MPH Part 7 - Retardation

The discussion of MPH degradation by CES1A has been moved to the article Duration of Drug Action in ADHD.

13. Immediate-release methylphenidate¶

Immediate release (“regular”) MPH typically lasts between 2.5 and 4 hours. However, for some individuals, the duration may be as short as 1 hour.¹ The duration of action remains the same throughout a person’s lifetime.
The advantage of the short duration of action is greater controllability, because the dose can be adjusted slightly earlier or later, or slightly less or more, as needed, making it easier to regulate daily coverage. The disadvantage is that it requires greater cooperation and discipline on the part of the person with ADHD. With ADHD in general—and in children with ADHD in particular—this level of reliability is not always guaranteed. By the time one realizes that a second dose is needed—because one has just “exploded” again for no apparent reason, or because one has been staring into space for quite some time—much of the potential for normalizing daily life has already been lost. In addition, taking medication frequently throughout the day reinforces the feeling of being affected by a disorder. In comparison, extended-release medications (10–14 hours) that need to be taken only once in the morning are significantly more effective at creating a sense of normalcy.

When determining the dose, an immediate release form is preferable, provided that the medication is taken reliably, since immediate release tablets can be divided into smaller units, and their shorter duration of action allows for better adjustment of the dose.

14. Sustained-release MPH, sustained-release techniques¶

Extended-release formulations result in an altered or slowed release of the active ingredient compared to formulations with immediate-release. The prolonged release is achieved through a special formulation and/or a special manufacturing process.²
In contrast to sustained-release formulations, “retard” formulations, in the narrower sense, refer to orally administered drug formulations. However, the two terms are often used interchangeably. Drugs that, due to their pharmacokinetic properties (and not their release mechanisms), are absorbed more slowly or—in the case of prodrugs—are first converted by the body into their active form are not considered sustained-release formulations.³

Depending on the formulation, sustained-release MPH works for between 4 and 12 hours by slowly releasing its active ingredients into the body.
The advantage is that the person with ADHD doesn’t have to remember to take their medication; the disadvantage is the lack of precision in dosing, since the capsules contain only the specified doses and cannot be split like tablets, and that once the effect wears off—if there are still a few hours left in the day— the duration of a capsule’s effect may be too long, which can then cause sleep problems.
Immediate release formulations can help reduce dysphoria and/or hyperactivity during the rebound phase as the effects of sustained release formulations wear off.⁴
Each person with ADHD must figure out for themselves what works best for them.

It is permissible to combine formulations with sustained release (as the standard daily dose) with tablets with immediate release (for a faster initial effect in the morning, as a supplement in the late afternoon or evening, and for fine-tuning the dose during periods of increased stress).⁴

As a general rule, the goal is to achieve once-daily dosing. With immediate release MPH, 3 to 4 single doses are required; with half-day extended-release formulations, 1 to 2 doses are required.⁵

For information on the individual sustained-release and immediate-release MPH formulations, see below.

14.1. Take with or without food¶

Some formulations (e.g., Medikinet Adult and Medikinet retard) must be taken with food. Otherwise, Medikinet will act as an immediate release formulation (twice as strong and half as long-acting).

With other long-acting medications as well, eating before taking the medication can affect how long the effect lasts. When taken on an empty stomach, there is an increased risk that the medication—which lacks acid-dependent sustained-release properties—will have already migrated so far into the intestine by the time the sustained-release components are supposed to take effect that complete absorption of the active ingredient can no longer be guaranteed.⁶ Similarly, for Ritalin LA (whose sustained-release mechanism is not acid-dependent), bioavailability is reported to be approximately 11 percent higher when taken after a meal than when taken on an empty stomach; therefore, taking Ritalin LA and Ritalin Adult with or after a meal is also recommended.⁷

14.2. Extended-release formulations of MPH¶

14.2.1. Tablets / Capsules¶

14.2.1.1. Medikinet Sustained-Release System¶

Medikinet®; Medikinet® CR; Medikinet® EM; Medikinet® MR; Medikinet® XL

Countries:⁸
Europe: Belgium, Denmark, Germany, Estonia, Finland, France, Ireland, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, Norway, Austria, Poland, Portugal, Romania, Sweden, Switzerland, Slovakia, Slovenia, Spain, the United Kingdom, and Cyprus.
Israel
Korea
South America: Argentina, El Salvador, Guatemala, Honduras

In Germany: Medikinet retard and Medikinet adult

Modified-release pellets. We have not yet found a detailed technical description of Medikinet’s sustained-release system.

