3) ベースラインからの個々の変化量付録 2.7.4:30 主な臨床検査値の推移 (045 試験 )( 続き ) Individual Change From Baseline in Creatinine (mg/dl) Over Time (All Patients as Treated) 24

(1)

2.7.4 臨床的安全性

- 563 -

in N

eutr

ophi

ls (/

mic

roL)

Cha

nge F

rom

Bas

elin

e

Weeks Since Randomization

24-wk MK-7009 300 mg b.i.d. + Peg-IFN + RBV

0123456789101112 16 20 24 FU4 FU12 FU20 FU24 -10000

-5000 0 5000 10000

(2)

- 564 -

in C

reat

inine

(m

g/dL

)

Cha

nge F

rom

Bas

elin

e

012345678 10 12 16 20 24 FU4 FU12 FU20 FU24 -0.5 -0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2

(3)

- 565 -

in A

spa

rtat

e A

min

otran

sfer

ase (

IU/L

)

Cha

nge F

rom

Bas

elin

e

012345678 10 12 16 20 24 FU4 FU12 FU20 FU24 -200 -100 0 100 200 300

(4)

- 566 -

in A

lani

ne A

mino

tran

sfer

ase

(IU

/L)

Cha

nge F

rom

Bas

elin

e

012345678 10 12 16 20 24 FU4 FU12 FU20 FU24 -200 -100 0 100 200 300 400 500

(5)

- 567 -

in B

ilirub

in (m

g/dL)

Cha

nge F

rom

Bas

elin

e

012345678 10 12 16 20 24 FU4 FU12 FU20 FU24 -1.0 -0.5 0.0 0.5 1.0 1.5

(6)

- 568 -

Patients in population 19 18 20 18 19

with one or more adverse

events 18 (94.7) 15 (83.3) 18 (90.0) 16 (88.9) 18 (94.7) with no adverse events 1 (5.3) 3 (16.7) 2 (10.0) 2 (11.1) 1 (5.3)

Blood and lymphatic system

disorders 4 (21.1) 2 (11.1) 2 (10.0) 0 (0.0) 4 (21.1) Anaemia 3 (15.8) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0) Leukopenia 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Neutropenia 1 (5.3) 1 (5.6) 2 (10.0) 0 (0.0) 2 (10.5) Pancytopenia 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Cardiac disorders 1 (5.3) 0 (0.0) 1 (5.0) 0 (0.0) 1 (5.3) Angina pectoris 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Palpitations 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 1 (5.3) Tachycardia 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

(7)

- 569 -

Tinnitus 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Eye disorders 5 (26.3) 3 (16.7) 3 (15.0) 1 (5.6) 2 (10.5) Dry eye 1 (5.3) 1 (5.6) 0 (0.0) 1 (5.6) 1 (5.3) Eye irritation 1 (5.3) 1 (5.6) 1 (5.0) 0 (0.0) 1 (5.3) Eye pain 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Eye pruritus 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Eye swelling 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Lacrimation increased 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Ocular icterus 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Photopsia 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) Vision blurred 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Xerophthalmia 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0) Gastrointestinal disorders 14 (73.7) 11 (61.1) 14 (70.0) 11 (61.1) 14 (73.7) Abdominal discomfort 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0)

(8)

- 570 -

Abdominal pain 0 (0.0) 0 (0.0) 1 (5.0) 1 (5.6) 0 (0.0)

Abdominal pain upper 3 (15.8) 1 (5.6) 2 (10.0) 4 (22.2) 2 (10.5)

Anal fissure 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Constipation 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Diarrhoea 4 (21.1) 1 (5.6) 6 (30.0) 2 (11.1) 4 (21.1) Dry mouth 0 (0.0) 1 (5.6) 2 (10.0) 2 (11.1) 1 (5.3) Dyspepsia 4 (21.1) 4 (22.2) 0 (0.0) 2 (11.1) 4 (21.1) Flatulence 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) Gastritis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (10.5) Gastrooesophageal reflux disease 1 (5.3) 2 (11.1) 0 (0.0) 2 (11.1) 0 (0.0) Gingival bleeding 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Glossodynia 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0) Haemorrhoids 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Lip dry 2 (10.5) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Nausea 5 (26.3) 5 (27.8) 8 (40.0) 7 (38.9) 6 (31.6)

(9)

- 571 -

Oesophageal pain 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Stomatitis 1 (5.3) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Vomiting 0 (0.0) 0 (0.0) 8 (40.0) 3 (16.7) 3 (15.8)

