Restricted Delivery Systems: Flow Restrictors for Oral Liquid Drug Products Guidance for Industry

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Restricted Delivery Systems:
Flow Restrictors for Oral
Liquid Drug Products
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. 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 draft document, contact Rhiannon Leutner (CDER) at 240-402-
5998.
For questions about this document regarding CBER-regulated products, contact the Office of
Communication, Outreach, and Development (OCOD) at 1-800-835-4709 or 240-402-8010.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Office of Combination Products (OCP)
March 2020
Drug Safety

Restricted Delivery Systems:
Flow Restrictors for Oral
Liquid Drug Products
Guidance for Industry
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., 4 th 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/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances
and/or
Office of Policy
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 66, Room 5431
Silver Spring, MD 20993-0002
Email: CDRH-Guidance@fda.hhs.gov
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-
and-radiation-emitting-products
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Office of Combination Products (OCP)
March 2020
Drug Safety

Contains Nonbinding Recommendations
Draft — Not for Implementation
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	DISCUSSION .................................................................................................................... 3
IV. 	GENERAL RECOMMENDATIONS ............................................................................. 5
A. 	Restriction Effects .......................................................................................................................... 5
B. 	Human Factors and Design Considerations ................................................................................ 6
C. 	Directions for Use........................................................................................................................... 7
APPENDIX A: PRODUCT-SPECIFIC RECOMMENDED RESTRICTION EFFECTS .... 9

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1
Restricted Delivery Systems: Flow Restrictors for Oral Liquid	1
Drug Products	2
Guidance for Industry1
3
4
5
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	6
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	7
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	8
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	9
for this guidance as listed on the title page.	10
11
12
13
I. 	INTRODUCTION	14
15
This guidance provides recommendations regarding the use of restricted delivery systems2,3 to	16
limit unintentional ingestion4 of oral liquid drug products (e.g., oral solution, oral suspension) by	17
children.5 The recommendations in this guidance apply broadly to oral liquid drug and	18
biological products.6,7 Accordingly, this guidance is intended for manufacturers of oral liquid	19
drug and biological products. In this guidance, the term manufacturer is used broadly to include	20
firms that market drug products under the Over-the-counter (OTC) Drug Review; holders of new	21
1 This guidance has been prepared by the Office of Surveillance and Epidemiology, the Division of Nonprescription
Drug Products, and the Division of Pediatric and Maternal Health in the Center for Drug Evaluation and Research
(CDER), in collaboration with the Center for Devices and Radiological Health (CDRH), the Center for Biologics
Evaluation and Research (CBER), and the Office of Combination Products at the Food and Drug Administration.
2 For the purpose of this guidance, a restricted delivery system is defined as “a Packaging system designed or
constructed to restrict (control) the amount of the drug product that may be delivered in order to limit unintended
access by children and other similarly vulnerable populations. [. . .] One component of the Restricted delivery system
is the flow restrictor, 	which is a Packaging component that restricts the flow of liquid. The flow restrictor may be
used as part of a Restricted delivery system or as an adaptor to facilitate use of a measuring device for oral medicinal
liquids. A flow restrictor should not compromise CPSC standards for special packaging [Child-resistant and Senior-
friendly packaging (16 CFR §1700.15 et seq.)].” General Chapter <659> Packaging and Storage Requirements,
United States Pharmacopeia (USP) 40-NF 35. As used in this guidance, the term restricted delivery 	system is
distinct from the term restricted device as defined in 21 CFR 807.3(i).
3 This guidance provides specific recommendations for flow restrictors and general recommendations that may be
applicable to a range of restricted delivery systems, including flow restrictors. FDA acknowledges the potential for
development of new restricted delivery systems and is including general recommendations for consideration.
4 Accessing medication without caregiver permission or oversight is also referred to in this guidance as accidental
exposure, unsupervised ingestion, unsupervised exposure, and accidental ingestion.
5 The principles in this guidance also apply to other similarly vulnerable populations.
6 References to drugs and biological products include drugs approved under section 505 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 355) and biological products licensed under section 351 of the Public Health Service
Act (42 U.S.C. 262) that are drugs. For the purposes of this guidance, drug product or drug will be used to refer to
human prescription drugs and biological products that are regulated as drugs.
7 Manufacturers should determine whether a restricted delivery system is appropriate for use with 	their product.
Restricted delivery systems may not be appropriate for some products (e.g., activated charcoal solutions, oral
glucose solutions, or bulk stock bottles).