Packages: Capsules of 5 mg, 10 mg, 20 mg, 30 mg, and 40 mg

Medikinet Retard

• 50% IR pellets
• 50% enteric-coated ER pellets

Medikinet Adult and Medikinet sustained release must be taken with food because the sustained-release component is coated with an acid-resistant membrane and relies on solid food to slow its passage from the stomach to the intestine. If transport into the alkaline region of the duodenum occurs too quickly, the sustained release component may be released prematurely⁹, resulting in an excessive and shortened duration of action.

• Dose-dumping issues may occur if the stomach pH is above 5.5⁶
  • The active ingredient is released too quickly, resulting in increased effects and side effects
  • e.g., by
    • Proton pump inhibitors (such as pantoprazole, omeprazole)
    • H2 blockers (such as ranitidine, famotidine) are less likely)
    • Antacids

14.2.1.2. OROS - Oral System with Osmotic Release¶

Products: Concerta®, Neucon®, Mefedenil®, Unicorn MPH®¹⁰

Concerta Extended-Release; Concerta® LP

Countries:⁸
Africa: Botswana, Brazil, Egypt, Namibia, Nicaragua, South Africa
Asia: Bahrain, China, Hong Kong, Indonesia, Israel, Japan, Jordan, Republic of Korea, Kuwait, Lebanon, Malaysia, Oman, Philippines, Qatar, Saudi Arabia, Singapore, Taiwan, United Arab Emirates, Yemen
Australia
New Zealand
Europe: Belgium, Denmark, Germany, Estonia, Finland, France, Greece, Ireland, Iceland, Croatia, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, the Netherlands, Norway, Austria, Poland, Portugal, Romania, Sweden, Switzerland, Slovakia, Slovenia, Spain, the Czech Republic, the United Kingdom
North America: Bahamas, Barbados, Canada, Cayman Islands, Dominican Republic, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Trinidad and Tobago, United States.
South America: Argentina, Aruba, Bolivia, Chile, Colombia, Costa Rica, Ecuador, Panama, Paraguay, Peru, Uruguay, Venezuela.

OROS (Osmotic Release Oral System) was the first sustained-release system developed for MPH.¹¹ It is also known as the “pulse-and-leak” mechanism.¹

With the OROS system, the initial release of the active ingredient (22%) occurs with an immediate release from the capsule coating (Pulse).
The semipermeable membrane of the capsule’s outer wall surrounds a three-layer core containing two layers of active ingredient and one osmotically active pressure layer. As water passes through the membrane, the osmotic pressure layer gradually expands and forces the 78% of MPH contained in the core out of the capsule through a laser-drilled hole (leak). After complete MPH release, the capsule remains intact and is excreted in the stool. OROS-MPH tablets must therefore be swallowed whole and must not be opened, crushed, split, or chewed.¹¹
There is a concentration gradient between the two internal active ingredient compartments, which also modifies the release rate of the active ingredient. OROS-MPH exhibits an initial peak concentration after approximately 1 hour and a gently rising plasma concentration profile, which is believed to minimize the development of “acute tolerance” and maintain full efficacy throughout the day.¹²
“Acute tolerance” was a concept proposed by Swanson, who hypothesized that optimal effects were achieved through a steady increase in MPH levels throughout the day, with tolerance being reset overnight so that the brain would start from scratch the following day.¹³ Concerta followed this concept with its heavily back-loaded dosage distribution (22 / 78).
However, the findings of Swanson et al. could not be replicated and do not align with clinical experience.¹ People with ADHD who self-administer an appropriate dose (in consultation with their doctor) use either

• an initial dose followed by several relatively smaller subsequent doses spread out over the course of the day (in our experience, this is the most common dosing regimen, which suggests the need to maintain a steady blood level)
• a single high dose (which, in our experience, is rather rare)
• a low initial dose and high subsequent doses throughout the day (A very rare combination.¹ We have received a report of one person with ADHD following this dosing regimen)

