Contains Nonbinding Recommendations  
Compliance Policy for Certain 
Compounding of Oral Oxitriptan (5-HTP) 
Drug Products for Patients With 
Tetrahydrobiopterin (BH4) Deficiency  
 
Immediately in Effect Guidance for 
Industry 
   
FDA is issuing this guidance for immediate implementation in accordance with 21 CFR 
10.115(g)(2). Comments may be submitted at any time for Agency consideration.  Submit 
written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to 
https://www.regulations.gov. All comments should be identified with the docket number listed in 
the notice of availability that publishes in the Federal Register. 
 
For questions regarding this document contact Tracy Rupp (CDER) at tracy.rupp@fda.hhs.gov.   
 
Additional copies are available from: 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor 
Silver Spring, MD 20993-0002 
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
     
  
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
July 2019 
Compounding 
 
 
 
1   Contains Nonbinding Recommendations  
Table of Contents 
 
I.   INTRODUCTION ................................................................................................................. 3 
II.   BACKGROUND .................................................................................................................... 4 
A.  Compounding From Bulk Drug Substances Under Section 503A of the FD&C 
Act............................................................................................................ 4 
B.   History of Rulemaking Involving Oxitriptan Under Section 503A of the FD&C 
Act............................................................................................................ 4 
III.  POLICY .................................................................................................................................. 6 
 
        
2   Contains Nonbinding Recommendations  
Compliance Policy for Certain Compounding of Oral Oxitriptan (5-
HTP) Drug Products for Patients With Tetrahydrobiopterin (BH4) 
Deficiency  
Immediately in Effect Guidance for Industry1 
  
  
This guidance represents the current thinking of the Food and Drug Administration (FDA, the Agency, or 
we) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. 
You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. 
To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title 
page.  
 
  
 
I.   INTRODUCTION 
  
This guidance describes the Food and Drug Administrations (FDA, we, or the Agency) policy 
concerning the conditions under which the Agency does not generally intend to take regulatory 
action against a licensed pharmacist in a State-licensed pharmacy or Federal facility or a licensed 
physician using the bulk drug substance oxitriptan (also known as 5-hydroxytryptophan or 5-HTP) 
to compound oral drug products for patients with tetrahydrobiopterin (BH4) deficiency.2,3  On 
February 19, 2019, FDA issued a final rule (84 FR 4696) (final rule) that established the list of 
bulk drug substances that can be used to compound drug products under section 503A of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act), even though they are not the subject of an 
applicable United States Pharmacopoeia (USP) or National Formulary (NF) monograph or a 
component of an FDA approved drug product (503A Bulks List).4  The final rule, codified at 21 
CFR 216.23, placed six bulk drug substances on the 503A Bulks List (21 CFR 216.23(a)), and 
identified four others, including oxitriptan, that cannot be used to compound drug products under 
section 503A of the FD&C Act (21 CFR 216.23(b)).  Additional bulk drug substances nominated 
by the public for inclusion on this list are currently under consideration and will be the subject of  
future rulemaking. 
 
FDA developed this guidance in response to communications from pharmacists and caregivers 
regarding the use of oxitriptan to treat patients with BH4 deficiency following issuance of the final 
rule.    According  to  those  communications  and  other  information  available  to  the  Agency, 
                                                 
