Background
MPH formulation | Synonyms | Product availability | Modified-release technology | Immediate-release: extended-release ratio (%) | Duration of actiona
|
---|---|---|---|---|---|
Biphentin® [10] | MPH ER | Canada | Multilayer-release (MLR) bead formulation | 40:60 | Not stated: biphasic delivery profile |
Concerta® [12] | Concerta extended release; Concerta® LP; methylphenidate hydrochloride; OROS MPH | Africab, Asiac, Australia, Europed, New Zealand, North Americae, South Americaf
| OROS® (Osmotic Release Oral System) | 22:78 | 12 hours |
Daytrana® [13] | MPH transdermal system; MethyPatch; MTS | USA | Transdermal patch | Continuous delivery | 9 hours |
Equasym XL® [11] | Equasym Depot®; Equasym Retard®, Equasym XR®, Quasym LP®; Metadate CD®; Metadate ER®
| Europeg, South Korea, USA | Diffucaps®
| 30:70 | 8 hours |
Focalin XR® [7] |
d-MPH-ER | Switzerland, USAh
| SODAS® (Spheroidal Oral Drug Absorption System) | 50:50 | Not stated: two distinct peaks approximately 4 hours apart |
Medikinet® retard [9] | Medikinet®; Medikinet® CR; Medikinet® EM; Medikinet® MR; Medikinet® XL | Europei, Israel, Korea, South Americaj
| Modified-release capsules | 50:50 | 8 hours |
Ritalin LA® [6] | Ritalin LP®; Miacalcic | France, Chile, USAh
| SODAS® (Spheroidal Oral Drug Absorption System) | 50:50 | Not stated: two distinct peaks approximately 4 hours apart |
Ritalin SR® [5] | n/a | Canada, USAh
| Wax matrix | Continuous release | 8 hours |
Methods
Results and discussion
Author, year | Long-acting MPH formulation and dosinga
| Sample size Age range | Diagnosis | Comorbid conditions | Outcome measures |
---|---|---|---|---|---|
Pharmacokinetic studies
| |||||
Gonzalez et al., 2002 [20] | Concerta® (18, 36, 54 mg) | n = 36 | Not applicable | Not stated | PK parameters for 24 hours post-dose, including bioequivalence |
Equasym XL® (20, 40, 60 mg) | 21–40 years | ||||
Haessler et al., 2008 [26] | Ritalin LA® (40 mg) | n = 28 | Not applicable | Not stated | PK parameters for 24 hours post-dose, including bioequivalence |
Medikinet® retard (40 mg) | 18–30 years | ||||
Markowitz et al., 2003 [22] | Concerta® (18 mg) | n = 20 | Not applicable | Not stated | PK parameters for 24 hours post-dose, including bioequivalence |
Ritalin LA® (20 mg) | 21–34 years | ||||
Modi et al., 2000 [23] | Concerta® (18 mg) | n = 36 | Not applicable | Not stated | PK parameters for 30 hours post-dose |
Ritalin SR® (20 mg) | 18–41 years | ||||
Pierce et al., 2010 [24] | Concerta® (18, 27, 36, 54 mg) | n = 71 | ADHD according to DSM-IV-TR criteria | Possibly ODD | PK properties of d,l-MPH after single, multiple, fixed and escalating doses of Concerta® and Daytrana®
|
Daytrana® (10, 15, 20, 30 mg/9 hours) | 6–17 years | ||||