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drug applications (NDAs), biologics license applications (BLAs), and abbreviated new drug	22
applications (ANDAs); and firms that manufacture components packaged or labeled for	23
commercial distribution with oral liquid drug products, including firms that buy product in bulk	24
to sell under their own label and add a flow restrictor to the product when they fill the bulk	25
product into direct-to-consumer packaging.	26
27
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	28
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	29
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	30
the word should in Agency guidances means that something is suggested or recommended, but	31
not required.	32
33
34
II. 	BACKGROUND	35
36
In 1970, the Poison Prevention Packaging Act (PPPA) was enacted to protect children (under 5	37
years of age) from unintentional exposure to certain household substances, including foods,	38
drugs, and cosmetics.8 Under the Federal Food, Drug, and Cosmetic Act (FD&C Act), a drug	39
that has packaging or labeling that is in violation of an applicable regulation issued pursuant to	40
section 3 or 4 of the PPPA is deemed to be misbranded.9 FDA was responsible for enforcing the	41
PPPA until 1973, when jurisdiction was transferred to the U.S. Consumer Product Safety	42
Commission (CPSC).10	
43
44
CPSC’s regulations list “standards for special packaging”11,12 (also referred to in this guidance	45
as child-resistant packaging (CRP)) for a wide range of household products, including most oral	46
prescription drugs and many nonprescription drug products.13 There are different ways to make	47
packaging child-resistant, with the most common forms being a child-resistant closure (e.g., a	48
safety cap) and certain unit-of-use blister packaging (e.g., puncture-resistant and peel-push	49
blisters). However, not all container closures (i.e., packaging components that contain and	50
protect drug products), including unit-of-use packaging, are child-resistant. Furthermore, child-	51
resistant should not be equated to child-proof, because CRP is not designed to completely	52
eliminate the possibility of an accidental pediatric ingestion. It can only impede access to	53
harmful products.	54
55
CRP is regarded as an important public health safety tool for reducing the incidence of harmful	56
health outcomes related to unintentional ingestions.14 Many oral liquid drug products are	57
8 Poison Prevention Packaging Act of 1970 (PPPA) (Pub. L. 91-601, 84 Stat. 1670), enacted December 30, 1970.
9 See section 502(p) of the FD&C Act (21 U.S.C. 352(p)).
10 Consumer Product Safety Act (Pub. L. 92-573, 86 Stat. 1207), October 27, 1972, Sec. 30.
11 See 16 CFR part 1700. See also definitions in section 2 (4) of the PPPA.
12 Special packaging and child-resistant packaging are used interchangeably in this guidance.
13 See 16 CFR part 1700 for substances requiring special packaging and the relevant packaging standards and testing
procedures.
14 Early studies in the 1960s demonstrated a nearly a 10-fold reduction in unsupervised pediatric ingestions with
medicines with special packaging distributed from the Fort Lewis-McChord Air Force Base in Washington. During
the years CRP has been used to package drugs, cosmetics, and household chemicals, the number of children who