1 This guidance has been prepared by multiple offices in the Center for Drug Evaluation and Research, in 
consultation with the Office of Regulatory Affairs at the Food and Drug Administration. 
2 Tetrahydrobiopterin (BH4) deficiency is also known as: primary tetrahydrobiopterin deficiency, atypical 
phenylketonuria (PKU), GTP cyclohydrolase (GTPCH) deficiency, 6-pyruvoyl-tetrahydropterin synthase (6-PTPS) 
deficiency, and dihydropteridine reductase (DHPR) deficiency. 
3 This guidance does not apply to drugs compounded for use in animals. 
All FDA guidances are available on the FDA guidance web page. FDA updates guidances regularly. To make sure 
you have the most recent version of a guidance, always consult the guidance web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
4 See section 503A(b)(1)(A) of the FD&C Act [21 U.S.C. 353a(b)(1)(A)]. 
3   Contains Nonbinding Recommendations  
oxitriptan is the standard of care for the treatment of BH4 deficiency, which is caused by several 
different rare enzyme defects that result from gene mutations.  Thus, this guidance addresses the 
conditions  under  which  FDA  does  not  intend  to  take  regulatory  action  against  a  licensed 
pharmacist in a State-licensed pharmacy or Federal facility or a licensed physician for the use of 
bulk oxitriptan to compound oral drug products for the treatment of identified individual patients 
with BH4 deficiency.  
 
We are issuing this guidance consistent with our good guidance practices (GGP) regulation (21 
CFR 10.115). This guidance is immediately effective because FDA has determined that prior 
public participation is not feasible or appropriate due to the public health need for patients with 
BH4 deficiency to access compounded oxitriptan oral drug products (21 CFR 10.115(g)(2)).   
  
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
  
 
II.   BACKGROUND 
  
A.  Compounding From Bulk Drug Substances Under Section 503A of the 
FD&C Act 
 
Section 503A of the FD&C Act describes the conditions that must be satisfied for human drug 
products compounded by a licensed pharmacist in a State-licensed pharmacy or Federal facility, 
or by a licensed physician, to qualify for exemptions from certain requirements of the FD&C Act 
related to FDA approval prior to marketing, current good manufacturing practice requirements, 
and labeling with adequate directions for use (sections 505, 501(a)(2)(B), and 502(f)(1)) [21 
U.S.C. 355, 351(a)(2)(B), and 352(f)(1)]. 
 
One of the conditions that must be met for a compounded drug product to qualify for these 
exemptions is that a licensed pharmacist or licensed physician compounds the drug product using 
bulk drug substances that (1) comply with the standards of an applicable USP or NF monograph, 
if a monograph exists, and the USP chapter on pharmacy compounding; (2) if such a monograph 
does not exist, are drug substances that are components of drugs approved by FDA; or (3) if such 
a monograph does not exist and the drug substance is not a component of a drug approved by 
FDA, appear on a list of bulk drug substances developed by FDA through regulation.5  
 
 
B.   History of Rulemaking Involving Oxitriptan Under Section 503A of the 
FD&C Act 
 
Because oxitriptan is neither the subject of an applicable USP or NF monograph nor a component 
of an FDA-approved drug, use of bulk oxitriptan to compound a drug product under section 503A 
                                                 
5 See section 503A(b)(1)(A)(i) of the FD&C Act [21 U.S.C. 353a(b)(1)(A)(i)]. 
4   Contains Nonbinding Recommendations  
of the FD&C Act requires that oxitriptan be placed on the 503A Bulks List.6  Oxitriptan was 
nominated and evaluated for inclusion on the 503A Bulks List for use in the treatment of insomnia 
and depression, not BH4 deficiency.  FDA convened an advisory committee to seek its advice 
about whether to include a number of bulk drug substances, including oxitriptan, on the 503A 
Bulks List.7  Based on its review and applying the criteria identified in the Federal Register (79 
FR 37747), FDA proposed to the Pharmacy Compounding Advisory Committee (PCAC) that 
oxitriptan not be included on the 503A Bulks List.8  At the PCAC meeting on June 17, 2015, the 
committee voted to recommend to FDA not to include oxitriptan on the 503A Bulks List.9  Taking 
into consideration the PCACs advice, and after consultation with USP, FDA determined that, on 
balance, the criteria that it considers when conducting evaluations for the 503A Bulks List weighed 
against inclusion of oxitriptan on the 503A Bulks List.  
 