Reiz et al., 2008 [25] | Concerta® (18 mg) | n = 24 | Not applicable | Not stated | PK parameters for 24 hours post-dose, including bioequivalence |
Biphentin® (20 mg) | 19–25 years | ||||
Schutz et al., 2009 [28] | Equasym XL® (20 mg) | n = 14 | Not applicable | Not stated | PK parameters for 24 hours post-dose, including bioequivalence |
Medikinet® retard (20 mg) | 22–43 years | ||||
Spencer et al., 2010 [21] | Concerta® (36 mg) | n = 21 | Not applicable | Not stated | PET imaging |
Equasym XL® (40 mg) | 18–55 years | ||||
Tuerck et al., 2007 [27] | Focalin XR® (20 mg) | n = 25 | Not applicable | Not stated | PK parameters for 24 hours post-dose, including bioequivalence |
Ritalin LA® (40 mg) | 19–45 years | ||||
Laboratory school studies
| |||||
Lopez et al., 2003 [31] | Concerta® (18, 36 mg) | n = 36 | ADHD according to C-DISC criteria | Not stated | SKAMP-Attention; SKAMP-Deportment; SKAMP-Combined; Math-Attempted; Math-Correct |
Ritalin LA® (20 mg) | 6–12 years | ||||
Muniz et al., 2008 [33] | Concerta® (36, 54 mg) | n = 84 | Combined-type ADHD (89%); Inattentive-type ADHD (11%) according to DSM-IV criteria, established by C-DISC | Not stated | SKAMP-Combined; SKAMP-Attention; SKAMP-Deportment; Math-Attempted; Math-Correct; CPRS |
Focalin XR® (20, 30 mg) | 6–12 years | ||||
Schulz et al., 2010 [38] | Ritalin LA® (20 mg) | n = 147 | Combined-type ADHD (55%); Inattentive-type ADHD (37%); Hyperactive/impulsive-type ADHD according to DSM-IV criteria, confirmed by K-SADS | Disturbance in social behaviour (n = 4), initial insomnia (n = 2), ODD (n = 2), dysphemia (n = 1), encopresis (n = 1) | SKAMP-Combined; Math-Attempted; Math-Correct; NCBRF-TIQ |
Medikinet® retard (20 mg) | 6–14 years | ||||
Silva et al., 2005 [32] | Concerta® (18 mg) | n = 54 | Combined inattentive/hyperactive-type ADHD (70%); Inattentive-type ADHD (28%); Hyperactive/impulsive-type ADHD (2%) according to DSM-IV criteria | Not stated | SKAMP-Attempted; SKAMP-Deportment; SKAMP-Combined; Math-Attempted; Math-Correct |
Ritalin LA® (20 mg) | 6–12 years | ||||
Silva et al., 2008 [18] | Concerta® (36, 54 mg) Focalin XR® (20, 30 mg) | n = 82 6–12 years | Combined-type ADHD (94%); Inattentive-type (6%) according to DSM-IV criteria | Not stated | SKAMP-Attention; SKAMP-Deportment; SKAMP-Combined; Math-Attempted; Math-Correct; CPRS |
Sonuga-Barke et al., 2004 [34] | Concerta® (18, 36, 54 mg) Equasym XL® (20, 40, 60 mg) | n = 184 6–12 years | Combined-type (82%); Inattentive-type (13%); Hyperactive/impulsive-type (5%) according to DSM-IV criteria and confirmed by DISC | Comorbid condition (25%), including anxiety and ODD | Placebo-adjusted SKAMP-Combined |
Post-hoc study of COMACS [37] | |||||
