesics in Children Under 12 Years 
of Age Subsequent to CYP2D6 Genetic Testing; Establishment of a Public 
Docket; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; establishment of a public docket; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
announcing the establishment of a docket to solicit public comment on

[[Page 38902]]

specific questions pertaining to the use of codeine for analgesia in 
children under 12 years of age, and the use of cytochrome P450 2D6 
(CYP2D6) testing in children under 12 years of age prior to treatment 
with codeine-containing analgesics. These questions are posed in 
section II.

DATES: Submit either electronic or written comments by August 28, 2020.

ADDRESSES: You may submit comments as follows:
    Please note that late, untimely filed comments will not be 
considered. Electronic comments must be submitted on or before August 
28, 2020. The https://www.regulations.gov electronic filing system will 
accept comments until 11:59 p.m. Eastern Time at the end of August 28, 
2020. Comments received by mail/hand delivery/courier (for written/
paper submissions) will be considered timely if they are postmarked or 
the delivery service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2020-N-1046 for ``Use of Codeine-Containing Analgesics in Children 
Under 12 Years of Age Subsequent to CYP2D6 Genetic Testing.'' Received 
comments, those filed in a timely manner (see ADDRESSES), will be 
placed in the docket and, except for those submitted as ``Confidential 
Submissions,'' publicly viewable at https://www.regulations.gov or at 
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through 
Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: LCDR Jessica Voqui, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 3121, 301-796-2280.

SUPPLEMENTARY INFORMATION:

I. Background

    Codeine-containing prescription analgesic products approved by FDA 
are currently contraindicated in children under 12 years of age.\1\ The 
Agency is considering a request for regulatory action to amend this 
contraindication to provide for use in children under 12 years of age 
who are shown to be cytochrome P450 isoenzyme 2D6 (CYP2D6) normal 
metabolizers (also known as ``extensive metabolizers'') or CYP2D6 
intermediate metabolizers based on pharmacogenetic testing that 
includes CYP2D6 copy number or gene duplication detection. As discussed 
in section I.C., below, concerns have been raised in a citizen petition 
that children under 12 years of age in acute pain may not be able to 
access appropriate opioid analgesic drugs, and FDA is interested in 
understanding the scope and impact of any potential access issues. To 
properly assess the appropriateness and potential impact of making this 
amendment to the contraindication, the Agency seeks input from the 
healthcare community and the public on the following issues: (1) Pain 
management in children under 12 years of age; (2) availability and 
clinical utility of CYP2D6 genotyping tests; and (3) e-prescribing 
availability as a potential mitigation approach for opioid analgesic 
access in urgent situations.
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    \1\ See April 20, 2017, Drug Safety Communication at https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-restricts-use-prescription-codeine-pain-and-cough-medicines-and. Codeine remains available through the over-the-
counter (OTC) Drug Monograph for Cold, Cough, Allergy, 
Bronchodilator, and Antiasthmatic Drug Products (21 CFR 341.14, 21 
CFR 341.74, 21 CFR 341.90) in combination with other medications for 
cough and cold symptoms.
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    Analgesic products with codeine as an active ingredient are opioids 
that are generally indicated for the relief of mild to moderate pain 
where the use of an opioid analgesic is appropriate and for which 
alternative treatments are inadequate. Codeine-containing products 
indicated for analgesia are marketed either as single ingredient 
codeine (a Controlled Substances Act (CSA) Schedule II drug) or in 
combination with other non-narcotic active ingredients, such as 
acetaminophen (the combination being a CSA Schedule III drug); most of 
the use is with the combination products.

[[Page 38903]]

There are also codeine-containing products indicated for the relief of 
cough, that contain a combination of codeine with other active 
ingredients in prescription products for cough and symptoms associated 
with upper respiratory allergies or common cold; however, the pediatric 
cough/cold indications were removed from prescription codeine cough/
cold products in January 2018.\2\ Codeine is partially metabolized to 
morphine, its most potent analgesic metabolite, through the CYP2D6 
pathway. CYP2D6 is a polymorphic enzyme, leading to a high degree of 
variability for metabolism of codeine because of underlying genetic 
differences in CYP2D6 activity. Because of this variability, depending 
on CYP2D6 activity, patients may be at risk for therapeutic failure 
(``poor metabolizers'') or at risk for opioid-related toxicity 
(``ultra-rapid metabolizers'').
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    \2\ See January 11, 2018, Drug Safety Communication at https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-requires-labeling-changes-prescription-opioid-cough-and-cold. But see fn. 1, supra.
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A. Regulatory History: 2007-2013