By design, one-sixth of the dose in Concerta remains in the capsule and is not bioavailable. Therefore, an 18-mg capsule actually releases only 15 mg of MPH, a 36-mg capsule delivers only 30 mg, and so on.¹

The half-life (“t1/2”) of MPH in healthy adults is approximately 3.3 to 4 hours. Despite the lower Cmax, the relative bioavailability of OROS-MPH was comparable to that of IR-MPH administered three times daily at 4-hour intervals.¹¹¹⁴

Advantages:

• Very long-lasting effect of up to 12 hours
• No dependence on food intake¹⁴

Disadvantages:

• Less flexible dosing compared to taking two consecutive doses of half-day-release MPH, where the dosage can be adjusted (the second dose is usually 1/2 to 2/3 of the first dose)

14.2.1.3. MAS-XR (SODAS) - A blend of pellets with immediate and delayed release¶

Medications: Ritalin LA, Ritalin LP, Ritalin Adult (EU, U.S.), Focalin XR (Switzerland, U.S.), Miacalcic
Chile

SODAS® Technology (Spheroidal Oral Drug Absorption System)

The capsule contains two different types of pellets.¹²

• Pellets that release the active ingredient immediately (active ingredient content: 40% or 50%)
• Pellets with an enteric polymer coating that becomes permeable to liquid approximately four hours after ingestion. The liquid then dissolves the active ingredient and releases it (active ingredient content: 60% or 50%)

For 50% IR / 50% ER:¹¹⁵

• two peak values
  • Cmax1 after about 2 hours
  • Cmax2 approximately 3.5 to 4.5 hours later
• Half-life
  • About 2.4 hours for children with ADHD
  • approximately 3.3 hours for healthy adult men (same as IR-MPH)
• Cmax
  • twice as high in children with ADHD as in healthy adults (20 mg MPH-LA)
  • presumably due to body weight and distribution volume

Advantages:

• No food is required before taking this medication
• Since the release is not controlled by the capsule coating, the capsule can be opened (e.g., to mix into cereal)
• slightly slower release than OROS (Medikinet)¹⁵
• Release independent of stomach pH; no risk of dose dumping as with OROS (Medikinet, Concerta)⁶

Available strengths:

• 10, 20, 30, 40 mg

Food intake:¹¹

• As with other formulations that use pellet technology
  • can be swallowed whole, opened, or sprinkled on applesauce
  • A spoonful of applesauce did not alter pharmacokinetics in healthy adults
  • high-fat food when taken
    • unchanged: AUC, Cmax1, Tmax2
    • reduced: Cmax2 by 23%
    • delayed: Tmax1 by one hour

FOCALIN XR® is the only pure D-MPH formulation with extended-release properties (D-MPH-ER).¹¹

Pharmacokinetic profile in healthy adults:

• First peak after about 1.5 to 2 hours
• Second peak after 5.5 to 6.5 hours
  • Slightly lower than IR-d-MPH
• A slightly longer Tmax2 than IR-d-MPH
  • Suggests lower peak-to-trough fluctuations for d-MPH-ER
• Trough in MPH plasma concentration between the two peaks
• Half-life in healthy adults: approximately 3 hours

20 mg of d-MPH-ER once daily was shown to be bioequivalent to

• two doses of IR-d-MPH, 10 mg each, taken 4 hours apart
• a 40-mg dose of MPH-LA

Available strengths:

• 5, 10, 15, 20, 25, 30, 35, 40 mg
• in healthy adults, in a dose-proportional range of 5 to 40 mg
• 2 to 3 cans per day required⁵

Food intake:

• not examined
• presumably similar to Ritalin-LA / Ritalin Adult

14.2.1.4. MPH-CD, Diffucaps¶

Preparations:
Equasym Depot®, Equasym Retard®, Equasym XR®, Quasym LP®, Metadate CD®, Metadate ER®

Countries:⁸
Europe: Denmark, Finland, France, Germany, Ireland, the Netherlands, Norway, Sweden, Switzerland, and the United Kingdom.
South Korea
United States

Bead Technology, Diffucaps®

MPH-CD Gelatin Capsules¹¹

• 30% IR pellets
• 70% ER pellets

According to Pheil et al., Metadate CD is said to use a system related to MAS-XR, in which a capsule contains two different types of pellets consisting of sugar beads impregnated with the active ingredient, some of which are coated without a release-delaying coating (IR) and others with one (ER).⁵

Pharmacokinetic Profile:⁵¹¹

• Two peak values
• Steep, initial incline
• First peak after about 1.5 hours (similar to immediate release MPH)
• Continued resorption
• Second peak (Cmax) approximately 3 hours later

In a multiple-dose pharmacokinetic study, 25% to 35% of children with ADHD exhibited a profile with only one peak concentration.