General disorders and administration site conditions 11 (57.9) 8 (44.4) 11 (55.0) 11 (61.1) 12 (63.2) Asthenia 3 (15.8) 2 (11.1) 2 (10.0) 3 (16.7) 1 (5.3) Chest pain 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (10.5) Chills 2 (10.5) 1 (5.6) 1 (5.0) 0 (0.0) 3 (15.8) Discomfort 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Fatigue 7 (36.8) 3 (16.7) 7 (35.0) 4 (22.2) 2 (10.5) Feeling cold 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Feeling of body temperature chan 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

(10)

- 572 -

administration site

conditions

Injection site erythema 0 (0.0) 1 (5.6) 2 (10.0) 1 (5.6) 0 (0.0)

Injection site irritation 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Injection site reaction 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0)

Irritability 2 (10.5) 2 (11.1) 1 (5.0) 0 (0.0) 1 (5.3)

Oedema peripheral 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

Pain 0 (0.0) 0 (0.0) 3 (15.0) 0 (0.0) 0 (0.0)

Pyrexia 2 (10.5) 0 (0.0) 1 (5.0) 1 (5.6) 4 (21.1)

Infections and infestations 3 (15.8) 2 (11.1) 4 (20.0) 6 (33.3) 5 (26.3)

Bronchitis 1 (5.3) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Herpes virus infection 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Infected sebaceous cyst 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Nasopharyngitis 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 2 (10.5)

(11)

- 573 -

Skin infection 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Tinea infection 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

Tracheobronchitis 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Upper respiratory tract

infectio 1 (5.3) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

Urinary tract infection 0 (0.0) 0 (0.0) 1 (5.0) 2 (11.1) 1 (5.3)

Viral infection 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 1 (5.3)

Vulvovaginal mycotic

infection 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

Injury, poisoning and

procedural complications 0 (0.0) 0 (0.0) 2 (10.0) 0 (0.0) 1 (5.3)

Burns second degree 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Contusion 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Post-traumatic pain 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

(12)

- 574 -

Blood bilirubin increased 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Blood glucose increased 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Body temperature

decreased 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Body temperature

increased 1 (5.3) 1 (5.6) 0 (0.0) 1 (5.6) 1 (5.3)

Glucose urine present 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Haemoglobin decreased 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

Neutrophil count

decreased 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0)

Weight decreased 1 (5.3) 0 (0.0) 2 (10.0) 0 (0.0) 0 (0.0)

White blood cell count

decreased 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 1 (5.3)

Metabolism and nutrition

disorders 2 (10.5) 4 (22.2) 5 (25.0) 2 (11.1) 1 (5.3)

(13)

- 575 -

connective tissue disorders

Arthralgia 1 (5.3) 3 (16.7) 2 (10.0) 1 (5.6) 0 (0.0) Back pain 1 (5.3) 0 (0.0) 3 (15.0) 0 (0.0) 2 (10.5) Muscular weakness 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Musculoskeletal chest pain 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Musculoskeletal pain 0 (0.0) 2 (11.1) 0 (0.0) 2 (11.1) 0 (0.0) Myalgia 3 (15.8) 1 (5.6) 1 (5.0) 1 (5.6) 0 (0.0) Myosclerosis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Pain in extremity 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Nervous system disorders 7 (36.8) 6 (33.3) 10 (50.0) 11 (61.1) 7 (36.8)

Cervicobrachial syndrome 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Disturbance in attention 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Dizziness 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Dysgeusia 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 1 (5.3)

(14)

- 576 -

Headache 7 (36.8) 4 (22.2) 9 (45.0) 8 (44.4) 4 (21.1) Hyperaesthesia 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Memory impairment 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) Migraine 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Paraesthesia 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Poor quality sleep 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Restless legs syndrome 1 (5.3) 0 (0.0) 1 (5.0) 0 (0.0) 1 (5.3)

Somnolence 0 (0.0) 0 (0.0) 0 (0.0) 2 (11.1) 1 (5.3) Psychiatric disorders 6 (31.6) 5 (27.8) 2 (10.0) 5 (27.8) 4 (21.1) Abnormal dreams 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) Agitation 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Anxiety 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Depressed mood 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Depression 2 (10.5) 1 (5.6) 1 (5.0) 1 (5.6) 0 (0.0) Initial insomnia 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

(15)

- 577 -

Insomnia 2 (10.5) 4 (22.2) 1 (5.0) 3 (16.7) 2 (10.5) Libido decreased 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) Mood swings 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0) Nervousness 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Restlessness 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Sleep disorder 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Renal and urinary disorders 0 (0.0) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0)

Pollakiuria 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Urine odour abnormal 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Reproductive system and

breast disorders 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0)

Erectile dysfunction 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

(16)