    Given the variability in the metabolism of codeine, the safety of 
codeine use in children has been a concern, particularly the risk of 
life-threatening or fatal respiratory depression. Over the past several 
years, FDA has updated the labeling for codeine-containing prescription 
products regarding the risk of respiratory depression. In 2007, 
prescription codeine product labeling was updated with information 
regarding polymorphic metabolism and the risk of respiratory 
depression, specifically in breastfed infants of mothers who used 
codeine. In August 2012, FDA issued a Drug Safety Communication (DSC) 
about reports of death and respiratory depression in pediatric 
patients, primarily with use of codeine following tonsillectomy and/or 
adenoidectomy. In February 2013, after completing a review of the 
available safety data for codeine in the FDA Adverse Event Reporting 
System (FAERS) and the medical literature, FDA required a Boxed Warning 
and Contraindication regarding the use of codeine-containing 
prescription analgesics following tonsillectomy and/or adenoidectomy, 
highlighting the risk to those children who are ultra-rapid 
metabolizers of codeine due to CYP2D6 polymorphism. These children may 
be particularly sensitive to the respiratory depressant effects of 
codeine because ultra-rapid metabolizers metabolize standard doses of 
codeine in the liver to high circulating levels of morphine (codeine's 
active metabolite). As part of the review of this issue, in addition to 
codeine, FDA evaluated the FDA Adverse Event Reporting System (FAERS) 
and the medical literature for cases of death or overdose in children 
related to the therapeutic use of immediate-release morphine, 
oxycodone, or hydrocodone. This search did not reveal clear cases of 
unexplainable or unconfounded death or opioid toxicity.
    In June 2013, following a review of the relevant data, the European 
Medicines Agency (EMA) made the determination that ``codeine-containing 
products indicated in the management of pain should only be indicated 
in children above 12 years of age and contraindicated in paediatric 
patients below 18 years of age undergoing tonsillectomy and/or 
adenoidectomy for obstructive sleep apnoea syndrome as well as in women 
during breast-feeding and in patients known to be CYP2D6 ultra-rapid 
metabolisers'' (https://www.ema.europa.eu/en/medicines/human/referrals/codeine-containing-medicines).

B. Regulatory History: 2015-2017

    In April 2015, the EMA completed a review of the use of codeine for 
cough and cold indications. The EMA contraindicated the use of codeine-
containing products in children under 12 years of age for cough and 
cold and recommended that codeine-containing cough and cold products 
not be used in children and adolescents ages 12 to 18 years of age who 
have breathing problems (see ``Codeine-containing medicinal products 
for the treatment of cough or cold in paediatric patients: Codeine not 
to be used in children below 12 years for cough and cold,'' available 
at https://www.ema.europa.eu/en/medicines/human/referrals/codeine-containing-medicinal-products-treatment-cough-cold-paediatric-patients).
    Subsequent to the release of the EMA recommendations about use of 
codeine-containing products in children for cough and cold indications, 
FDA initiated a safety review of available data regarding respiratory 
depression and death with codeine-containing product use for cough in 
children. In addition, FDA also re-evaluated available safety data 
regarding codeine use for analgesia in children. Because of the 
potential for shifting use to other opioids if the scope of the 
February 2013 contraindication for codeine use in children was expanded 
(i.e., beyond pain management following tonsillectomy and/or 
adenoidectomy), FDA also evaluated the safety of other opioid-
containing potential treatments, including hydrocodone-containing cough 
and cold products, and tramadol products.
    The Office of Surveillance and Epidemiology (OSE) within FDA's 
Center for Drug Evaluation and Research (CDER) completed a Pediatric 
Postmarketing Epidemiological, Pharmacovigilance, and Drug Utilization 
Review on November 13, 2015. The review identified 64 cases in the 
FAERS database from 1965 to May 2015 of serious respiratory depression, 
including 24 deaths, in children 18 years of age and below receiving 
codeine-containing products. Most of the cases (50 out of 64), 
including fatal cases (21 out of 24), involved children under 12 years 
of age. Among the 48 cases that reported the reason for use, 34 
reported pain management (17 were post-adenotonsillectomy), and 14 
reported cough and cold management; 12 of 21 deaths in children under 
12 years of age occurred when a codeine-containing product was used 
unrelated to pain post-adenotonsillectomy (cough and cold, n=7; general 
pain, n=2; other postoperative pain, n=2; sore/strep throat pain, n=1). 
Ten of 64 cases mentioned CYP2D6 genotype (7 were ultra-rapid 
metabolizers and 3 were normal metabolizers); the remaining 54 cases 
did not report CYP2D6 genotyping. Of the three cases that occurred in 
normal metabolizers, two involved 3-year-old twin brothers who received 
inadvertent overdoses of codeine for treatment of a cold (one resulted 
in death) and one involved a 3-year-old female who underwent 
tonsillectomy for obstructive sleep apnea. Other risk factors for 
codeine toxicity were noted in several cases such as obesity, 
obstructive sleep apnea, and overdose. OSE concluded that there is case 
report evidence of respiratory depression following codeine use for 
both pain and cough and cold treatment, particularly in pediatric 
patients under 12 years of age.
    FDA held a joint meeting of the Pulmonary and Allergy Drugs and the 
Drug Safety and Risk Management Advisory Committees (PADAC/DSaRM AC) on 
December 10, 2015 (80 FR 65770, October 27, 2015; minutes available at 
https://www.fda.gov/media/95855/download), to discuss the safety of 
codeine in pediatric patients. The issue of whether to add a 
recommendation to the labeling for prescription codeine drug products 
to genotype children prior to prescribing codeine was not raised as a 
specific topic of discussion for the AC. However,