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marketed with CRP features. However, even with the availability of this safety tool, adverse	58
events related to unintentional ingestion of drug products, including oral liquid drug products,	59
continue to be reported. One analysis of the National Electronic Injury Surveillance System-	60
Cooperative Adverse Drug Event Surveillance (NEISS-CADES)15 data estimated that children	61
younger than 6 years old account for more than 9,500 annual Emergency Department (ED) visits	62
attributed to the unintentional ingestion of oral liquid drug products.16	
63
64
Additional measures should also be considered to help reduce unintentional ingestion of oral	65
liquid drug products, including safe and secure product storage.17 Exposure-limiting packaging,	66
such as a restricted delivery system, is one such measure that complements CRP. Specifically,	67
restricted delivery systems are intended to restrict the flow of liquid from the opening of a	68
container. Restricted delivery systems are not a replacement for CRP and use of restricted	69
delivery systems should not compromise CRP. Rather, manufacturers should consider using a	70
combination of CRP and restricted delivery systems to further reduce unintentional ingestion of	71
oral liquid drug products.	72
73
74
III. 	DISCUSSION OF FLOW RESTRICTORS	75
76
An example of a restricted delivery system is a flow restrictor, which can be added to the neck of	77
a bottle to restrict or control the flow of liquid. Flow restrictors can be added to a container at	78
the site of manufacture, or they can be co-packaged with the drug product and added to the	79
container at the time of use. Alternatively, the design of the container can be such that the flow	80
restrictor is molded and integrated into the bottle neck and cannot be separated from the bottle.	81
Bottles containing a flow restrictor may need a dosing device, such as an oral syringe, to extract	82
the drug product. Depending on the design and technology, flow restrictors can be of the open or	83
closed type.	84
85
1. 	Closed Flow Restrictors. In general, a closed flow restrictor limits access to a single-unit	86
volume at one time. A closed flow restrictor can be designed with a self-closing valve	87
have died from ingesting toxic household substances has declined significantly. See
https://www.cpsc.gov/Regulations-Laws--Standards/Statutes/Poison-Prevention-Packaging-Act/.
15 NEISS-CADES is an expansion of the CPSC National Electronic Injury Surveillance System (NEISS), used to
monitor consumer-product-related injuries. NEISS-CADES collects data on all adverse drug events treated in U.S.
hospital emergency departments, whether or not associated with consumer products. NEISS data are collected from
a nationally representative sample of U.S. hospital emergency departments; NEISS-CADES uses a subsample of
those emergency departments for its data collection. See https://www.cpsc.gov/Research--Statistics/NEISS-Injury-
Data.
16 Lovegrove MC, Weidle NJ, Budnitz DS. Trends in emergency department visits for unsupervised pediatric
medication exposures, 2004-2013. Pediatrics 2015 Oct;136(4): e821-829 (annual national estimate in ED visits for
unsupervised exposures involving oral liquid medication by children younger than 6 years old between 2010 and
2013).
17 Safe and secure product storage is a complementary safety measure that is important to keep in mind. When
medications are stored in reach and sight of children, children are able to gain access to and defeat CRP or restricted
delivery systems in some instances, thereby reducing the effectiveness of these packaging measures. Therefore,
FDA recommends that all drugs, irrespective of the type of packaging, be stored safely out of the reach and sight of
children to further the overall public health efforts to address unintentional ingestion of drug products.

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that opens when the dosing device is inserted and reseals after removal of the dosing	88
device. Closed flow restrictors are designed such that the valve orifice matches a	89
corresponding dosing device, and in some cases, the design may be so specific that it	90
includes a lock-and-key mechanism needing a designated dosing device.	91
92
2. 	Open Flow Restrictors. An open flow restrictor allows for a continuous, controlled	93
volume. When an oral syringe is used, an open flow restrictor does not reseal after	94
removal of the oral syringe and when the bottle is inverted it permits a slow flow of	95
liquid from the container.	96
97
The efficacy of flow restrictors has been demonstrated in the pediatric population.18,19 Children	98
age 3 to 4 years are typically able to empty the entire contents of bottles without flow restrictors	99
within 2 minutes; however, when a bottle was fitted with a flow restrictor, children of the same	100
age were prevented from completely emptying the bottle contents within a 6-minute period.20 In	101
cases of unintentional liquid acetaminophen ingestions, the average individual dose was lower in	102
cases that involved bottles with flow restrictors.21 In general, the incorporation of a flow	103
restrictor reduces the total volume of liquid children are able to extract from liquid medicine	104
bottles, which may reduce the risk of harm resulting from unintentional ingestions.	105
106
18 Lovegrove MC, Hon S, Geller RJ, Rose KO, Hampton LM, Bradley J, Budnitz DS. Efficacy of flow restrictors in
limiting access of liquid medications by young children. Journal of Pediatrics 2013 Oct; 163(4): 1134-1139.
19 Geller RJ, Hon SL, Reynolds KM, Burnham RI, Badillo R, Ketcham S, Muresan N, Peters ME, Stokkeland KL,
Green JL. Do New Child Resistant Closures Reduce Injury Following Accidental Ingestion? 2015 Annual Meeting
of the North American Congress of Clinical Toxicology (NACCT). Clinical Toxicology 2015: 53:639-777.
20 Lovegrove et al. assessed the efficacy of flow restrictors in 110 children age 36 to 59 months in a block
randomized trial with a convenience sample from five preschools. The authors noted that flow restrictors on
uncapped (open) bottles decreased the ability of young children to remove liquid medicine from bottles when
compared to uncapped or partially opened bottles without flow restrictors. In this randomized study, 3- and 4-year-
old children were able to remove the entire contents of nearly all bottles without flow restrictors that were either
open (96%; 25 out of 26 children) or incompletely closed (82%; 68 out of 83 children) within 2 minutes. However,
none of the children emptied a bottle with a flow restrictor in less than 6 minutes, and only 6% (7 out of 110
children) emptied a bottle with a flow restrictor within the full 10-minute testing period. Furthermore, the maximum
amount of liquid the youngest children studied (age 36 to 41 months) were able to remove was less than 5 milliliters.
Overall, the study findings showed that children removed less total liquid from bottles with flow restrictors when
compared to open or incompletely closed control bottles.
21 Geller et al. conducted a 6-month poison center phone survey of 1,952 parents of children who had unintentional
ingestions of liquid drug products that demonstrated the potential efficacy of flow restrictors in children younger
than 12 years old. The survey identified 289 cases of single-ingredient unintentional acetaminophen ingestions
among children of the 528 parents who completed the survey. The majority (88.1%) of these children were younger
than 3 years old. The authors noted that the unintentional ingestions involving liquid acetaminophen with flow
restrictors resulted in a lower estimated average dose, whereas the unintentional ingestions involving packaging
without flow restrictors resulted in a 2.5 times larger risk of an estimated exposure greater than 150 milligrams
(mg)/kilogram (kg), which is the threshold dose used by some poison centers for referral to a health care facility.
The American Academy of Clinical Toxicology (ACCT) guidelines and POISINDEX recommend 200 mg/kg as the
threshold dose for which referral to ED is suggested in cases of acetaminophen toxicity.