Sonuga-Barke et al., 2007 [35] | Concerta® (18, 36, 54 mg) Equasym XL® (20, 40, 60 mg) | n = 184 6–12 years | Females: Combined-type (77%); Inattentive-type (15%); Hyperactive/impulsive-type (8%). Males: Combined-type (84%); Inattentive-type (12.4%); Hyperactive/impulsive-type (4%) | Comorbid condition (25%), including anxiety and ODD | SKAMP-Combined; PERMP |
Post-hoc study of COMACS [37] | |||||
Sonuga-Barke et al., 2008 [36] | Concerta® (18, 36, 54 mg) | n = 184 | Combined-type (82%); Inattentive-type (13%); Hyperactive/impulsive-type (5%) according to DSM-IV criteria, confirmed by DISC | Comorbid condition (25%), including anxiety and ODD | GMM analysis |
Equasym XL® (20, 40, 60 mg) | 6–12 years | ||||
Post-hoc study of COMACS [37] | |||||
Swanson et al., 2004 [37] | Concerta® (18, 36, 54 mg) | n = 184 | Combined-type (82%); Inattentive-type (13%); Hyperactive/impulsive-type (5%) according to DSM-IV criteria, confirmed by DISC | Comorbid condition (25%), including anxiety and ODD | SKAMP-Attention; SKAMP-Deportment; PERMP |
Equasym XL® (20, 40, 60 mg) | 6–12 years | ||||
COMACS study | |||||
Randomized controlled trials
| |||||
Doepfner et al., 2011 [42] | Concerta® (18, 36 mg) | n = 113 | Combined-type ADHD according to DSM-IV, confirmed by interview (DCL-ADHD) | ODD or conduct disorder (36%) | SKAMP-D; DAYAS; FBB-ADHD |
Medikinet® retard (10, 20, 30 mg) | 6–16 years | ||||
Findling et al., 2008 [43] | Concerta® (18, 27, 36, 54 mg) | n = 282 | Combined-type ADHD (71–86%); Inattentive-type ADHD (11–26%); Hyperactive/impulsive-type ADHD (1–2%) according to DSM-IV-TR criteria | Possibly ODD | ADHD-RS-IV mean total score; CTRS-R; CPRS-R; CGI–S; CGI–I; PGA; MPH plasma concentrations at 7.5, 9 and 10 hours post-dose |
Daytrana® (10, 15, 20, 30 mg) | 6–12 years | ||||
Switching studies
| |||||
Arnold et al., 2010 [46] | Concerta® (18, 27, 36, 45, 54 mg) | n = 171 | Combined-type ADHD (77%); Inattentive-type ADHD (21%); Hyperactive/impulsive -type ADHD (2%) according to DSM-IV-TR criteria | Possibly ODD | ADHD-RS-IV mean total scores; CGI–I; PGA, CPRS-R; CGI–S |
Ritalin LA® (10, 20, 30, 40, 50 mg) | 6–12 years | ||||
Equasym XL® (10, 15, 20, 30, 40, 50 mg) | |||||
Daytrana® (10, 15, 20, 30 mg) | |||||
Bukstein et al., 2009 [47] | Concerta® (18, 27, 36, 45, 54 mg) | n = 171 | See Arnold et al., 2010 [46] | Possibly ODD | AIM-C; MSS |
Ritalin LA® (10, 20, 30, 40, 50 mg) | 6–12 years | ||||
Equasym XL® (10, 15, 20, 30, 40, 50 mg) | |||||
Daytrana® (10, 15, 20, 30 mg) | |||||
Dirksen et al., 2002 [48] | Equasym XL® (20, 40, 60 mg) | n = 308 | ADHD according to DSM-IV criteria (diagnostic code 314.01) | Not stated | CGI–I; CGI–S; CGI-Efficacy Index |
Concerta® (18, 36, 54, 72 mg) | 6–17 years | ||||
Other long-acting MPH (excluding Concerta®; dose not stated) | |||||
Observational studies
| |||||
