Anticipating Drug Shortages During Supply Chain Disruptions: Implications for Children With ADHD

Supply chain issues have increased dramatically over the past several years, with prescription drug shortages impacting the health care system at every level. The American Medical Association labeled the recent strain on the supply chain as an urgent public health crisis.¹

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In October 2022, the FDA announced shortages of Adderall, which subsequently increased the demand for therapeutic alternative medications for the treatment of attention-deficit hyperactivity disorder (ADHD), including various methylphenidate (MPH) formulations.² This increase in demand of MPH products, secondary to shortages of Adderall, resulted in a short supply of some popular MPH products, including Ritalin and Concerta.³

Known as the domino effect, the resulting shortage of one medication increases demand for a therapeutic alternative, subsequently causing this alternative to be in short supply.² With the fluctuating global supply chain, it is likely that drug shortages are here to stay, making it imperative for pediatric clinicians to be aware of effective therapeutic alternatives if their patient's ADHD medication becomes unavailable.

To provide a quick onset and long duration of action, these modified delivery systems all contain both immediate-release (IR) and extended-release (ER) components. The IR portion of modified release MPH formulations ranges from 22%-50% of the total dose, depending on which technology is used.⁴

Many studies show that when the overall MPH exposure is considered, many of these dosage forms demonstrate bioequivalence.⁴ However, the differences in time-action profile of each formulation can be clinically significant for individual children.

When distinguishing between which form of MPH to prescribe, providers should note the importance of the time to peak plasma MPH concentration (T_max), as well as the area under the curve (AUC) during which times would be most beneficial for symptom control. This review aims to highlight the pertinent differences between available MPH products in the United States, including Concerta, Ritalin LA, Metadate CD, Daytrana, Jornay PM, Quillivant XR, and Quillichew ER, Aptensio XR, Cotempla XR, Focalin XR, and Azstarys.

Aptensio XR is a capsule with multi-layered beads. Forty percent of the MPH dose is IR, and 60% is a controlled release layer. Aptensio XR displays a bimodal distribution with its first max concentration at 2 hours, followed by a gradual decrease over the next 4-6 hours and then another peak at 8 hours post administration.⁵

Azstarys is a unique formulation in that it consists of both dexmethylphenidate and its prodrugserdexmethylphenidate. This formulation is a capsule, which gives patients the flexibility to swallow whole or sprinkle on food. Thirty percent of the formulation is dexmethylphenidate, and the other 70% is serdexmethylphenidate. The pro-drug portion of the capsule works in an ER manner, having a duration of action of 13 hours, whereas the dexmethylphenidate portion works immediately with maximum concentrations being reached 2 hours post administration.⁶

Concerta utilizes an osmotic controlled release delivery (OROS) to release the pharmacologically active ingredient at a controlled rate, with 22% of the dosage form delivered as IR and 78% delivered over the course of the day.⁷ The IR portion serves as the drug overcoat to the trilayer core, which is composed of the active MPH and inactive ingredients, surrounded by a push layer containing the osmotically active components. This semipermeable membrane, along with the hole drilled into the drug layer end of the tablet, controls the rate at which water enters the tablet core, which ultimately controls the delivery rate.⁷

Cotempla XR is an orally disintegrating tablet with a grape flavor. Twenty-five percent of this formulation is IR and 75% is ER. Maximum plasma concentrations are reached at 5 hours after administration. Administration with a high-fat meal decreased C_max and increased AUC of total MPH by 24% and 16%, respectively.⁸ Thus, the nature of this formulation may be a good option for children who cannot swallow other formulations.

Daytrana is a multipolymeric adhesive patch that gives children an alternative if they are unable to use any of the oral MPH dosage forms. This patch is applied on the hip 2 hours prior to the needed symptom control, and removed after 9 hours of continuous wear.⁹

After removal of the patch, MPH continues to be absorbed in the skin for an additional 2 to 3 hours, although the plasma concentrations steadily decline.¹⁷ With repeat patch applications, one can expect the maximum concentration of MPH in the blood to be reached around 8 hours post application.⁹

Focalin XR is dexmethylphenidate, a prodrug of the active MPH. This is a capsule formulation that uses spheroidal oral drug absorption system (SODAS) technology. Each bead contains 50% IR and 50% enteric-coated delayed release, exhibiting a bi-modal release profile. There are 2 distinct plasma peaks that occur 4 hours apart, with the first at 1.5 and the second at 6.5 hours post dose.¹⁰

Jornay PM uses a drug delivery platform called Delexis, delaying the release of the medication overnight.¹¹ This formulation is a capsule consisting of beads that have 2 functional film coatings, as well as an outer delayed release film and an inner ER film surrounding the drug core coated with MPH.

The outer delayed-release coating works to delay the initial release of MPH, ensuring that no more than 5% of the total drug is available within 10 hours of administration. The inner ER coat then controls the gradual release throughout the day, with maximum concentrations being reached at 14 hours post administration. This capsule formulation can be swallowed whole or sprinkled onto food.¹¹

Metadate CD capsules contain 30% IR and 70% ER beads. Diffucaps are described as, “a multi-particulate bead system comprised of multiple layers of drug, excipients, and release-controlling polymers.”³ Unique to this dosage form is a buffer layer intended to control the solubility of the drug.¹²

Controlling which physiological fluid the drug is most soluble in can dictate when it has the highest concentration in plasma, thus the most symptomatic control. MPH CD has a duration of action of 8 hours.¹²

A characteristic unique to metadate CD is the half-life of 6.8 hours, almost double that of any other MPH delivery.⁴ The package insert suggests that this is due to the elimination process being controlled by the release rate of this specific form.¹⁴ Unlike the LA formulation, MPH CD does not have 2 distinct peaks, demonstrating a more gradual increase and decrease of plasma concentrations.^4,12