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IV. 	GENERAL RECOMMENDATIONS	107
108
Manufacturers should consider the use of a restricted delivery system, such as a flow restrictor,	109
as an additional measure to further reduce the risk of unintended ingestions of oral liquid drug	110
products.	111
112
As manufacturers seek to develop restricted delivery systems, they are strongly encouraged to	113
discuss with FDA any proposed restricted delivery system early in the development process.22	
114
115
Standardized test methodologies23,24 for assessing restricted delivery systems for liquid	116
consumer products are currently being developed. We recommend that manufacturers consider	117
general testing methods and parameters that assess product functionality for labeled use and	118
assess performance necessary to prevent unintentional ingestions. Manufacturers should also	119
consider elements such as those discussed below when developing a restricted delivery system	120
for their oral liquid drug product.	121
122
A. 	Restriction Effects25	123
124
FDA recommends targeted restriction effects to limit the amount of an oral liquid drug product	125
that may be delivered over a period of time. The majority of unintended ingestion cases occur	126
within 5 minutes of access to drug products,26 and an analysis of NEISS-CADES data reports	127
that 60% of unintentional OTC liquid medication ingestions involve children 2 years old and	128
younger.27 Accordingly, the recommended targeted restriction effects of the restricted delivery	129
system should reduce the amount of liquid that flows from a bottle in a 5-minute period based on	130
the toxic dose of the drug product to a 2-year-old child.28,29	
131
132
22 For products marketed under the OTC Drug Review, contact the Division of Nonprescription Drug Products in
CDER’s Office of New Drugs. For products requiring premarket review (i.e. “new drugs” under section 201(p) of
the FD&C Act (21 U.S.C. 321(p)), contact the appropriate review division within FDA.
23 See ASTM Standard F3375-19 Test Method for Assessing Non-Metered Restricted Delivery Systems for Liquid
Consumer Products at: https://www.astm.org/Standards/F3375.htm
24 ASTM News Release, New Standard Aims to Limit Children’s Access to Liquid Medicines, Other Products. See
link: https://www.astm.org/cms/drupal-7.51/newsroom/new-standard-aims-limit-children%E2%80%99s-access-
liquid-medicines-other-products
25 In this guidance, restriction effects are the changes to the amount of liquid drug product that may be delivered
over a period of time in order to limit access by children and other similarly vulnerable populations.
26 Ozanne-Smith J, Day L, Parsons B, Tibballs J, and Dobbin M. Childhood poisoning: Access and prevention.
Journal of Pediatric Child Health. 2001; 37: 262–265.
27 Lovegrove MC, Weidle NJ, Budnitz DS. Trends in emergency department visits for unsupervised pediatric
medication exposures, 2004-2013. Pediatrics 2015; 136.
28 FDA recommends using the 50th percentile weight for age estimates in toxic dose calculations; see CDC growth
charts at https://www.cdc.gov/growthcharts/.
29 Lovegrove, Weidle, Budnitz (Pediatrics 2015; 136) also note that children younger than 1 year of age accounted
for 5% of ED visits for unsupervised ingestions. The visits for those age 1 and 2 years accounted for the majority of
visits (this includes visits for unintended ingestion of both oral solid and liquid dosage forms). However, visits for
oral OTC liquid medication exposures involved a proportionally greater number of children over the age of 2 years,
which is one of the reasons why FDA chose 2-year-olds for the recommended targeted restriction effects.