Half-life in healthy adults: approximately 5.6 to 6.4 hours.
Compared with IR-MPH administered twice daily at 4-hour intervals, both Cmax and AUC were slightly lower with once-daily MPH-CD at a similar total daily dose of 20 mg

Dosage strengths:

• 10, 20, 30, 40, 50, 60 mg

Children:

• Linear dose proportionality between 20 mg and 40 mg
  Healthy Adults
• Linear dose proportionality between 10 mg and 60 mg

MPH-CD capsules can either be swallowed whole or opened and sprinkled on applesauce without affecting their bioavailability if people with ADHD have difficulty swallowing.
Food Intake When Taken by Adults with ADHD

• Tmax delayed by 1 hour
• increased Cmax by 30%
• increased AUC by 17%

14.2.1.5. MPH-SR, wax matrix¶

Medication: Ritalin SR®¹⁶
United States, Canada

MPH-SR was one of the first retardation techniques.
MPH-SR uses tablets with a wax-based matrix.¹⁷

A duration of up to 8 hours is probably only theoretical.
In practice, no effect during the first 2 hours, then effective for 4 hours, and no further effect after that.¹
The efficacy may be lower than that achieved with multiple doses of immediate release MPH.
The flat drug release profile of MPH-SR (zero-order) could be responsible for the reduced efficacy of MPH-SR compared to MPH-IR, as reported in some studies, and for the development of acute MPH tolerance within a single day, which leads to reduced efficacy in the afternoon.¹²¹⁸

14.2.1.6. MPH-MLR, MLRTM, Multilayer Composite Beads¶

14.2.1.6.1. 40% IR / 60% ER¶

Product: APTENSIO XR® (U.S.), Biphentin®

MPH-MLR (MLRTM) uses multilayer composite beads:⁵

• outer IR layer, approx. 40% MPH
• inner layer with sustained release formulation, approx. 60% MPH

Dosage strengths:

• 10, 15, 20, 30, 40, 50, 60 mg

Food:

• as whole capsules
• as a topping on applesauce

Pharmacokinetics:¹¹

• rapid initial release, comparable to IR-MPH
  • Cmax 1: approximately 2 hours after ingestion
• followed by a slight but noticeable decrease in MPH release during lunchtime
  • a moderate decrease in plasma concentration between hours 4 and 6
• second controlled release of MPH throughout the rest of the day
  • a gradual increase leading to a less pronounced second peak (Cmax 2) between 7 and 8 hours after administration
• a gradual decrease in MPH levels during dinner and at bedtime
• Duration of effect: approximately 10 to 12 hours

Half-life

• About 5 hours (healthy adults, on an empty stomach)

Food:
high-fat breakfast

• increased Cmax by approximately 28%
• increased AUC by approximately 19%
• reduced the second peak
• delayed Tmax by 1 hour

14.2.1.6.2. 20% IR / 80% ER¶

Product: ADHANSIA XR®

Multilayer bead technology such as MPH-MLR

• outer IR layer, approx. 20% MPH
• inner layer with controlled release of approximately 80% MPH

Pharmacokinetics:¹¹

• first peak after about 1.5 hours
• second peak after about 12 hours
• Age-independent pharmacokinetics after adjustment for body weight

Half-life:

• about 7 hours for adults
• for adolescents, about 5 hours
• for children, about 4 to 7 hours

Steady State

• In healthy adults, on an empty stomach, 100 mg: starting on day 3
  then
  • First Cmax increased by 22%
  • Second Cmax similar to that observed with 20 mg IR-MPH 3 times daily every 4 hours
  • AUCcum 50% higher than with IR MPH

Dosage strengths:

• 25, 35, 45, 55, 70, 85 mg
• Take as a whole capsule or sprinkle on applesauce

Food:
A high-fat meal caused

• Cmax unchanged
• AUC unchanged
• Tmax1 and Tmax2 are delayed by one hour (compared to when fasting)

14.2.1.6.3. 40 Or 50% IR / 50 or 60% ER¶

Biphentin®
Canada

The capsule contains pellets consisting of two layers and a core.