Quillichew ER is a chewable tablet that comes in a cherry flavor, with 30% of this formulation being IR and 70% ER. Peak plasma levels also occurred at 5 hours after administration.¹³

Quillivant XR is an oral suspension that comes in banana flavor. Twenty percent of the suspension consists of uncoated IR particles, whereas the other 80% are coated ER particles.¹⁴ Peak plasma levels occurred at 5 hours post administration with an onset of action 45 minutes after administration.¹⁴

Ritalin LA uses a SODAS, incorporating controlled-release beads into its capsule.¹⁵ Fifty percent of the capsule contains IR beads, and 50% has delayed-release beads (enterically coated). Ritalin LA has a half-life of 3.5 hours.¹⁵

This long-acting formulation has a “bi-modal release profile,” showing 2 peaks at 4 hours apart. The relative bioavailability of Ritalin LA is similar to that of IR but showcases higher interpeak concentrations with less dramatic peak-trough fluctuations.⁴

Given the many MPH products on the market, pediatric providers must be equipped to use this information in a clinical capacity to best individualize their treatment approach. Looking at the full picture of each patient includes evaluating their daily routine, school and family life, administration preferences, and many other considerations that can help solidify the best MPH product to use.

Sometimes a patient or a parent may want a greater degree of symptom control to occur into the evening, to aid in homework and family interactions, for example.¹⁶ In this case, it would be best to give the patient an MPH formulation with a longer duration of action.

If the patient experiences loss of appetite or has trouble sleeping due to the medication, it may be best to opt for a shorter duration of action.¹⁶ This would enable their plasma levels to fall back to normal around dinner and the time they fall asleep.

Ritalin LA, Metadate CD, Azstarys, Focalin XR, Aptensio XR, and Jornay PM all come in capsules and sprinkling on food has not been shown to affect bioavailability. This may be an advantage if a patient prefers not to swallow whole capsules.¹⁶

The wide array of delivery forms can give providers an opportunity to individualize their treatment plans. Considering shortages of many MPH products, pharmacists must be aware of the pharmacokinetic differences among the available MPH products, as the need for switching products is common today.

When switching between methylphenidate formulations, patients should be advised to report any changes in symptom control, as well as any new or worsening adverse effects. Blood pressure, pulse, weight, height, and appetite should be monitored prior to and throughout a product switch.¹⁷

In summary, each MPH formulation has unique pharmacokinetic parameters that must be considered when product switches are necessary in children and adolescents. In response to a large increase in supply chain disruptions, it is important for clinicians to understand the best alternatives given their patients' individual needs.

Table. Methylphenidate formulations for attention-deficit hyperactivity disorder.

About the Author

Hannah Van de Roovaart, PharmD candidate 2024, Cedarville University School of Pharmacy.

References

1. Arwood, L. AMA says drug shortages an urgent public health crisis. Tribune-Star. https://www.tribstar.com/news/local_news/ama-says-drug-shortages-an-urgent-public-health-crisis/article_2c130d04-ba01-5dcb-8b8f-3a11089550d6.html. Published January 26, 2023. Accessed January 26, 2023.
2. Murray, C. Ritalin Drug Shortage Explained: Low Supplies Of Adderall And Prescription Startups Fueled Crisis. Forbes Business.https://www.forbes.com/sites/conormurray/2023/01/27/ritalin-drug-shortage-explained-low-supplies-of-adderall-and-prescription-startups-fueled-crisis/?sh=58e36633421a. Published January 27, 2023. Accessed February 1, 2023.
3. ASHP. Methylphenidate Hydrochloride Extended Release Oral Presentations. Current Drug Shortages. https://www.ashp.org/drug-shortages/current-shortages/drug-shortage-detail.aspx?id=896&loginreturnUrl=SSOCheckOnly. Published January 10, 2023. Accessed February 01, 2023.
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5. Aptensio [Prescribing Information]. Silver Spring, Maryland: The Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205831s003lbl.pdf. Revised January 2017.
6. Azstarys [Prescribing Information]. Silver Spring, Maryland: The Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212994s000lbl.pdf. Published March 2021.
7. Concerta [Package insert]. Silver Spring, Maryland: The Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021121s014lbl.pdf. Published March 2007.
8. Cotempla [Prescribing Information]. Silver Spring, Maryland: The Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205489s000lbl.pdf. Revised June 2017.
9. Daytrana [Prescribing Information]. Silver Spring, Maryland: The Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021514s011lbl.pdf. Revised June 2010.
10. Focalin [Prescribing Information]. Silver Spring, Maryland: The Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021802s033lbl.pdf. Published January 2017.
11. Jornay PM [Prescribing Information]. Silver Spring, Maryland: The Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209311s000lbl.pdf. Published August 2018.
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13. Quillichew ER [Prescribing Information]. Silver Spring, Maryland: The Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207960s000lbl.pdf. Published December 2015.
14. Quillivant XR [Prescribing Information]. Silver Spring, Maryland: The Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202100s012lbl.pdf. Revised February 2015.
15. Ritalin LA[Prescribing Information]. Silver Spring, Maryland: The Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021284s016s029lbl.pdf. Revised January 2019.
16. Coghill, D., Banaschewski, T., Zuddas, A., Pelaz, A., Gagliano, A. and Doepfner, M., 2013. Long-acting methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies. BMC Psychiatry, 13(1).
17. Pheils J, Ehret MJ. Update on methylphenidate and dexmethylphenidate formulations for children with attention-deficit/hyperactivity disorder. Am J Health Syst Pharm. 2021;78(10):840-849. doi:10.1093/ajhp/zxab069