- 578 -

mediastinal disorders Cough 0 (0.0) 2 (11.1) 0 (0.0) 2 (11.1) 0 (0.0) Dry throat 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0) Dyspnoea 3 (15.8) 3 (16.7) 0 (0.0) 0 (0.0) 2 (10.5) Epistaxis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Nasal congestion 0 (0.0) 1 (5.6) 2 (10.0) 0 (0.0) 0 (0.0) Nasal dryness 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Oropharyngeal pain 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 1 (5.3) Productive cough 0 (0.0) 0 (0.0) 2 (10.0) 0 (0.0) 0 (0.0) Rhinorrhoea 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Sinus congestion 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Throat irritation 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

Skin and subcutaneous

tissue disorders 9 (47.4) 8 (44.4) 5 (25.0) 5 (27.8) 6 (31.6)

(17)

- 579 -

tissue disorders Dermatitis 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0) Dry skin 3 (15.8) 1 (5.6) 0 (0.0) 1 (5.6) 1 (5.3) Eczema 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 1 (5.3) Erythema 1 (5.3) 1 (5.6) 0 (0.0) 1 (5.6) 0 (0.0) Hyperhidrosis 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Night sweats 1 (5.3) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) Pruritus 3 (15.8) 3 (16.7) 0 (0.0) 1 (5.6) 2 (10.5) Rash 4 (21.1) 2 (11.1) 2 (10.0) 3 (16.7) 2 (10.5) Rash papular 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 1 (5.3) Rash vesicular 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Skin burning sensation 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Skin reaction 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Skin ulcer 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

(18)

- 580 -

Hot flush 1 (5.3) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

Hyperaemia 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Every patient is counted a single time for each applicable specific adverse event. A patient with multiple adverse events within a system organ class is counted a single time for that system organ class.

A system organ class or specific adverse event appears on this report only if its incidence in one or more of the columns is greater than or equal to the percent incidence specified in the report title, after rounding.

(19)

- 581 -

n (%) n (%) n (%) n (%) n (%)

with one or more adverse

events 38 (95.0) 42 (100.0) 40 (97.6) 46 (100.0) 41 (97.6)

with no adverse events 2 (5.0) 0 (0.0) 1 (2.4) 0 (0.0) 1 (2.4)

Blood and lymphatic system

disorders 10 (25.0) 12 (28.6) 13 (31.7) 12 (26.1) 8 (19.0) Anaemia 5 (12.5) 8 (19.0) 8 (19.5) 5 (10.9) 7 (16.7) Anisocytosis 0 (0.0) 1 (2.4) 1 (2.4) 0 (0.0) 0 (0.0) Leukopenia 2 (5.0) 2 (4.8) 0 (0.0) 1 (2.2) 0 (0.0) Lymphadenitis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Lymphadenopathy 0 (0.0) 1 (2.4) 1 (2.4) 0 (0.0) 0 (0.0) Neutropenia 8 (20.0) 5 (11.9) 3 (7.3) 8 (17.4) 2 (4.8) Thrombocytopenia 1 (2.5) 0 (0.0) 1 (2.4) 1 (2.2) 1 (2.4)

(20)

- 582 -

n (%) n (%) n (%) n (%) n (%)

Cardiac disorders 2 (5.0) 2 (4.8) 0 (0.0) 4 (8.7) 1 (2.4)

Bradycardia 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Cardiac failure congestive 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

Palpitations 1 (2.5) 0 (0.0) 0 (0.0) 4 (8.7) 1 (2.4)

Tachycardia 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

Congenital, familial and

genetic disorders 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Ichthyosis 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Ear and labyrinth disorders 4 (10.0) 2 (4.8) 3 (7.3) 5 (10.9) 0 (0.0)

Deafness unilateral 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Ear pain 1 (2.5) 1 (2.4) 1 (2.4) 3 (6.5) 0 (0.0)

(21)

- 583 -

n (%) n (%) n (%) n (%) n (%)

Ear and labyrinth disorders 4 (10.0) 2 (4.8) 3 (7.3) 5 (10.9) 0 (0.0)

Hypoacusis 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Tinnitus 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Vertigo 3 (7.5) 2 (4.8) 2 (4.9) 1 (2.2) 0 (0.0) Endocrine disorders 1 (2.5) 2 (4.8) 1 (2.4) 4 (8.7) 2 (4.8) Autoimmune thyroiditis 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Hyperthyroidism 0 (0.0) 0 (0.0) 0 (0.0) 2 (4.3) 0 (0.0) Hypothyroidism 1 (2.5) 1 (2.4) 1 (2.4) 3 (6.5) 2 (4.8) Eye disorders 4 (10.0) 3 (7.1) 8 (19.5) 10 (21.7) 4 (9.5) Blepharitis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Chalazion 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Conjunctival haemorrhage 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 1 (2.4)