• The capsule shell is coated with a layer that delays dissolution
• The outer capsule layer contains the immediate-release active ingredient (active ingredient content: 40% or 50%)
• The outer capsule and inner capsule are separated by a membrane
• The inner capsule layer contains an active ingredient that can only slowly pass through the surrounding membrane (active ingredient content: 60% or 50%)
• Inside the inner layer of the capsule is a capsule core

14.2.1.7. MPH-ERCT¶

Product: QUILLICHEW ER® (U.S.)

MPH-ERCT are cherry-flavored chewable tablets.⁵

Retard distribution:

• 30% IR MPH, uncoated microparticles
• 70% ER MPH, coated microparticles

Active Ingredient Distribution:¹¹
MPH comes from

• 15% MPH hydrochloride
• 85% of which is MPH ionically bound to the sulfonate groups of sodium polystyrene sulfonate particles

Dosage strengths:

• 20, 30, 40 mg

Pharmacokinetics:

• In healthy adults, on an empty stomach, 40 mg:
  • Peak after about 5 hours
  • Half-life: 5.2 hours
  • Duration of effect: approx. 12 hours
• in children and adolescents with ADHD
  • not examined

Bioavailability of a single 40 mg dose of MPH-ERCT

• Equivalent to two 20-mg IR-MPH chewable tablets taken 6 hours apart until Cmax is reached
  • Cmax for MPH-ERCT is 20% lower than the second peak of IR-MPH
• Lasts 12 hours

Food:
A high-fat meal resulted in the following effects with a single 40 mg dose:

• Tmax remains unchanged
• Cmax increased by 20%
• AUC increased by 4%

14.2.1.8. MPH XR-ODT¶

Drug: COTEMPLA XR-ODT® (U.S., 2017)

A once-daily, orally disintegrating tablet⁵

• 25% IR-MPH
• 75% ER-MPH

Retardation technology:
Ion-exchange resin technology in which MPH is ionically bound to the sulfonate group of polystyrene sulfonate microparticles. To produce MPH-loaded microparticles, MPH salts are dissociated in solution, and the positively charged MPH replaces the Na+ in the resin. These microparticles are either uncoated (IR) or coated (ER) and are then compressed into tablets.¹¹

Dosage strengths:

• 8.6; 17.3; 25.9 mg
• equivalent to 10, 20, 30 mg of MPH hydrochloride
• Do not chew or crush
• Remove from the blister pack with dry hands

Pharmacokinetics:

• Healthy adults, on an empty stomach. 51.8 mg MPH XR-ODT
  • wide brim
  • Maximum after 5 hours
  • followed by an apparent first-order elimination phase
  • Duration of effect: approximately 12 hours
• in children
  • Cmax is twice as high as in adults
• among adolescents
  • Cmax is the same as in adults
• by body weight
  • No differences between the age groups.

Half-life: 4 hours

Food:
A high-fat meal caused:

• Tmax reduced by 30 minutes
• Cmax reduced by 24%
• AUC increased by 16%

14.2.1.9. DR/ER-MPH¶

Product: JORNAY PM™ (U.S.)

DELEXIS® Drug Delivery Platform

Special note: Take in the evening.

Uniform microspheres consisting of a core surrounded by two functional layers.¹¹¹⁹

• outer layer with delayed release (DR layer)
  • hydrophobic, hygroscopic, pH-dependent polymers
  • are intended to provide a therapeutic effect upon waking
• inner ER layer
  • hydrophobic, soluble polymers
  • are intended to maintain effectiveness for the rest of the day
• Core with IR-MPH

Dosage strengths.

