How to Dose Attention-Deficit/Hyperactivity Disorder Medications Without a Grain of Salt

Abstract

To the Editor:

Many clinicians have asked why some stimulant medications for the treatment of attention-deficit/hyperactivity disorder (ADHD) with the same active moiety (often methylphenidate or amphetamine) differ in the labeled dosage. Currently, 25 medications are available, 20 of which deliver the active moiety as a salt. For example, Ritalin^® (Novartis Pharmaceuticals Corporation, East Hanover, NJ) contains methylphenidate hydrochloride, and Adderall XR^® (Shire US, Inc., Lexington, MA) provides a mixture of four amphetamine salts: amphetamine aspartate monohydride, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate. The remaining five deliver the active moiety dispersed in an adhesive (Daytrana^® [Noven Pharmaceuticals, Inc., Miami, FL]) or bound to a resin particle (Cotempla XR-ODT™ [Neos Therapeutics, Grand Prairie, TX]; Adzenys ER™ [Neos Therapeutics]; Adzenys XR-ODT™ [Neos Therapeutics]; and Dyanavel XR^® [Tris Pharma, Inc., Monmouth Junction, NJ]).

Historically, the dosage of stimulant ADHD medications has been labeled according to the amount of the drug in the salt form (e.g., 60 mg methylphenidate hydrochloride or 30 mg mixed amphetamine salts). The nonsalt medications, however, are dosed by the amount of active moiety. Simple conversions that account for the molecular differences between the salt form and the active moiety alone (using a salt-to-base conversion factor) show that the amount of amphetamine or methylphenidate in some salt form doses is equivalent to that found in nonsalt medications (Table 1); however, this does not mean that one formulation of a stimulant medication can be substituted for another, as different formulations provide different release profiles. Switching between products with the same active moiety requires proper dose titration.

Table 1.

Comparison of Attention-Deficit/Hyperactivity Disorder Medications with a Salt or Nonsalt Form of the Active Ingredient

Drug	Active ingredient	Salt amount (mg)	Conversion factor ^a	Active moiety amount (mg)
Methylphenidate
Cotempla XR-ODT	Methylphenidate	—	—	25.9
Ritalin LA	Methylphenidate hydrochloride	30	86.47%	25.9
Concerta	Methylphenidate hydrochloride	36	86.47%	31.1
Amphetamine
Adzenys XR-ODT	Amphetamine	—	—	18.8
Evekeo	Amphetamine sulfate	20	73.40%	14.7
Adderall XR	Total mixed amphetamine salts	30	—	18.8
	Amphetamine sulfate	7.5	73.40%	5.51
	Amphetamine aspartate monohydrate	7.5	47.22%	3.54
	Dextroamphetamine sulfate	7.5	73.40%	5.51
	Dextroamphetamine saccharate	7.5	56.26%	4.22

Divide molecular weight of the active moiety by that of the salt.

Instituted by the Food and Drug Administration in May 2013, the United States Pharmacopeia (USP) Salt Policy rule requires newly approved medications to express the dose as the active moiety instead of the salt form (Food and Drug Administration 2015, United States Pharmacopeia); however, medications approved before May 2013 are not required to apply the policy. The USP Salt Policy rule will help to clarify the relationship between the salt and nonsalt forms as new medications become available; however, clinicians should be aware of the labeling differences and be able to explain them to patients to avoid potential medication errors (McDougall et al. 2016).

Footnotes

Acknowledgment

Editorial and submission support for this article was done by Nicole Seneca, PhD, of AlphaBioCom, LLC.

Disclosures

D.E., R.M., and C.R.S. are employees of Neos Therapeutics, Inc. D.E. and R.M. also own stock or stock options in Neos Therapeutics, Inc. C.R.S. has stock options in Neos and stock in Pfizer. A.C.C. has received research support from, consulted with, acted as invited speaker for, and/or served on advisory boards for Alcobra Pharma, Alkili, Arbor Pharmaceuticals, Forest Research Institute, Ironshore Pharmaceuticals, KemPharm, Inc., Lilly USA, Lundbeck, Neos Therapeutics, Neurovance, NextWave Pharmaceuticals, NLS Pharma Group, Noven Pharmaceuticals, Otsuka Pharmaceutical, Pfizer, Purdue Pharma, Rhodes Pharmaceuticals, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Supernus Pharmaceuticals, Theravance Biopharma, and Tris Pharma.

References

Food and Drug Administration: Guidance for Industry: Naming of Drug Products Containing Salt Drug Substances. Center for Drug Evaluation and Research, Food and Drug Administration: Silver Spring, MD, 2015. Available at: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm379753.pdf. Accessed on October 16, 2017 .

McDougall

, Hoehns

, Feller

, Kriener

, Witry

: Inclusion of salt form on prescription medication labeling as a source of patient confusion: A pilot study. Pharm Pract (Granada), 14:677, 2016.

United States Pharmacopeia: Monograph Naming Policy for Salt Drug Substances. In: Drug Products and Compounded Preparations, USP General Chapter [1121] Nomenclature. United States Pharmacopeial Convention, Inc, Rockville, MD. Available at: http://www.drugfuture.com/pharmacopoeia/usp32/pub/data/v32270/usp32nf27s0_c1121.html. Accessed on October 16, 2017 .