(22)

- 584 -

n (%) n (%) n (%) n (%) n (%) Eye disorders 4 (10.0) 3 (7.1) 8 (19.5) 10 (21.7) 4 (9.5) Conjunctivitis 3 (7.5) 0 (0.0) 1 (2.4) 2 (4.3) 1 (2.4) Diplopia 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Dry eye 1 (2.5) 0 (0.0) 4 (9.8) 2 (4.3) 2 (4.8) Eczema eyelids 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Eye disorder 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Eye irritation 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Eye pain 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Eye pruritus 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Myopia 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Ocular hyperaemia 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Photophobia 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Presbyopia 0 (0.0) 0 (0.0) 0 (0.0) 2 (4.3) 0 (0.0) Retinal detachment 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

(23)

- 585 -

n (%) n (%) n (%) n (%) n (%) Eye disorders 4 (10.0) 3 (7.1) 8 (19.5) 10 (21.7) 4 (9.5) Retinal vascular thrombosis 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Vision blurred 0 (0.0) 0 (0.0) 2 (4.9) 0 (0.0) 0 (0.0)

Visual acuity reduced 2 (5.0) 1 (2.4) 0 (0.0) 2 (4.3) 0 (0.0)

Visual impairment 0 (0.0) 0 (0.0) 0 (0.0) 2 (4.3) 0 (0.0) Vitreous floaters 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Xerophthalmia 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Gastrointestinal disorders 32 (80.0) 35 (83.3) 32 (78.0) 41 (89.1) 23 (54.8) Abdominal discomfort 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Abdominal distension 1 (2.5) 0 (0.0) 2 (4.9) 2 (4.3) 1 (2.4) Abdominal pain 4 (10.0) 4 (9.5) 3 (7.3) 4 (8.7) 2 (4.8)

Abdominal pain lower 1 (2.5) 2 (4.8) 1 (2.4) 0 (0.0) 2 (4.8)

(24)

- 586 -

n (%) n (%) n (%) n (%) n (%) Gastrointestinal disorders 32 (80.0) 35 (83.3) 32 (78.0) 41 (89.1) 23 (54.8) Abdominal rigidity 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Abnormal faeces 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Anal fissure 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Aphthous stomatitis 2 (5.0) 3 (7.1) 1 (2.4) 0 (0.0) 2 (4.8) Chapped lips 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Cheilitis 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Constipation 2 (5.0) 0 (0.0) 1 (2.4) 3 (6.5) 0 (0.0) Crohn's disease 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Dental caries 1 (2.5) 1 (2.4) 1 (2.4) 1 (2.2) 0 (0.0) Diarrhoea 17 (42.5) 18 (42.9) 13 (31.7) 25 (54.3) 5 (11.9) Dry mouth 3 (7.5) 0 (0.0) 2 (4.9) 2 (4.3) 1 (2.4) Dyspepsia 13 (32.5) 9 (21.4) 9 (22.0) 6 (13.0) 5 (11.9) Dysphagia 1 (2.5) 1 (2.4) 2 (4.9) 0 (0.0) 0 (0.0)

(25)

- 587 -

n (%) n (%) n (%) n (%) n (%) Gastrointestinal disorders 32 (80.0) 35 (83.3) 32 (78.0) 41 (89.1) 23 (54.8) Epigastric discomfort 0 (0.0) 0 (0.0) 1 (2.4) 1 (2.2) 0 (0.0) Eructation 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Faeces discoloured 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Flatulence 1 (2.5) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Frequent bowel movements 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Gastritis 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Gastritis erosive 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Gastritis haemorrhagic 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Gastrointestinal disorder 2 (5.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Gastrointestinal pain 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Gastrooesophageal reflux disease 7 (17.5) 3 (7.1) 4 (9.8) 5 (10.9) 1 (2.4) Gingival bleeding 0 (0.0) 1 (2.4) 0 (0.0) 2 (4.3) 0 (0.0)

(26)

- 588 -

n (%) n (%) n (%) n (%) n (%) Gastrointestinal disorders 32 (80.0) 35 (83.3) 32 (78.0) 41 (89.1) 23 (54.8) Gingival pain 0 (0.0) 0 (0.0) 2 (4.9) 0 (0.0) 1 (2.4) Gingivitis 3 (7.5) 1 (2.4) 1 (2.4) 0 (0.0) 0 (0.0) Glossitis 0 (0.0) 1 (2.4) 0 (0.0) 1 (2.2) 0 (0.0) Glossodynia 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Haemorrhoidal haemorrhage 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Haemorrhoids 2 (5.0) 2 (4.8) 2 (4.9) 2 (4.3) 1 (2.4) Infrequent bowel movements 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Lip dry 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Mouth ulceration 1 (2.5) 1 (2.4) 1 (2.4) 3 (6.5) 3 (7.1) Nausea 20 (50.0) 16 (38.1) 13 (31.7) 29 (63.0) 6 (14.3) Oesophageal pain 0 (0.0) 0 (0.0) 2 (4.9) 0 (0.0) 1 (2.4) Oral disorder 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4)