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Recommended restriction effects are described in Appendix A for some of the commonly	133
identified oral liquid drug products that result in ED visits from unintentional ingestion. The	134
restriction effects in Appendix A incorporate the recommendation above (regarding a 5-minute	135
period and a 2-year-old child) and are based on general parameters used by poison center	136
professionals (e.g., POISINDEX) in determining threshold doses that call for emergency	137
evaluation, as well as on practice guidelines developed by the American Academy of Clinical	138
Toxicology (AACT).30,31	
139
140
The use of a restricted delivery system that limits access to a single-unit volume at one time,	141
such as a closed flow restrictor, is warranted for drug products with a narrow therapeutic index32	
142
because there is a small difference between therapeutic and toxic doses. This type of restricted	143
delivery system should also be considered for oral liquid drug products with significant toxicities	144
at doses that are close to the therapeutic dose. For drug-drug combinations, manufacturers	145
should consider the most toxic agent in the combination as well as the combined toxicity of all	146
product ingredients in determining the desired restriction effect.	147
148
Viscosity of the liquid is another important consideration because it will determine the rate at	149
which a liquid flows and influence the performance of restricted delivery systems. Restricted	150
delivery systems should be suitable for use with a liquid with the viscosity of the particular	151
formulation so that typical volumes can be reasonably dispensed by the target	152
consumer/patient/caregiver populations. Products with high viscosity may be difficult for a	153
parent or caregiver to extract from some restricted delivery system designs. Conversely,	154
products with low viscosity, which flow freely, may benefit from a more restrictive packaging	155
design.	156
157
B. 	Human Factors and Design Considerations	158
159
In addition to the preceding information, the following design considerations should be taken	160
into account in selecting the most appropriate restricted delivery system for an oral liquid drug	161
product:	162
163
• 	Restricted delivery systems should be constructed of materials that are safe for oral, skin,	164
and mucosal contact, as well as compatible with the drug formulation.33	
165
30 Chyka PA, Erdman AR, Manoguerra AS, Christianson G, Booze LL, Nelson LS, Woolf AD, Cobaugh DJ,
Caravati EM, Scharman EJ, Troutman WD. Dextromethorphan poisoning: An evidence-based consensus guideline
for out-of-hospital management. Clinical Toxicology 2008; 45(6): 662-677, DOI: 10.1080/15563650701606443.
31 Scharman EJ, Erdman AR, Wax PM, Chyka PA, Caravati EM, Nelson LS, Manoguerra AS, Christianson G,
Olson KR, Woolf AD, Keyes DC, Booze LL, Troutman WG. Diphenhydramine and dimenhydrinate poisoning: An
evidence-based consensus guideline for out-of-hospital management. Clinical Toxicology 2008; 44(3): 205-223,
DOI: 10.1080/15563650600585920.
32 Narrow therapeutic index drugs are defined as those drugs where small differences in dose or blood concentration
may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent
or significant disability or incapacity. See: Yu LX, Jiang W, Zhang X, Lionberger R, Makhlouf F, Schuirmann DJ,
Muldowney L, Chen ML, Davit B, Conner D, Woodcock J. Novel bioequivalence approach for narrow therapeutic
index drugs. Clinical Pharmacology and Therapies 2015; 97(3): 286-291.
33 Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics (May 1999). We
update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.