Doepfner et al., 2011 [49] | Equasym XL® (10–120 mg) | n = 822 | Disturbance of activity/attention (F90.0; 55%); hyperkinetic conduct disorder (F90.1; 36%); other hyperkinetic disorders (F90.8; 8%) according to ICD-10 criteria | Not stated | CGI–S; CGI–I; FBB-ADHD; DAYAS; SDQ-P |
Other long-acting MPH (most commonly Medikinet® retard; approximately 0.85 mg/kg/day) | 6–17 years | ||||
OBSEER study | |||||
Doepfner et al., 2011 [50] | Equasym XL® (10–120 mg) | n = 782 | For total study sample (n = 822) see Doepfner et al., 2011 [49] | Not stated | FBB-ADHD; CGI–S; DAYAS; KINDL |
Other long-acting MPH (mean [SD] 29.2 [11.28] mg) | 6–17 years | ||||
Post-hoc study of OBSEER [49] | |||||
Rothenberger et al., 2011 [51] | See Doepfner et al., 2011 [49] | n = 822 6–17 years | See Doepfner et al., 2011 [49] | Not stated | KINDL; SAMS |
Post-hoc study of OBSEER [49] | |||||
Meta-analyses
| |||||
Faraone et al., 2006 [55] | Equasym XL®; Ritalin LA®; | n = 29 articles | Effect size expressed as SMD | ||
Concerta®; Daytrana®
| Children and adolescents | ||||
Faraone and Buitelaar, 2010 [56] | Equasym XL®; Ritalin LA®; | n = 23 articles | Effect size expressed as SMD | ||
Concerta®; Daytrana®
| Children and adolescents | ||||
Faraone and Glatt, 2010 [57] | Concerta®; | n = 18 articles | Effect size expressed as SMD | ||
Focalin XR®
| Adults | ||||
Peterson et al., 2008 [58] | Concerta®; | n = 22 articles | Ratio of relative risks | ||
Focalin XR®
| Adults | ||||
Systematic reviews
| |||||
Banaschewski et al., 2006 [52] | Concerta®; Ritalin LA®; Equasym XL®; Medikinet® retard | Not stated | Effect size expressed as SMD | ||
Brams et al., 2008 [53] | Concerta®; Daytrana®; Focalin XR®; Equasym XL®; Ritalin LA®
| n = 18 articles | SKAMP, CADS-T, IOWA Conners’ Rating Scale, ADHD-RS-IV, PERMP, CGIS-T | ||
Children and adolescents | |||||
Brams et al., 2010 [19] | Concerta®; Focalin XR®; Equasym XL®; Ritalin LA®
| n = 15 articles | PERMP | ||
Children, adolescents and adults | |||||
Swanson et al., 2002 [54] | Concerta®; Equasym XL®; Ritalin LA®
| Not stated | SKAMP, 10-Minute Math Test, PK measures, effect size |
PK studies
Head-to-head PK studies of Concerta ® versus Equasym XL ® , Ritalin LA ® , Ritalin SR ® , Daytrana ® and Biphentin ®
Bioequivalence to Concerta ® and overall MPH exposure
Time to peak plasma MPH concentration (Tmax)
Cmax, ng/mL | Tmax, hours | AUC, ng • h/mL | |||||||
---|---|---|---|---|---|---|---|---|---|
Cmax0–4
| Cmax4–10
| Cmax
| Tmax0–4
| Tmax4–10
| Tmax
| AUC0–4
| AUC4–10
| AUC0–∞
| |
Concerta®
| – | – | – | – | – | – | 6.28 | – | 36.43 |
(18 mg) | (2.65) | (13.50) | |||||||
Equasym XL®
| – | – | – | – | – | – | 10.01 | – | 39.74 |
(20 mg) | (3.06) | (11.75) | |||||||
Concerta®
| – | – | – | – | – | – | 11.88 | – | 94.05 |