(27)

- 589 -

n (%) n (%) n (%) n (%) n (%) Gastrointestinal disorders 32 (80.0) 35 (83.3) 32 (78.0) 41 (89.1) 23 (54.8) Portal hypertensive gastropathy 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Proctalgia 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Proctitis 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Reflux gastritis 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Retching 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Stomatitis 0 (0.0) 1 (2.4) 1 (2.4) 0 (0.0) 0 (0.0) Tongue ulceration 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Tooth disorder 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Toothache 1 (2.5) 0 (0.0) 2 (4.9) 1 (2.2) 2 (4.8) Upper gastrointestinal haemorrhage 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Varices oesophageal 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

(28)

- 590 -

n (%) n (%) n (%) n (%) n (%)

Gastrointestinal disorders 32 (80.0) 35 (83.3) 32 (78.0) 41 (89.1) 23 (54.8)

Vomiting 12 (30.0) 12 (28.6) 5 (12.2) 13 (28.3) 1 (2.4)

General disorders and administration site conditions 35 (87.5) 31 (73.8) 34 (82.9) 32 (69.6) 31 (73.8) Asthenia 9 (22.5) 11 (26.2) 10 (24.4) 10 (21.7) 10 (23.8) Chest discomfort 0 (0.0) 0 (0.0) 0 (0.0) 2 (4.3) 0 (0.0) Chest pain 1 (2.5) 2 (4.8) 0 (0.0) 2 (4.3) 0 (0.0) Chills 2 (5.0) 4 (9.5) 4 (9.8) 1 (2.2) 0 (0.0) Early satiety 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Face oedema 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Fatigue 19 (47.5) 16 (38.1) 18 (43.9) 13 (28.3) 10 (23.8) Feeling abnormal 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

(29)

- 591 -

n (%) n (%) n (%) n (%) n (%)

General disorders and administration site conditions

35 (87.5) 31 (73.8) 34 (82.9) 32 (69.6) 31 (73.8)

Feeling hot 0 (0.0) 0 (0.0) 3 (7.3) 0 (0.0) 0 (0.0)

General physical health

deterioration 0 (0.0) 1 (2.4) 0 (0.0) 1 (2.2) 0 (0.0)

Influenza like illness 10 (25.0) 9 (21.4) 14 (34.1) 10 (21.7) 9 (21.4)

Injection site erythema 2 (5.0) 2 (4.8) 2 (4.9) 1 (2.2) 0 (0.0)

Injection site

inflammation 0 (0.0) 0 (0.0) 2 (4.9) 0 (0.0) 0 (0.0)

Injection site pain 1 (2.5) 1 (2.4) 1 (2.4) 0 (0.0) 0 (0.0)

Injection site pruritus 2 (5.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Injection site reaction 0 (0.0) 1 (2.4) 1 (2.4) 1 (2.2) 1 (2.4)

Irritability 3 (7.5) 4 (9.5) 4 (9.8) 5 (10.9) 7 (16.7)

(30)

- 592 -

n (%) n (%) n (%) n (%) n (%)

General disorders and administration site conditions 35 (87.5) 31 (73.8) 34 (82.9) 32 (69.6) 31 (73.8) Mucosal dryness 3 (7.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Mucosal inflammation 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Oedema peripheral 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Pain 0 (0.0) 1 (2.4) 2 (4.9) 2 (4.3) 2 (4.8) Pyrexia 6 (15.0) 7 (16.7) 5 (12.2) 10 (21.7) 10 (23.8)

Sensation of foreign body 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

Spinal pain 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

Swelling 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

Thirst 1 (2.5) 1 (2.4) 1 (2.4) 0 (0.0) 0 (0.0)

(31)

- 593 -

n (%) n (%) n (%) n (%) n (%) Hepatobiliary disorders 1 (2.5) 3 (7.1) 2 (4.9) 1 (2.2) 0 (0.0) Cholelithiasis 0 (0.0) 0 (0.0) 1 (2.4) 1 (2.2) 0 (0.0) Hepatic cirrhosis 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Hepatomegaly 1 (2.5) 3 (7.1) 0 (0.0) 0 (0.0) 0 (0.0)