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166
• 	If a dosing device should be used for the restricted delivery system, a compatible dosing	167
device should be included in the product packaging.	168
169
The following considerations apply specifically to flow restrictors:	170
171
• 	Different types of flow restrictors (e.g., open or closed) should be considered and the	172
optimal flow restrictor should be used.	173
174
• 	The flow restrictor should not leak when used.	175
176
• 	Performance testing should include testing for the maximum number of doses available in	177
the liquid drug container multiplied by a factor of 1.5. For example, a 100 milliliter (mL)	178
bottle that is intended to deliver 5 mL doses (contains 20 total 5 mL doses), should be	179
tested 30 times (20 doses available x 1.5 safety margin = 30 performance tests). These	180
performance tests should be conducted at all specified orientations or when not specified,	181
all possible container orientations as defined by the product label.34 Compatibility of the	182
dosing device (e.g., a calibrated and labeled oral syringe) with the restricted delivery	183
system should be carefully considered and evaluated during the design process.	184
185
When designing or selecting an appropriate restricted delivery system, manufacturers should	186
balance the degree of restrictiveness with the need to ensure ease of use. For example, the	187
restricted delivery system should not be overly burdensome in ways that discourage product use	188
or that encourage improper use. In addition, it is vital that the restricted delivery system not be	189
easily removed or pushed through the neck of the bottle, to avoid contaminating the drug product	190
or presenting a choking hazard to children.	191
192
We encourage working with the appropriate review division at FDA to determine the submission	193
information and types of studies that may be necessary for products that require premarket	194
review. We recommend manufacturers consider human factors principles and usability studies	195
as part of their development program.35	
196
197
C. 	Directions for Use	198
199
Drug products must have labeling that bears adequate directions for use,36 with limited	200
exceptions;37 when manufacturers choose to use a restricted delivery system for a drug product,	201
this requirement includes providing adequate directions for using the drug product with the	202
34 Specified by a compendial test or standardized test by a testing body, such as American Society for Testing and
Materials (ASTM) or International Organization for Standardization (ISO).
35 See Guidance for Industry and FDA Staff, Applying Human Factors and Usability Engineering to Optimize
Medical Device Design (February 2016), and Guidance for Industry, Safety Considerations for Product Design to
Minimize Medication Errors (April 2016). See also draft Guidances for Industry and FDA Staff, Applying Human
Factors and Usability Engineering to Medical Devices (June 2011) and Human Factors Studies and Related
Clinical Study Considerations in Combination Product Design and Development (February 2016).
36 Section 502(f)(1) of the FD&C Act.
37 See, e.g., 21 CFR 201.100 (prescription drugs for human use).

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restricted delivery system.38 In addition to meeting the general requirement for the labeling of a	203
drug product to bear adequate directions for use, the Agency recommends that the labeling of	204
drug products with a restricted delivery system include a toll-free telephone number or email	205
address for consumers, patients, or caregivers to obtain replacement parts, when such parts (such	206
as syringes) are needed to ensure optimal performance of the restricted delivery system.	207
208
To include a restricted delivery system in the packaging of drug products undergoing premarket	209
review, we recommend contacting the appropriate review division staff to discuss the	210
information to be submitted to the Agency to ensure that the drug product’s labeling bears	211
adequate directions for using the drug product with the restricted delivery system.	212
213
For oral liquid drug products marketed under the OTC Drug Review, at this time and based on	214
our current understanding of the risks of these products, FDA does not intend to object to the use	215
of an appropriate restricted delivery system, provided the labeling includes non-graphical	216
instructions in the Drug Facts labeling that explain how to appropriately use the restricted	217
delivery system, as well as applicable OTC drug monograph directions, and provided that the	218
labeling satisfies all other applicable labeling requirements.39 The additional non-graphical	219
instructions should be limited to describing how to use the restricted delivery system to deliver	220
the appropriate dose. If graphical images are necessary to ensure effective use of the restricted	221
delivery system, a labeling insert may be included in the packaging to provide the necessary	222
information to the consumer, patient or caregiver. If additional language is added to the Drug	223
Facts labeling or a separate labeling insert is included in the packaging of products marketed	224
under the OTC Drug Review, we recommend that the manufacturer establish that the target	225
consumer/patient/caregiver population comprehends the additional language.40	
226
227
38 Section 502(f)(1) of the FD&C Act. In addition, as a general matter, an ANDA is required to contain information
to show that the labeling proposed for the generic drug is the same as the labeling for the reference listed drug
(RLD), except for changes required because of differences approved under a suitability petition (see section
505(j)(2)(C) of the FD&C Act and 21 CFR 314.93), or because the generic drug and the RLD are produced or
distributed by different manufacturers (see section 505(j)(2)(A)(v) of the FD&C Act). See also FDA’s Draft
Guidance entitled Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device
Combination Product Submitted in an ANDA.
39 See, e.g., 21 CFR part 201 and 21 CFR 330.1.
40 See Guidance for Industry, Label Comprehension Studies for Nonprescription Drug Products (August 2010).