[[Page 38904]]

FDA did explain why a recommendation for routine genotyping prior to 
receiving codeine was not added to product labeling at the time of the 
2013 labeling change. First, normal metabolizers, in some cases, 
convert codeine to morphine at levels similar to ultra-rapid 
metabolizers. Second, the positive predictive value of the genotyping 
tests is low; thus, the number needed to be screened in order to 
prevent one adverse event is very high. Third, genotyping may be 
logistically difficult to implement because preoperative lab tests are 
not routinely obtained before adenotonsillectomy.
    There was some discussion at the AC meeting about patient access 
issues. The patient representative, a mother of a child with sickle 
cell disease (SCD), expressed concerns focused on her daughter being 
able to get any opioid for use at home, rather than codeine/
acetaminophen specifically. The overall theme of her comments was the 
difficulty with accessing opioid medications for control of SCD-related 
intermittent painful crises if a patient has to go to the emergency 
department for care and see physicians who are not familiar with the 
patient or the patient's family.
    Another issue raised at the 2015 PADAC/DSaRM AC meeting was that 
the pediatric pain specialists on the committee contended that codeine/
acetaminophen was not an appropriate drug for the treatment of painful 
sickle cell crises because the acetaminophen limits the dose of codeine 
that can be administered.
    Two-thirds of the AC panel (20 out of 29) recommended that FDA 
contraindicate use of codeine-containing drug products for analgesia in 
children under 18, and the same number (20 out of 29) recommended that 
FDA contraindicate use of codeine-containing drug products for cough in 
children under 18.
    Subsequent to internal discussions about the AC's recommendations, 
in April 2017, the Division of Anesthesia, Analgesia, and Addiction 
Products (DAAAP) and the Division of Pulmonary, Allergy, and 
Rheumatology Products (DPARP), both within CDER's Office of New Drugs, 
issued a Safety Labeling Change (SLC) notification letter related to 
the risk of life-threatening respiratory depression in children 
associated with the use of codeine-containing products and the risk of 
life-threatening respiratory depression in breastfed infants whose 
mothers were treated with codeine-containing products. Although the AC 
panel recommended contraindicating codeine-containing drug products for 
children under 18, FDA chose to limit the contraindication to children 
under 12 years of age. The Agency also included in the SLC notification 
letter a requirement to add warning language regarding use of codeine-
containing products in children ages 12 to 18 years of age who may have 
risk factors (e.g., obstructive sleep apnea, obesity, respiratory 
conditions) making them more susceptible to life-threatening or fatal 
respiratory depression with codeine.
    These labeling changes were based upon the following 
considerations:
     Available data suggest that younger children (under 12 
years of age) may be at highest risk of life-threatening or fatal 
respiratory depression.
     In addition to the risk factor of CYP2D6 ultra-rapid 
metabolizer status, some case reports suggested that other risk 
factors/conditions (e.g., obesity, obstructive sleep apnea, 
oropharyngeal swelling (post-tonsillectomy)) may make patients more 
susceptible to respiratory depression with codeine.
     There was some sentiment from the AC that prescribing of 
codeine-acetaminophen combination drug products, which are CSA Schedule 
III drugs, for pain in children resulted in opioids with lower abuse or 
diversion potential being in the household compared to Schedule II 
opioids being prescribed.
     Contraindication of codeine-containing drug products in 
children under 12 years of age would support continued availability of 
codeine-containing drug products for use in children ages 12 to 18 
years of age who rely on codeine for pain management.
     A contraindication of codeine-containing drug products in 
children under 12 years of age is consistent with decisions made by 
other regulatory authorities, such as EMA and Health Canada (see 
https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/33915a-eng.php).
    On August 29, 2017, the supplements submitted in response to the 
SLC notification letter were approved with updated labeling that 
included new language in the sections outlined above.