(36 mg) | (5.86) | (44.51) | |||||||
Equasym XL®
| – | – | – | – | – | – | 20.36 | – | 98.49 |
(2 × 20 mg) | (8.74) | (52.05) | |||||||
Concerta®
| – | – | – | – | – | – | 18.81 | – | 143.38 |
(54 mg) | (7.18) | (64.83) | |||||||
Equasym XL®
| – | – | – | – | – | – | 32.01 | – | 145.34 |
(3 × 20 mg) | (13.09) | (65.21) | |||||||
Ritalin LA®
| 11.8 | 12.8 | 13.3 | – | – | – | 33.5 | 57.8 | 126.8 |
(40 mg) | (3.95) | (4.13) | (4.04) | (11.07) | (16.91) | (34.5) | |||
Medikinet® retard | 16.5 | 18.3 | 19.6 | – | – | – | 42.4 | 68.0 | 141.5 |
(40 mg) | (6.69) | (5.66) | (5.95) | (16.54) | (19.47) | (38.3) | |||
Ritalin LA®
| 10.0 | 14.5 | 14.5 | – | – | – | 27.6 | 57.1 | 114.1 |
(40 mg) | (3.51) | (3.02) | (3.02) | (8.89) | (14.36) | (30.8) | |||
Medikinet® retard | 16.5 | 14.7 | 17.1 | – | – | – | 44.9 | 49.3 | 115.7 |
(40 mg) | (4.62) | (4.45) | (4.88) | (14.77) | (18.47) | (37.2) | |||
Concerta®
| 3.4 | – | 5.9 | 3.3 | – | 6.0 | 9.3 | – | 66.9 |
(18 mg) | (44)a
| (37)a
| (36)a
| (28)a
| (51)a
| (49)a
| |||
Ritalin LA®
| 7.0 | – | 9.9 | 2.1 | – | 5.5 | 18.5 | – | 78.7 |
(20 mg) | (47)a
| (41)a
| (48)a
| (15)a
| (44)a
| (54)a
| |||
Concerta®
| – | – | 3.75 | – | – | 6.7 | – | – | 42.0 |
(18 mg) | (1.0) | (1.8) | (14) | ||||||
Ritalin SR®
| – | – | 4.84 | – | – | 3.7 | – | – | 46.7 |
(20 mg) | (1.6) | (1.6) | (16) | ||||||
Concerta®
| – | – | 7.80 | – | – | 6.02 | – | – | 94.2 |
(18 mg) | (3.35) | (4.0–10.0)b
| (43.8) | ||||||
Daytrana®
| – | – | 9.30 | – | – | 10.0 | – | – | 99.2 |
(10 mg/9 hours) | (3.60) | (8.0–12.0)b
| (42.9) | ||||||
Concerta®
| – | – | 4.95 | – | – | 8.0 | – | – | 60.1 |
(18 mg) | (1.42) | (1.0–10.0)b
| (16.3) | ||||||
Daytrana®
| – | – | 4.15 | – | – | 10.0 | – | – | 48.7 |
(10 mg/9 hours) | (2.59) | (6.0–12.0)b
| (21.9) | ||||||
Concerta®
| 3.33 | 4.09 | 4.13 | 2.51 | 5.86 | 4.96 | 8.77 | 26.29 | 48.21 |
(18 mg) | (1.03) | (1.01)c
| (1.01) | (1.15) | (1.61)c
| (2.56) | (3.37) | (5.57)c
| (9.79) |
Biphentin®
| 4.8 | 4.73 | 5.07 | 2.26 | 6.02 | 3.71 | 12.35 | 28.57 | 54.01 |
(20 mg) | (1.39) | (1.09)c
| (1.32) | (0.64) | (1.26)c
| (2.03) | (3.78) | (6.68)c
| (13.11) |
Equasym XL®
| 3.82 | – | 4.05 | 3.24 | – | 3.99 | 9.66 | – | 37.35 |
(20 mg) | (0.96) | (0.96) | (1.13) | (1.88) | (3.24) | (10.92) | |||
Medikinet® retard | 4.83 | – | 5.26 | 2.82 | – | 4.06 | 11.72 | – | 39.90 |
(20 mg) | (1.87) | (2.11) | (1.00) | (1.65) | (4.64) | (13.77) | |||
Focalin XR®
| 13.7 | 14.9 | 15.5 | 1.5 | 6.5 | 5.8 | 36.3 | 59.1 | 119 |
(20 mg) | (4.6) | (4.0) | (4.3) | (1.0–2.0)b
| (4.5–7.0)b
| (1.0–7.0)b
| (10.6) | (16.0) | (40.7) |
Ritalin LA®
| 13.2 | 16.3 | 16.4 | 2.0 | 6.5 | 6.5 | 35.0 | 60.9 | 122 |
(40 mg) | (3.0) | (4.5) | (4.4) | (1.5–4.5)b
| (4.0–8.0)b
| (2.0–7.0)b
| (8.7) | (15.0) | (36.3) |