Immune system disorders 1 (2.5) 1 (2.4) 0 (0.0) 1 (2.2) 0 (0.0)

Anaphylactic reaction 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

Drug hypersensitivity 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Seasonal allergy 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

Abscess limb 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

Acute sinusitis 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

(32)

- 594 -

n (%) n (%) n (%) n (%) n (%)

Bronchitis 2 (5.0) 1 (2.4) 2 (4.9) 2 (4.3) 1 (2.4) Candidiasis 1 (2.5) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Cellulitis 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Conjunctivitis infective 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Conjunctivitis viral 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Cystitis 2 (5.0) 2 (4.8) 2 (4.9) 1 (2.2) 1 (2.4) Diarrhoea infectious 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Ear infection 0 (0.0) 0 (0.0) 1 (2.4) 1 (2.2) 0 (0.0) Eczema infected 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Folliculitis 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Gastroenteritis 0 (0.0) 2 (4.8) 1 (2.4) 1 (2.2) 0 (0.0) Gastroenteritis viral 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) H1N1 influenza 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

(33)

- 595 -

n (%) n (%) n (%) n (%) n (%)

Herpes ophthalmic 0 (0.0) 1 (2.4) 1 (2.4) 0 (0.0) 0 (0.0) Herpes simplex 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Herpes zoster 0 (0.0) 1 (2.4) 1 (2.4) 0 (0.0) 0 (0.0) Hordeolum 1 (2.5) 1 (2.4) 0 (0.0) 1 (2.2) 0 (0.0) Infected bites 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Influenza 0 (0.0) 0 (0.0) 1 (2.4) 1 (2.2) 0 (0.0) Intertrigo candida 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Localised infection 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Lower respiratory tract

infection 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

Lung infection 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

Nasopharyngitis 0 (0.0) 5 (11.9) 3 (7.3) 4 (8.7) 2 (4.8)

(34)

- 596 -

n (%) n (%) n (%) n (%) n (%)

Oral herpes 1 (2.5) 0 (0.0) 1 (2.4) 3 (6.5) 3 (7.1) Otitis externa 1 (2.5) 2 (4.8) 1 (2.4) 0 (0.0) 0 (0.0) Otitis media 1 (2.5) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Pertussis 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Pharyngitis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Pharyngitis streptococcal 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Pneumonia 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Pyelonephritis 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Pyelonephritis acute 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Rhinitis 0 (0.0) 0 (0.0) 2 (4.9) 0 (0.0) 1 (2.4) Sinusitis 2 (5.0) 2 (4.8) 1 (2.4) 4 (8.7) 1 (2.4) Skin infection 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Tinea pedis 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

(35)

- 597 -

n (%) n (%) n (%) n (%) n (%)

Tonsillitis 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

Tooth abscess 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Tooth infection 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

infection 1 (2.5) 5 (11.9) 2 (4.9) 2 (4.3) 4 (9.5)

Urinary tract infection 2 (5.0) 1 (2.4) 0 (0.0) 2 (4.3) 1 (2.4)

Urinary tract infection

bacterial 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Vaginal infection 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4)

Vaginitis bacterial 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

Viral infection 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

(36)

- 598 -

n (%) n (%) n (%) n (%) n (%)

Vulvovaginal mycotic

infection 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Wound infection 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

procedural complications 2 (5.0) 5 (11.9) 7 (17.1) 6 (13.0) 7 (16.7) Accidental overdose 0 (0.0) 1 (2.4) 1 (2.4) 0 (0.0) 1 (2.4) Animal bite 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Burn oesophageal 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Carbon monoxide poisoning 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Contusion 1 (2.5) 1 (2.4) 0 (0.0) 2 (4.3) 0 (0.0) Excoriation 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 2 (4.8) Fall 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

(37)

- 599 -

n (%) n (%) n (%) n (%) n (%)

procedural complications 2 (5.0) 5 (11.9) 7 (17.1) 6 (13.0) 7 (16.7) Femur fracture 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Foot fracture 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Joint sprain 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Laceration 0 (0.0) 1 (2.4) 0 (0.0) 2 (4.3) 0 (0.0) Limb injury 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Muscle strain 1 (2.5) 0 (0.0) 0 (0.0) 1 (2.2) 1 (2.4) Overdose 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Post-traumatic pain 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Road traffic accident 0 (0.0) 1 (2.4) 1 (2.4) 0 (0.0) 1 (2.4)

Skeletal injury 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

Thermal burn 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4)

(38)

- 600 -

n (%) n (%) n (%) n (%) n (%) Investigations 6 (15.0) 5 (11.9) 7 (17.1) 9 (19.6) 3 (7.1) Alanine aminotransferase increased 0 (0.0) 0 (0.0) 1 (2.4) 1 (2.2) 1 (2.4) Aspartate aminotransferase increased 0 (0.0) 0 (0.0) 1 (2.4) 1 (2.2) 1 (2.4)