C. Citizen Petition Submission--December 2017

    A citizen petition (Petition) dated December 14, 2017 (Docket no. 
FDA-2017-P-6918), was submitted to FDA by Kelly Caudle, MD, Director, 
Clinical Pharmacogenetics Implementation Consortium, St. Jude 
Children's Research Hospital, Memphis, TN, along with other clinical 
pharmacologists (Petitioners) from around the country. The Petitioners 
requested that, with the exception of the post-adenotonsillectomy 
setting, the contraindication of codeine-containing analgesics be 
amended to provide for use of these products in children under 12 years 
of age who are known to be CYP2D6 normal metabolizers or intermediate 
metabolizers based on adequate pharmacogenetic testing (i.e., capable 
of measuring copy number or detect gene duplications). The Petitioners 
suggest that the current contraindication may cause children under 12 
years of age with recurrent acute pain to have decreased access to 
opioid analgesics, which may result in more emergency department and 
urgent care visits. According to the Petition, such decreased access 
could occur because codeine/acetaminophen combination drug products are 
CSA Schedule III (able to be prescribed by telephone) whereas other 
opioid analgesics that would be suitable to treat a patient's pain are 
Schedule II and cannot be prescribed by telephone.
    In FDA's view, if Petitioners' proposed labeling were adopted, a 
CYP2D6 genotype/phenotype determination would be essential for the safe 
and effective use of codeine drug products. Thus, under the Agency's 
authorities governing prescription drug labeling, the approved labeling 
of codeine-containing analgesics would also need to specify that, with 
respect to use in children under 12 years of age, the products are 
intended for use only subsequent to the necessary genotype/phenotype 
determination using an appropriate, FDA-authorized companion diagnostic 
device.\3\
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    \3\ For more information about relevant law and policy regarding 
companion diagnostics and the corresponding therapeutic products, 
see FDA's guidance titled, In Vitro Companion Diagnostic Devices 
(available at https://www.fda.gov/media/81309/download).
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    FDA is aware of several available CYP2D6 genotype tests, each of 
which assess different alleles of CYP2D6 and which may not uniformly 
assess gene copy number. FDA is also aware that these tests have been 
shown to vary in performance with respect to identifying the range of 
genotype combinations. For example, most CYP2D6 tests, the wild type 
(referred to as ``*1'') is typically a default result, i.e., no variant 
is detected and therefore the allele is assigned as the wild type (*1). 
FDA is concerned that, if a test does not have the ability to detect 
rare genotype variants, then patients who have these rare variants 
would be called wild type, and the wrong genotype result (potentially

[[Page 38905]]

normal metabolizer) could be given for those patients.
    Based on prescription dispensing data obtained from a proprietary 
drug utilization database available to FDA, the Agency understands that 
the number of patients ages 0 to 11 who were dispensed codeine-
containing analgesic products decreased from an estimated 735,000 
patients in 2013 to 230,000 patients in 2017. Following the addition of 
the contraindication of codeine-containing drug products in children 
under 12 years of age to the codeine product labeling in August 2017, 
FDA has seen the prescription use of codeine decline further to 84,000 
patients ages 0 to less than 12 years of age in 2018.\4\
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    \4\ Source: IQVIA Total Patient TrackerTM, 2013-2018. 
Data extracted May 2018 and June 2019.
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II. Additional Issues for Consideration and Request for Information