Contains Nonbinding Recommendations
Draft — Not for Implementation
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228
29
30
APPENDIX A: PRODUCT-SPECIFIC RECOMMENDED RESTRICTION EFFECTS	231
232
Consider the following flow diagram when considering the use of a restricted delivery system.	233
Single ingredient
product
Fixed-combination drugs	no
yes
Consider toxicity of product
to 2 year old child
Consider the most toxic agent in
the combination as well as the
combined toxicity of all
ingredients to 2 year old child
Narrow therapeutic
index
no
yes 	Use of a restricted delivery system
that limits access to a single unit
volume at one time (e.g. closed
flow restrictor) is warranted
Determine harmful dose to 2 year
old child (e.g. quantity sufficient to
require medical care and/or
observation, POISINDEX/AACT
Guidelines)
Consider use of restricted delivery
system that limits the egress of this
harmful dose (quantity of liquid) in
no less than 5 minutes
218
The following drug product examples1 are provided to illustrate the goal of restricting a toxic or	219
harmful volume of liquid (based on the 50th percentile weight estimate for a 2-year-old)2	
220
accessible to a child within 5 minutes.	221
222
Acetaminophen3: Restricted delivery systems for acetaminophen-containing products should	223
restrict the flow of liquid to a deliverable quantity not to exceed 2,400 milligrams (mg) of	224
acetaminophen in a 5-minute interval. Due to the risk of liver failure, consider the use of a	225
restricted delivery system that limits access to a single-unit volume at one time, such as a closed	226
flow restrictor.	227
228
1 These examples were chosen because 91% of ED visits for OTC liquid medication exposures involved
acetaminophen, cough and cold remedies, ibuprofen, or diphenhydramine. See Lovegrove MC, Weidle NJ, Budnitz
DS. Trends in emergency department visits for unsupervised pediatric medication exposures, 2004-2013. Pediatrics
2015;136.
2 See footnote 27.
3 Assumes a 200 mg/kg threshold and a12 kg child. For a 160 mg/5 mL concentration, this results in not to exceed
(NTE) 75 mL in 5 minutes (min). Source: 200 mg/kg American Academy of Clinical Toxicology Guidelines (2,400
mg); 200 mg/kg POISINDEX (2,400 mg).

Contains Nonbinding Recommendations
Draft — Not for Implementation
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Dextromethorphan4: Restricted delivery systems for dextromethorphan-containing products	229
should restrict the flow of liquid to a deliverable quantity not to exceed 90 mg of	230
dextromethorphan in a 5-minute interval.	231
232
Diphenhydramine5: Restricted delivery systems for diphenhydramine-containing products	233
should restrict the flow of liquid to a deliverable quantity not to exceed 90 mg of	234
diphenhydramine in a 5-minute interval.	235
236
Ibuprofen6: Restricted delivery systems for ibuprofen-containing products should restrict the	237
flow of liquid to a deliverable quantity not to exceed 2,400 mg of ibuprofen in a 5-minute	238
interval.	239
240
Pseudoephedrine7: Restricted delivery systems for pseudoephedrine-containing products should	241
restrict the flow of liquid to a deliverable quantity not to exceed 144 mg of pseudoephedrine in a	242
5-minute interval.	243
244
4 Assumes a 7.5 mg/kg threshold and a12 kg child. For a 30 mg/5 mL concentration, this results in NTE 15 mL in 5
min. For a 15 mg/5 mL concentration, this results in NTE 30 mL in 5 min. Source: 7.5 mg/kg AACT Guidelines (90
mg); 10 mg/kg POISINDEX (120 mg).
5 Assumes a 7.5 mg/kg threshold and a12 kg child. For a 12.5 mg/5 mL concentration, this results in NTE 36 mL in
5 min. Source: 7.5 mg/kg AACT (90 mg); 7.5 mg/kg POISINDEX (90 mg).
6 Assumes a 200 mg/kg threshold and a12 kg child. For a 100 mg/5 mL concentration, this results in NTE 120 mL
in 5 min. Source: 200 mg/kg POISINDEX (2400 mg).
7 Assumes a 12 mg/kg threshold and a12 kg child. For a 30 mg/5 mL concentration, this results in NTE 24 mL in 5
min. Source: 12 mg/kg POISINDEX.