Blood bilirubin increased 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Blood creatine phosphokinase increased 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Blood creatinine increased 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Blood lactate dehydrogenase increased 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Blood potassium increased 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Blood thyroid stimulating

(39)

- 601 -

n (%) n (%) n (%) n (%) n (%)

Investigations 6 (15.0) 5 (11.9) 7 (17.1) 9 (19.6) 3 (7.1)

Blood thyroid stimulating

hormone increased 1 (2.5) 1 (2.4) 0 (0.0) 2 (4.3) 0 (0.0)

Blood urine present 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Electrocardiogram QT

prolonged 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

Electrocardiogram T

wave amplitude increased 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

Gastric pH decreased 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Haemoglobin decreased 0 (0.0) 2 (4.8) 1 (2.4) 0 (0.0) 1 (2.4)

Liver function test

abnormal 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Neutrophil count

decreased 0 (0.0) 2 (4.8) 1 (2.4) 0 (0.0) 0 (0.0)

Platelet count decreased 0 (0.0) 1 (2.4) 0 (0.0) 1 (2.2) 0 (0.0)

(40)

- 602 -

n (%) n (%) n (%) n (%) n (%)

Investigations 6 (15.0) 5 (11.9) 7 (17.1) 9 (19.6) 3 (7.1)

Weight increased 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

decreased 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

disorders 9 (22.5) 15 (35.7) 10 (24.4) 8 (17.4) 3 (7.1) Decreased appetite 8 (20.0) 13 (31.0) 8 (19.5) 5 (10.9) 3 (7.1) Dehydration 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Diabetes mellitus 0 (0.0) 0 (0.0) 0 (0.0) 2 (4.3) 0 (0.0) Fat intolerance 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Hyperuricaemia 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Hypokalaemia 1 (2.5) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Hypomagnesaemia 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

(41)

- 603 -

n (%) n (%) n (%) n (%) n (%)

disorders 9 (22.5) 15 (35.7) 10 (24.4) 8 (17.4) 3 (7.1)

Type 2 diabetes mellitus 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Musculoskeletal and

connective tissue disorders 18 (45.0) 19 (45.2) 21 (51.2) 23 (50.0) 21 (50.0)

Amyotrophy 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Arthralgia 7 (17.5) 6 (14.3) 5 (12.2) 8 (17.4) 7 (16.7) Back pain 5 (12.5) 3 (7.1) 3 (7.3) 6 (13.0) 2 (4.8) Bone pain 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Costochondritis 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Flank pain 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Muscle fatigue 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 1 (2.4) Muscle spasms 1 (2.5) 2 (4.8) 4 (9.8) 2 (4.3) 1 (2.4)

(42)

- 604 -

n (%) n (%) n (%) n (%) n (%)

Musculoskeletal and

connective tissue disorders 18 (45.0) 19 (45.2) 21 (51.2) 23 (50.0) 21 (50.0)

Muscle twitching 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Muscular weakness 0 (0.0) 1 (2.4) 1 (2.4) 0 (0.0) 0 (0.0) Musculoskeletal chest pain 0 (0.0) 1 (2.4) 1 (2.4) 0 (0.0) 1 (2.4) Musculoskeletal pain 1 (2.5) 1 (2.4) 3 (7.3) 5 (10.9) 1 (2.4) Musculoskeletal stiffness 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Myalgia 4 (10.0) 4 (9.5) 13 (31.7) 11 (23.9) 9 (21.4) Myositis 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Neck pain 1 (2.5) 3 (7.1) 1 (2.4) 0 (0.0) 1 (2.4) Osteoporosis 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Pain in extremity 0 (0.0) 1 (2.4) 2 (4.9) 2 (4.3) 2 (4.8) Periarthritis 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Synovial cyst 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

(43)

- 605 -

n (%) n (%) n (%) n (%) n (%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

0 (0.0) 0 (0.0) 1 (2.4) 1 (2.2) 0 (0.0)

Malignant melanoma 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Seborrhoeic keratosis 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

Ageusia 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Amnesia 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Carotid arteriosclerosis 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Carpal tunnel syndrome 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Disturbance in attention 1 (2.5) 1 (2.4) 1 (2.4) 3 (6.5) 1 (2.4)

Dizziness 3 (7.5) 5 (11.9) 4 (9.8) 7 (15.2) 5 (11.9)

(44)

- 606 -

n (%) n (%) n (%) n (%) n (%)