On December 16, 2016, FDA published a proposed rule (81 FR 91071) to not include oxitriptan 
on the 503A Bulks List and provided for a 90-day period to allow for comments to be submitted 
for FDAs consideration in finalizing the rule.  In the preamble to the December 16, 2016 
proposed rule, FDA stated that, on balance, the criteria weighed against the inclusion of oxitriptan 
on the 503A Bulks List.  In particular, the Agencys evaluation of oxitriptan revealed serious 
safety concerns related to the use of oxitriptan for depression, a potentially life-threatening 
condition, in lieu of, or causing a delay in, treatment with an available approved product and the 
lack of adequate warnings that would inform patients and prescribers of the risks associated with 
taking a compounded oxitriptan drug product.  Such risks include, for example, the concomitant 
use of oxitriptan with antidepressant drugs, which could result in serotonin syndrome, a serious 
and life-threatening drug interaction (81 FR 91078). 
 
The Agency received comments to the 2016 proposed rule, some of which related to oxitriptan.  
None of the comments identified treatment of BH4 deficiency as a proposed use of compounded 
oxitriptan drug products.  On February 19, 2019, FDA issued a final rule in the Federal Register 
that identified four bulk drug substances, including oxitriptan, that FDA considered and did not 
include on the 503A Bulks List (84 FR 4696).  The rule became effective on March 21, 2019.   
 
Following publication of the February 19, 2019 final rule, several pharmacists and caregivers 
contacted FDA to advise the Agency that oxitriptan is an essential and standard treatment for 
patients with BH4 deficiency, a rare genetic disorder characterized by deficiency of the cofactor 
BH4 which leads to deficiency of the neurotransmitter serotonin (and its precursor 5-hydroxy-
tryptophan) within the central nervous system.  As noted above, FDA did not consider BH4 
deficiency during its initial review of this substance for the 503A Bulks List.   
 
 
                                                 
6 See section 503A(c)(2) of the FD&C Act [21 U.S.C. 353a(c)(2)]. 
7 See section 503A(c)(1) of the FD&C Act [21 U.S.C. 353a(c)(1)]. 
8 See https://wayback.archive-
it.org/7993/20170405230419/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/
Drugs/PharmacyCompoundingAdvisoryCommittee/UCM449535.pdf.   
9 See https://wayback.archive-
it.org/7993/20170404155231/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/
Drugs/PharmacyCompoundingAdvisoryCommittee/UCM458513.pdf.  
5   Contains Nonbinding Recommendations  
III.   POLICY 
  
In light of the information brought to the Agencys attention about the standard of care for treating 
patients with BH4 deficiency, FDA does not intend to take action for violations of sections 
501(a)(2)(B), 502(f)(1), or 505 of the FD&C Act against a licensed pharmacist in a State-licensed 
pharmacy or Federal facility or a licensed physician who compounds with the bulk drug substance 
oxitriptan, provided the following conditions are met: 
 
  The compounded oxitriptan-containing drug product is intended only for oral 
administration; 
  The compounder provides the oxitriptan-containing oral drug product solely for 
identified individual patients with BH4 deficiency, after receiving a valid prescription for 
such identified individual patient indicating the diagnosis;10   
  The compounder maintains records documenting that the drug product was compounded 
for a patient with BH4 deficiency; and 
  All other conditions of section 503A and other applicable requirements of the FD&C Act 
and FDA regulations are met. 
 
FDA intends to take regulatory action against entities that compound drug products using bulk 
oxitriptan for non-oral routes of administration or to treat conditions other than BH4 deficiency.  
FDA  intends  to  evaluate  compliance  during  inspections  by  reviewing  information  (e.g., 
documentation on prescriptions) stating whether the drug product was compounded for an 
identified individual patient with BH4 deficiency. 
 
In light of the new information regarding use of oral oxitriptan to treat BH4 deficiency, FDA is 
considering whether to reevaluate the exclusion of oxitriptan from the 503A Bulks List.   
 
 
 
                                                 
10 If the prescription does not specify that the identified patient has been diagnosed with BH4 deficiency, the 
compounder should contact the prescriber to obtain and document this information. 
6