Safety and tolerability of flexible dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder

Figures & data

Figure 1 Flow of patients from the double-blind phase through the open-label phase of the trial.

Notes: ^aPatients at German centers began with 18 mg/day; ^bOther includes patients who took no drug on the visit day or did not have a visit during the time interval (week 1 [1–13 days], week 3 [14–31 days], week 7 [≥32 days]).
Abbreviation: OROS, osmotic release oral system.

Table 1 Study medication administered during the open-label phase

Treatment summarya	Descriptive statistic (N =370)
	Mean (SD)	Median	Range
Treatment duration (days)	47.6 (9.13)	49.0	2–90
Average daily dose (mg)b	47.5 (13.93)	46.4	18–82
Average daily dose (mg)c	46.5 (14.18)	46.3	15–82
Last dose (mg)	52.6 (19.29)	54.0	18–90
Maximum dose (mg)	57.6 (18.11)	54.0	18–108
Minimum dose (mg)d	29.4 (8.88)	36.0	18–54

Distribution of last dose and maximum dose, n (%)
Daily dose	Last dose	Maximum dose
18 mg	29 (7.9)	5 (1.4)
36 mg	108 (29.3)	96 (26.0)
54 mg	127 (34.4)	133 (36.0)
72 mg	73 (19.8)	93 (25.2)
90 mg	32 (8.7)	40 (10.8)
108 mg	–	2 (0.5)e

Notes:

a Medication data not available for one patient;

b Excludes zero dose days;

c Includes zero dose days;

d Excludes zero dose days; minimum dose was generally the starting dose;

e Two patients assigned to a 54 mg daily dose took a double dose for one day and two days, respectively.

Table 2 Adverse events during the open-label phase

Category	Treated patients (N =370) n (%)
Any serious adverse event	2 (<1)
Discontinued due to adverse event	17 (5)
Any adverse event	253 (68)
Possibly related to trial medicationa	195 (53)
Adverse event >2% totalb
Headache	62 (16.8)
Decreased appetite	47 (12.7)
Insomnia	41 (11.1)
Nausea	26 (7.0)
Nasopharyngitis	21 (5.7)
Restlessness	19 (5.1)
Initial insomnia	17 (4.6)
Dry mouth	15 (4.1)
Fatigue	15 (4.1)
Dizziness	14 (3.8)
Anxiety	13 (3.5)
Palpitations	12 (3.2)
Depressed mood	11 (3.0)
Tachycardia	10 (2.7)
Nervousness	10 (2.7)
Influenza	9 (2.4)
Hyperhidrosis	9 (2.4)
Disturbance in attention	8 (2.2)

Notes:

a Includes relationship of ‘possibly’, ‘probably’, and ‘very likely’;

b Summarized by preferred term according to Medical Dictionary for Regulatory Activities (MedDRA).

Table 3 Percent of patients who reported an adverse event by daily dose and treatment period

Treatment period	Daily dosage of OROS methylphenidate (N =370)
	18 mg	36 mg	54 mg	72 mg	90 mg
Week 1	46% (46/101)	44% (104/237)	36% (4/11)	0% (0/1)	100% (1/1)
Week 3	38% (9/24)	30% (40/133)	49% (76/154)	49% (16/33)	0% (0/4)
Week 7	33% (7/21)	23% (19/82)	26% (29/110)	31% (20/65)	38% (12/32)

Notes: Numerator is number of patients reporting any adverse event; denominator is total number of patients in the same dosage and treatment week. Excludes patients who took no drug on the visit day for the treatment week or did not attend the visit day (see Figure 1).

Abbreviation: OROS, osmotic release oral system.

Table 4 Adverse events by daily dose at final treatment visit

Adverse event, n (%)	Daily dosage of OROS methylphenidate (N = 370)
	18mg	36 mg	54 mg	72 mg	90 mg
Headache	2 (9.5)	2 (2.4)	4 (3.6)	5 (7.7)	1 (3.1)
Decreased appetite	0	0	1 (0.9)	1 (1.5)	2 (6.3)
Insomnia	1 (4.8)	1 (1.2)	4 (3.6)	1 (1.5)	1 (3.1)
Nausea	0	1 (1.2)	1 (0.9)	0	0
Nasopharyngitis	1 (4.8)	6 (7.3)	3 (2.7)	3 (4.6)	1 (3.1)
Restlessness	1 (4.8)	1 (1.2)	1 (0.9)	2 (3.1)	0
Dry mouth	1 (4.8)	0	0	0	1 (3.1)
Fatigue	0	1 (1.2)	0	0	0
Dizziness	1 (4.8)	0	0	1 (1.5)	0
Anxiety	1 (4.8)	2 (2.4)	0	0	0
Palpitations	1 (4.8)	1 (1.2)	0	1 (1.5)	0
Depressed mood	0	0	2 (1.8)	2 (3.1)	1 (3.1)
Tachycardia	0	1 (1.2)	1 (0.9)	1 (1.5)	0
Nervousness	1 (4.8)	0	0	0	0
Influenza	0	0	0	1 (1.5)	0
Disturbance in attention	0	0	0	1 (1.5)	1 (3.1)

Notes: Adverse events reported in >2% total patients (see Table 2); n =number of patients with a particular adverse event at week 7 visit; percentage denominator is total number of patients with the same dosage at final treatment week. Excludes patients who took no drug on the final visit day or did attend the visit (see Figure 1).

Abbreviation: OROS, osmotic release oral system.

Table 5 Patients who met clinically relevant criteria for cardiovascular-related measurements by daily dose at final treatment visit

Measurement, n (%)	Daily dosage of OROS methylphenidate (N = 370)
	18 mg	36 mg	54 mg	72 mg	90 mg
	n = 21	n = 82	n = 110	n = 65	n = 32
Systolic blood pressure (≥ 140 mmHg)	2 (9.5)	13 (15.9)	20 (18.2)	14 (21.5)	11 (34.4)
Diastolic blood pressure (≥ 90 mmHg)	6 (28.6)	23 (28.0)	25 (22.7)	22 (33.8)	12 (37.5)
Pulse (≥ 90 beats per minute)	7 (33.3)	29 (35.4)	37 (33.6)	32 (49.2)	16 (50.0)

Note: Measured while patient standing; n = number of patients who met criteria; percentage denominator is total number of patients with the same dosage at final treatment week. Excludes patients who took no drug on the visit day for the treatment week or did not attend the visit day (see Figure 1).