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MPH Part 8 - Interchangeability of MPH Products

MPH Part 8 - Interchangeability of MPH Products

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Extended-release formulations containing the same active ingredient differ in their onset and duration of action throughout the day. Formulations with a high proportion of immediate-release active ingredient (e.g., Medikinet Retard, Ritalin LA, Equasym) had a stronger effect in the morning. Concerta, with its small immediate-release component, had a longer-lasting effect in the late afternoon and evening. The effect in the morning depended primarily on the amount of the immediate-release active ingredient. This allows a formulation to be chosen to suit the day’s needs: Those who primarily need a strong effect in the morning are better served by a formulation with a high immediate-release component, while those who need the effect to last into the evening are better served by a formulation with a high sustained-release component.

1. Direct Comparisons of Sustained-Release MPH Formulations

Sustained-release MPH formulations mimic the twice- or thrice-daily administration of immediate release MPH. However, they differ in the magnitude of peak plasma concentrations and in the rate at which these are reached and decline. According to a review, this allows for the selection of a formulation based on an individual’s symptom profile throughout the day. (Narrative review, manufacturer-funded, E 4.)1

1.1. A Direct Comparison of Pharmacokinetics

For the same total exposure (AUC), sustained-release MPH formulations differed significantly in the temporal profile of plasma levels. Formulations with a higher proportion of immediate-release MPH achieved higher levels in the first few hours, while OROS-MPH reached higher levels in the late afternoon and evening. Results in healthy subjects for:

  • MPH-LA (Ritalin LA) 20 mg versus OROS-MPH 18 mg: approximately double the drug absorption during the first 4 hours (AUC0-4 18.5 versus 9.3 µg·h/l, p < 0.001), first peak of 7 µg/l after 2.1 hours and second peak of 9.3 µg/l after 5.6 hours; for OROS-MPH, a plateau of 3.4 µg/l after 3.3 hours and 5.9 µg/l after approximately 6 hours, total exposure was higher with MPH-LA when uncorrected (AUC0-∞ 78.7 vs. 66.9 µg·h/l, p = 0.024), similar when dose-adjusted at the same oral clearance (Open-label randomized crossover study, n = 20, healthy subjects, fasting, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)2
  • MPH-CD (Metadate CD, Equasym XL) compared to OROS-MPH (20 vs. 18 mg, 40 vs. 36 mg, 60 vs. 54 mg): Total exposure was the same; early exposure (AUC0-4, AUC0-6, first peak, levels at 1.5, 3, and 4 hours) was higher with MPH-CD; concentrations at 8, 10, and 12 hours higher with OROS-MPH; therefore, not bioequivalent (Two randomized crossover studies, n = 36 and n = 24, healthy subjects, fasting; full text not available to us, E 1b.)3
  • MPH-MLR (Biphentin) 20 mg versus OROS-MPH 18 mg: Higher AUC0-4, AUC0-8, and AUC0-12 with MPH-MLR (p < 0.001); no difference in AUC8-12; after dose normalization, relative AUC 100.72% and Cmax 111.82%; Tmax 3.71 vs. 4.96 hours (Randomized crossover single-dose PK study, n = 24, healthy subjects, after breakfast, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)4
  • Equasym Retard 20 mg versus Medikinet Retard 20 mg after a meal: AUC0-t bioequivalent (35.5 versus 39.2 ng·h/mL), Cmax not bioequivalent (4.05 versus 5.26 ng/mL), Equasym showed a less pronounced first peak and a lower second peak; no bioequivalence in the first 4 hours (Open-label randomized crossover study, n = 14, healthy subjects, authors employed by the manufacturer, full text not available to us, E 1b.)5
  • Dexmethylphenidate extended-release (Focalin XR) 20 mg versus MPH-LA (Ritalin LA) 40 mg and two 10-mg doses of immediate-release d-MPH administered 4 hours apart: bioequivalent, two separate peaks, Cmax 15.5 vs. 16.4 and 17.9 ng/mL, AUC0-∞ 119 vs. 122 and 115 ng·h/ml, respectively (triple crossover study, n = 25, healthy subjects, author(s) employed by the manufacturer, full text not available to us, E 2a.)6
  • OROS-MPH 18 mg versus MPH-SR (Ritalin SR) 20 mg and three 5-mg doses of immediate-release MPH every 4 hours: Peak concentration with OROS-MPH after 6 to 8 hours, with MPH-SR after approximately 4 hours; dose-normalized Cmax significantly lower with OROS-MPH; relative bioavailability fully (Two open-label PK studies, including one randomized crossover study, n = 36 and n = 32, healthy subjects, fasting, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)7