• 20, 40, 60, 80, 100 mg
• Dose proportionality between the 20-mg and 100-mg doses

Pharmacokinetics:

• MPH begins to be released approximately 8 to 10 hours after ingestion
  • During the night, there is barely any significant release, amounting to less than 5% of the total active ingredient
  • Long-lasting effects from early morning through late afternoon or evening¹⁹
• single peak
  • in healthy adults, 14 to 16 hours after ingestion
  • For children and adolescents with ADHD, 16 to 18 hours after taking the medication
• followed by a prolonged, controlled release throughout the day
  • The drug is released in the large intestine because the coated capsule travels through the digestive tract for several hours before the active ingredient takes effect
  • More than 50% of MPH is released after peak concentrations are reached
• remains nearly constant regardless of age once adjusted for dose and body weight
• Steady state is achieved with the second dose.
• a prolonged elimination phase and 25% lower bioavailability compared to IR-MPH
• due to absorption by the large intestine, which is less efficient at absorbing nutrients
• Some of the released MPH is not absorbed but is excreted in the stool
• Due to the properties of the multiple polymers in the DR and ER layers of the DR/ER-MPH micropellets, the initial dissolution and subsequent absorption of MPH do not depend on a single factor, such as pH, fluctuations in the gastrointestinal tract, or the site of release. Consequently, DR/ER-MPH is less susceptible to the influence of individual factors, resulting in reduced variability in absorption and, consequently, smaller (subjective) differences in efficacy between patients and within individual patients over the course of treatment.
• The duration of the effect increased with higher doses¹⁹
• Response rate up to 97%¹⁹
• Remission rate up to 87%¹⁹
• Sleep problems were the most common side effect and resolved in 97% of the people with ADHD by the end of the 6-week trial¹⁹
• In a retrospective patient cohort of individuals aged 16 years and older, the mean initial dose of DR/ER-MPH was 53.6 mg/day, and the mean optimized dose after more than 3 months of treatment was 81.9 mg/day. More than half of these patients titrated to a dose of 100 mg/day. Due to absorption in the lower gastrointestinal tract, DR/ER-MPH has reduced bioavailability compared to other MPH formulations. In adults, the relative bioavailability of DR/ER-MPH is 73.9% compared to MPH-IR. The titrated doses of DR/ER-MPH ranged from 1.8 to 4.3 times those of previous long-acting stimulants and from 4.7 to 6.0 times those of previous short-acting stimulants.¹⁹

Half-life in healthy adults, while fasting: approximately 5.9 to 6.5 hours

Food:

• DR/ER-MPH capsules can be swallowed whole or opened and sprinkled on applesauce
• A high-fat meal in the evening, when taken, caused
  • AUC unchanged
  • Cmax reduced by 11% to 14%
  • Tmax delayed by approximately 2.5 hours
• Low-fat or high-fat breakfast
  • No effect on pharmacokinetics
  • presumably because the DR/ER-MPH microspheres are already in the large intestine

14.2.1.10. Novo-MPH ER-C¶

MPH Novo-MPH ER-C tablets were first approved in Canada in 2010²⁰ and are considered bioequivalent to OROS-MPH there.²¹

Product: Teva Methylphenidate ER-C (Canada)

We have not yet found any information on the mechanism of action of Novo-MPH ER-C.

14.2.1.11. Matrix Technology¶

Product:

• Kinecteen® (Germany, Austria, Switzerland)
• Rubicrono® (Spain)
• Xaggitin® (United Kingdom)
• Radd®¹⁰

Slow-release matrix tablet. Swells upon contact with liquid and forms a translucent gel. As the gel layer breaks down, MPH is released in a controlled manner.²²

Dosages:

• 18, 27, 36, 45, 54 mg (Kinecteen)

We have not yet found any further information on the mechanism of action of Kinecteen.