    FDA is soliciting information and comment from stakeholders 
regarding the issues described in this document. In addition to any 
other aspects of these issues that stakeholders may care to comment 
upon, FDA is interested in answers to the following questions in 
particular:

Topic 1: Pain Management in Children Under 12 Years of Age (for 
Prescribers and Other Stakeholders, as Appropriate)

    1. What factors do you consider in choosing to prescribe an opioid 
analgesic for children under 12 years of age who require treatment for 
recurrent episodes of acute pain (e.g., severity of pain, lack of 
response to other analgesics, or the specific disease, such as children 
with sickle cell disease-related pain crises)?
    2. Which pediatric populations, other than children with sickle 
cell disease, typically use an opioid analgesic for recurrent episodes 
of acute pain?
    3. What role, if any, do you see for codeine/acetaminophen 
combination drug products in the treatment of children under 12 years 
of age with recurrent episodes of acute pain?
    4. What is your institution/department/clinical practice's 
recommended approach (or specific formulary options) for selecting an 
opioid analgesic for a child under 12 years of age? Was your 
institution/department/clinical practice's current approach modified 
following FDA's August 2017 codeine labeling revision that 
contraindicated codeine-containing drug products in children under 12 
years of age? If there is not a recommended approach, what opioid 
analgesics are typically prescribed in your practice to patients under 
12 years of age?
    5. In your view/experience, is the contraindication for use of 
codeine/acetaminophen combination drug products in children under 12 
years of age hampering optimal patient care?
    6. What are the issues you have faced regarding urgent access to 
opioid analgesics (e.g., after hours, on weekends, and holidays) for a 
child under 12 years of age with recurrent episodes of acute pain 
requiring an opioid analgesic?
    a. For clinicians: If you have had to face these issues, how do 
they impact prescribing decisions? For example, would you consider 
giving a hard copy prescription for a small amount of opioid analgesic 
to be used in urgent or after-hours situations so the patient can avoid 
making a visit for urgent/emergency care?
    b. For caregivers/patient advocates: How have you handled these 
issues?

Topic 2: CYP2D6 Genotyping Tests (for Prescribers and Technical 
Experts)

    1. Would amending the contraindication to provide for CYP2D6 
genotyping for children under 12 years of age prior to prescription of 
codeine-containing drug products change your clinical practice?
    2. Have you utilized a CYP2D6 genotyping test when determining 
which opioid analgesic to select for a child under 12 years of age who 
has recurrent acute pain severe enough to warrant treatment with an 
opioid analgesic? Describe why or why not.
    3. Describe your experience with interpreting CYP2D6 genotyping 
test results and using those results to make drug prescribing 
decisions.
    4. For a CYP2D6 genotyping test to appropriately identify patients 
who can safely receive a codeine-containing drug product, what is the 
minimum genotyping accuracy and minimum acceptable coverage of the 
currently known genotypes that typically result in a poor metabolizer 
or ultra-rapid metabolizer phenotype?
    5. Regarding detection of ultra-rapid metabolizers, what is the 
type of test output that would be needed for copy number? Is a result 
of ``duplication present'' (i.e., more than one copy) sufficient, or is 
specific quantitation of the number of copies needed?

Topic 3: E-Prescribing Availability (for Prescribers)

    1. Is e-prescribing available in your institution/department/
clinical practice?
    2. What is your practice regarding e-prescribing of Schedule II 
opioids? Are there any limitations in your institution/department/
clinical practice for e-prescribing of Schedule II opioids?
    3. Would you e-prescribe a Schedule II opioid based on a telephone 
discussion with a child's caregiver? Would you e-prescribe any opioid 
(including those in Schedule III and Schedule IV) based on a telephone 
discussion with a child's caregiver? Describe why or why not.
    4. If you do not have e-prescribing available, how does that impact 
your ability to prescribe Schedule II opioids for children under 12 
years of age, particularly with recurrent acute pain episodes?

    Dated: June 24, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-13974 Filed 6-26-20; 8:45 am]
BILLING CODE 4164-01-P