10 hours after administration, d-MPH plasma levels and DAT occupancy in healthy subjects were higher after 36 mg of OROS-MPH than after 40 mg of DBDS-MPH (5.2 ± 2.0 vs. 3.8 ± 1.2 ng/mL, DAT occupancy 44.3 ± 11.8% versus 34.8 ± 12.9%). A plasma difference of 1.4 ng/ml corresponded to approximately 10% DAT binding. (Randomized crossover PET study, healthy subjects, n = 21; full text not available to us, E 1b.)8

1.2. Direct Comparison of Effect Over the Course of the Day

In a direct comparison of efficacy, formulations with a higher proportion of immediate-release ingredients were more effective in the morning, while OROS-MPH was more effective in the late afternoon or evening. At each time point, the formulation with the higher expected plasma concentration was superior. Results in children with ADHD for:

  • MPH-CD (Metadate CD, Equasym XL) compared with OROS-MPH at approximately the same daily dose (20 vs. 18 mg, 40 vs. 36 mg, 60 vs. 54 mg): MPH-CD was superior in the morning (1.5 to 4.5 hours), equivalent in the afternoon (6 to 7.5 hours), OROS-MPH was superior after 12 hours, and MPH-CD was superior throughout the school day (1.5 to 7.5 hours). Effect sizes for SKAMP-Btragen in centers with higher baseline values after 1.5 to 3 hours: 1.2 to 1.3 (MPH-CD) versus 0.75 to 0.82 (OROS-MPH); after 12 hours, 0.12 versus 0.41 (double-blind, randomized, placebo-controlled crossover RCT (COMACS), n = 184, laboratory classroom setting, 1 week each, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)9
  • MPH-LA (Ritalin LA) 40 mg versus OROS-MPH 36 mg: Ritalin LA was superior to OROS-MPH on all efficacy measures in the time-to-maximum-effect intervals of 0 to 4, 0 to 8, and 0 to 12 hours; Ritalin LA 20 mg was equivalent to OROS-MPH 18 and 36 mg during the first 8 hours; from 8 to 12 hours, all active formulations were equivalent to (Single-blind, randomized, placebo-controlled crossover RCT, n = 54, laboratory classroom setting, 6 weeks, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)10
  • MPH-LA (Ritalin LA) 20 mg versus OROS-MPH 18 and 36 mg: Ritalin LA in the morning (duration of action 0 to 4 hours, SKAMP-Combined -2.05 versus -0.78 and -1.01, respectively, p < 0.001 and p = 0.003, respectively), and superior over 8 hours compared with OROS-MPH 18 mg (-3.58 vs. -1.70, p = 0.010), not significantly superior to 36 mg (-2.22, p = 0.061) (Single-blind, randomized, placebo-controlled crossover RCT, n = 36, laboratory classroom setting, 4 weeks, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)11
  • Medikinet retard versus OROS-MPH in everyday school life (SKAMP-D teacher assessment during the first 3 school hours): Medikinet retard, at approximately the same daily dose (20 or 30 mg with 10 or 15 mg of immediate release component), was superior to Concerta 18 or 36 mg (4 or 8 mg of immediate release component, p = 0.0009), Medikinet retard, with a similar immediate release component (5 or 10 mg) and a lower daily dose (10 or 20 mg), was not inferior; the same pattern was observed in school hours 4 through 6; no superiority of Concerta was observed in the afternoon and evening (Double-blind, randomized, 3x3 crossover RCT in a natural setting, n = 113, ages 6 to 16, 3 weeks, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)12
  • MPH-LA (Ritalin LA) 20 mg versus Medikinet retard 20 mg: Ritalin LA was non-inferior between 1.5 and 4.5 hours (p = 0.0003); both were superior to placebo (double-blind, randomized, placebo-controlled crossover RCT, n = 147, laboratory classroom setting, 3 periods of 7 days each, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)13
  • Dexmethylphenidate extended-release (Focalin XR) 20 and 30 mg compared with d,l-MPH extended-release 36 and 54 mg: d-MPH extended-release has a faster onset of action and a stronger effect in the morning (SKAMP-Combined after 2 hours, p < 0.001), d,l-MPH extended-release has a stronger effect at the end of the 12-hour day (double-blind, randomized, placebo-controlled crossover RCT, n = 84, laboratory classroom setting, 5 periods of 7 days each, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)14 * (Double-blind, randomized, placebo-controlled crossover RCT, n = 82, lab classroom, full text not available to us, E 1b.)*15