Product:

• Metadate ER tablets

The matrix-release system works by the formation of a water channel through the tablet. The active ingredient is released through the channel, and the thickness of the matrix layer in the tablet determines the release rate.²³
The tablets cannot be split, as breaking them increases the surface area of the tablet, which alters the rate of release. The tablets must be swallowed whole.⁵

Dosages:

• 20 mg

Pharmacokinetics:

• Maximum after 4 to 5 hours

14.2.1.12. “Lumpy gravy” technology¶

Preparations:

• Metadate ER®
• Methylin ER®

“Lumpy gravy” is a good linear release mechanism and was one of the first effective technologies for the extended release of methylphenidate.¹

MPH is mixed with treated cellulose and wax to bind the tablets together.
When the tablets come into contact with stomach acid, they swell up, much like lumps in a sauce. The physical action of the stomach breaks up the lumps and releases the MPH.
Although the tablets are sustained-release, they can be split to fine-tune the dose.¹

Typical duration of effect: approximately 6 hours.
While this is certainly better than the 2.5 to 4 hours of the immediate release MPH, it is still too short for a school day or workday, which requires at least 8 hours.¹

14.2.1.13. ER Film-Coated Tablets¶

Extended-release film-coated tablet

• Acerta®¹⁰

Dosages: 18 mg, 27 mg, 36 mg, 54 mg

14.2.1.14. MUPS (Multi-unit Pellet System)¶

• Contramyl XR®

Dosages: 18 mg, 27 mg, 36 mg, 54 mg

14.2.1.15. ODX¶

ODX-Methylphenidate ER uses an osmotic pump design similar to the OROS system.
In an early study of healthy young men, ODX and OROS produced comparable plasma concentration-time curves.²⁴

14.2.2. Transdermal delivery via a patch¶

14.2.2.1. MTS¶

Product: DAYTRANA® (U.S.)

DOT Matrix® Technology

MTS delivers racemic MPH transdermally via a diffusion-based patch.¹¹
The patch consists of a backing film made of a polyester/ethylene acetate laminate, which carries a multipolymer adhesive layer containing MPH.
Apply to intact skin.
Continuous MPH release as a function of patch size and duration of wear.
Transdermal administration reduces first-pass metabolism.
Lasting up to 9 hours

Dosage strengths:

• 10 mg (12.5 cm²)
• 15 mg (18.75 cm²)
• 20 mg (25 cm²)
• 30 mg (37.5 cm²)

Dose proportionality:

• For children with ADHD, 10 mg to 30 mg
  • Cmax of l-MPH is dose-proportional
  • AUC slightly above average
• A 12.5 cm² patch applied for 9 hours showed
  • 2-hour delay in d-MPH absorption
  • Peak plasma concentration after 10 hours
  • Half-life: approximately 4 to 5 hours
• Accumulation through continuous use
  • Steady state is likely reached after about 14 days
  • compared to a single dose
    • AUC increased by 64% and 76%, respectively
    • Cmax increased by 69% and 100%, respectively
  • Systemic exposure in children is 1.4 to 1.6 times higher with systemic OROS-MPH
  • Systemic exposure in adolescents, however, is similar for both formulations

14.2.3. Suspension¶

14.2.3.1. MEROS: ER Suspension¶

Product: QUILLIVANT XR® (USA)

MEROS: LiquiXR® Technology

Powder in bottles containing 300, 600, or 750 mg. When water is added, it forms a suspension containing 5 mg/mL of MPH.¹¹ The suspension is stable for 4 months at room temperature and must be shaken for 10 seconds before each use.⁵

MEROS contains two types of microparticles:

• solid particles containing ion-exchange resin that form a complex with MPH through ionic bonding
  • release 20% of the MPH immediately
• Particles coated with a layer of an aqueous, pH-independent polymer of varying thickness
  • release 80% of the MPH over time

Pharmacokinetic Profile:

• a rapid initial increase in MPH concentration
• then gradual, prolonged release

In healthy adults, a single dose of 60 mg administered on an empty stomach resulted in:

• maximum d-MPH concentration after 5 hours
• Half-life: 5.65 hours
• bioequivalent to two 30-mg doses of IR-MPH oral solution administered 6 hours apart
• Onset of effect within 45 minutes

In children and adolescents with ADHD, this resulted in

• Single dose of 20 or 60 mg:
  • maximum d-MPH concentration after 2 to 4 hours
• Single dose of 60 mg:
  • Cmax in children is approximately twice as high as in adults
  • Cmax in adolescents is comparable to that in adults

Dose proportionality:

• Cmax and AUC are similar after adjustment for body weight

Food intake:

• A high-fat breakfast resulted in:
  • reduced Tmax by 1 hour
  • increased Cmax by 28%
  • increased AUC by 19%