1.3. Effect of the immediate release component on the morning effect

The effect in the morning depended on the absolute amount of immediate-release MPH, not on the formulation. The effect sizes 1.5 and 3 hours after ingestion correlated strongly with the immediate release dose (memory, r = 0.93; attention, r = 0.87; arithmetic test, r = 0.91). When the immediate release component was the same at 12 mg (MPH-CD 40 mg, OROS-MPH 54 mg), the effect sizes were equal (approximately 0.75). (Double-blind, randomized, placebo-controlled crossover RCT (COMACS), n = 184, laboratory classroom setting, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)9
MPH-CD 20 and 40 mg were just as effective as OROS-MPH 36 and 54 mg between 1.5 and 6 hours. OROS-MPH 18 and 36 mg were just as effective after 7.5 and 12 hours as MPH-CD 40 and 60 mg. The choice of formulation allows the total daily dose to be reduced for a specific part of the day. (Post-hoc secondary analysis of an RCT, dose levels not randomized, n = 184, manufacturer-funded, author(s) employed by the manufacturer, E 2b.)16
Similarly, Medikinet retard—which had a similar proportion of immediate release component as Concerta but a lower daily dose (10 versus 18 mg, 20 versus 36 mg)—was not inferior during the first 3 school hours. (Double-blind, randomized, 3x3 crossover RCT in a natural setting, n = 113, ages 6 to 16, 3 weeks, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)12

1.4. Smoothness of the release profiles

In a model calculation, the smoothness of the plasma concentration-time curves varied greatly among sustained-release MPH formulations (normalized smoothness value; lower values indicate greater smoothness): (Modeling study based on population pharmacokinetic models of healthy adults, manufacturer-funded, author(s) employed by the manufacturer, E 2b.)17

  • d-MPH retard (Focalin XR) 20 mg: 6.65
  • MPH-MLR 60 mg: 5.72
  • OROS-MPH 54 mg: 2.37
  • MEROS 60 mg: 1.29
  • MPH-CD 60 mg: 1.18
  • DR/ER-MPH (Jornay PM) 100 mg: 0.05

It has not been determined whether smoother dose profiles offer clinical benefits, such as fewer fluctuations in efficacy or less of an afternoon rebound effect.

2. Generic versions of sustained-release MPH formulations and bioequivalence

Implications for People with ADHD

Generic versions of sustained-release MPH formulations must demonstrate that the total amount of active ingredient absorbed is the same and that the peak concentration is similar. For sustained-release formulations with multiple release phases, this is not always sufficient to ensure a consistent drug profile throughout the day. In the U.S., two generic versions of Concerta had their equivalence designation revoked. Other generics also met stricter comparison criteria. If, after switching to a different brand-name or generic medication, the effect diminishes or the course of action changes, this should be discussed with the treating physician.

The standard bioequivalence criteria (AUC and Cmax with a 90% CI between 80 and 125%) do not adequately reflect the concentration-time profile of multiphase sustained-release formulations. Formulations with significantly divergent concentration profiles during the absorption phase were thus considered bioequivalent. Partial AUCs (areas under the curve for specific time intervals during the day), on the other hand, showed clear differences. (Review with reanalysis of PK data, E 4.)18
For generic versions of Concerta, the FDA additionally requires partial AUCs from 0 to 3, 3 to 7, and 7 to 12 hours. (Randomized crossover bioequivalence studies, n = 80 and n = 46, healthy subjects, author(s) employed by the manufacturer, E 1b.)19 The FDA and EMA recommend the partial AUC from 0 to 3 hours for Concerta and Ritalin-LA generics; the EMA additionally recommends the Cmax from 0 to 3 hours. In PK/PD simulations, the early partial AUC more accurately reflected the early SKAMP effect than Cmax0-3 or the concentration after 3 hours. (PK/PD simulation study; full text not available to us; E 2b.)20 Partial AUC and partial effect area in the SKAMP correlated at approximately 90%. (Simulation study, full text not available to us, E 2b.)21 The sensitivity of the partial AUCs to changes in absorption rate depended on the formulation, so that separate parameters may be necessary for each formulation. (Modeling and simulation study based on pharmacokinetic data from two reference formulations, n = 34 and n = 19, E 2b.)22 * (Modeling and simulation study based on PK data from three formulations, n = 34, n = 19, and n = 31, E 2b.)*23
A critical review identified 33 studies with pharmacokinetic data on sustained-release MPH, including 10 direct comparisons. When additional, more stringent kinetic criteria were applied, only one study met the bioequivalence criteria. It remains unclear whether bioequivalence is an appropriate measure of the interchangeability of extended-release MPH formulations. (Critical narrative review, n = 33, full text not available to us, E 4.)24

In the U.S., starting in 2011 and 2012/2013, respectively, three generic drugs were considered therapeutically equivalent to Concerta (FDA AB classification): an authorized generic manufactured by Janssen (Actavis), which was identical except for the packaging, as well as products from Mallinckrodt (approved in December 2012) and Kudco (July 2013). After evaluating adverse event reports, re-examining the approval data, and conducting its own laboratory tests, the FDA revoked the AB classification for the Mallinckrodt and Kudco products (according to Fife et al. 2015) because they might not have the same effect in some patients. After switching from Concerta to one of these generics, 24.6% switched back to Concerta; after switching to the authorized generic, 19.7% switched back. A combined endpoint (switching back, change in adjunctive medication, discontinuation, new medication) was reached by 39.5% versus 32.9% (risk ratio 1.20, 95% CI 0.94 to 1.54, not significant). The high rate observed even with the identical authorized generic indicates that some of the problems following a switch in medication are not pharmacologically driven. (Retrospective cohort study, n = 732, author(s) employed by the manufacturer, E 3.)25
In 14 children and adolescents who had received a non-OROS generic medication, the T-score for inattention (Conners-3, parent rating) decreased by 23 points (p < 0.0001) after switching to OROS-MPH at the same dose, from clinically significant to normal. (Retrospective case series, n = 14 children and adolescents, E 3.)26
In an independent laboratory analysis of all MPH products available in 2023 from a major U.S. wholesaler, 12 out of 24 generic extended-release tablets differed significantly from the brand-name product in terms of active ingredient release. All immediate release generics exhibited similar release profiles. (In vitro release analysis; full text not available to us; E 2b.)27

In several studies, generic osmotic-release tablets demonstrated bioequivalence to Concerta, including the partial parameters for:

  • Consiv 54 mg (Brazil): both fasting (n = 80) and postprandial (n = 46) Cmax values were within the 90% CI, AUC, and partial AUCs ranged from 80% to 125% of the (Two open-label randomized crossover studies, healthy subjects, authors employed by the manufacturer, E 1b.)19
  • Sandoz MPH OCR 18, 36, and 54 mg on an empty stomach and 54 mg after a meal: bioequivalent for AUC0-t and Cmax, and bioequivalent on an empty stomach for AUC0-2, AUC2-24, Cmax(0-2), and Cmax(2-24); after a meal, only about half of the profiles for both formulations showed a biphasic pattern (Four open-label randomized crossover studies, n = 24 each, healthy subjects, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)28
  • Generic extended-release tablet 18 mg (China): Cmax, AUC0-∞, and partial AUCs were bioequivalent when taken on an empty stomach and after a meal (Cmax on an empty stomach: 91.57 to 101.48%) (Open-label, randomized, fully replicated four-way crossover study, n = 36, healthy subjects; full text not available to us; E 1b.)29

Children and adolescents who experienced inadequate efficacy or tolerability with Medikinet retard (average dose 28.2 mg) were switched to OROS-MPH (initial dose 38.1 mg, final dose 41.2 mg). Over 12 weeks, parental ratings (CPRS –11.7 points), functional level, and quality of life improved (p < 0.0001 for each). 72.8% were more satisfied with OROS-MPH. In the absence of a control group and given the concurrent dose increase, it remains unclear whether the change in medication or the higher dose was responsible for the improvement. (Open-label, non-interventional observational study, n = 180, 12 weeks, manufacturer-funded, author(s) employed by the manufacturer, E 2b.)30

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