Dysgeusia 4 (10.0) 3 (7.1) 4 (9.8) 1 (2.2) 1 (2.4) Headache 16 (40.0) 11 (26.2) 21 (51.2) 16 (34.8) 13 (31.0) Hyperaesthesia 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Hypoaesthesia 0 (0.0) 1 (2.4) 0 (0.0) 1 (2.2) 0 (0.0) Lethargy 0 (0.0) 0 (0.0) 1 (2.4) 1 (2.2) 0 (0.0) Memory impairment 0 (0.0) 0 (0.0) 1 (2.4) 1 (2.2) 0 (0.0) Migraine 1 (2.5) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Neuralgia 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 1 (2.4) Paraesthesia 2 (5.0) 0 (0.0) 4 (9.8) 1 (2.2) 0 (0.0) Parosmia 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Presyncope 1 (2.5) 1 (2.4) 1 (2.4) 0 (0.0) 0 (0.0)

Restless legs syndrome 1 (2.5) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

(45)

- 607 -

n (%) n (%) n (%) n (%) n (%)

Sinus headache 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Somnolence 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 1 (2.4) Syncope 0 (0.0) 2 (4.8) 2 (4.9) 0 (0.0) 0 (0.0) Tension headache 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 1 (2.4) Psychiatric disorders 19 (47.5) 20 (47.6) 24 (58.5) 25 (54.3) 17 (40.5) Abnormal dreams 1 (2.5) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Affect lability 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Affective disorder 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Aggression 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 2 (4.8) Anxiety 4 (10.0) 3 (7.1) 1 (2.4) 2 (4.3) 1 (2.4) Apathy 0 (0.0) 0 (0.0) 1 (2.4) 1 (2.2) 0 (0.0) Bruxism 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

(46)

- 608 -

n (%) n (%) n (%) n (%) n (%) Psychiatric disorders 19 (47.5) 20 (47.6) 24 (58.5) 25 (54.3) 17 (40.5) Completed suicide 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Depressed mood 1 (2.5) 3 (7.1) 6 (14.6) 2 (4.3) 3 (7.1) Depression 3 (7.5) 7 (16.7) 9 (22.0) 9 (19.6) 1 (2.4) Dysthymic disorder 1 (2.5) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Emotional disorder 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Insomnia 7 (17.5) 7 (16.7) 12 (29.3) 6 (13.0) 10 (23.8) Libido decreased 0 (0.0) 1 (2.4) 1 (2.4) 0 (0.0) 0 (0.0) Libido disorder 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Loss of libido 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Major depression 1 (2.5) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Mood altered 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Mood swings 2 (5.0) 2 (4.8) 0 (0.0) 1 (2.2) 0 (0.0) Nervousness 0 (0.0) 0 (0.0) 2 (4.9) 0 (0.0) 0 (0.0)

(47)

- 609 -

n (%) n (%) n (%) n (%) n (%) Psychiatric disorders 19 (47.5) 20 (47.6) 24 (58.5) 25 (54.3) 17 (40.5) Panic attack 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Sleep disorder 7 (17.5) 5 (11.9) 4 (9.8) 8 (17.4) 4 (9.5) Suicidal ideation 1 (2.5) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

Chromaturia 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Dysuria 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Haematuria 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Micturition urgency 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Nephrolithiasis 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 1 (2.4) Nocturia 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Pollakiuria 0 (0.0) 0 (0.0) 2 (4.9) 0 (0.0) 1 (2.4) Polyuria 0 (0.0) 0 (0.0) 2 (4.9) 0 (0.0) 0 (0.0)

(48)

- 610 -

n (%) n (%) n (%) n (%) n (%)

Urethral pain 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

Urinary retention 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0)

breast disorders 0 (0.0) 0 (0.0) 5 (12.2) 3 (6.5) 0 (0.0) Erectile dysfunction 0 (0.0) 0 (0.0) 2 (4.9) 1 (2.2) 0 (0.0) Menorrhagia 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Menstrual discomfort 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Metrorrhagia 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Ovarian cyst 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Vaginal haemorrhage 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Vulvovaginal pruritus 0 (0.0) 0 (0.0) 1 (2.4) 1 (2.2) 0 (0.0)

(49)

- 611 -

n (%) n (%) n (%) n (%) n (%)

Respiratory, thoracic and

mediastinal disorders 13 (32.5) 22 (52.4) 18 (43.9) 19 (41.3) 16 (38.1) Asthma 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Cough 5 (12.5) 14 (33.3) 5 (12.2) 13 (28.3) 11 (26.2) Dry throat 0 (0.0) 0 (0.0) 1 (2.4) 2 (4.3) 0 (0.0) Dysphonia 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Dyspnoea 2 (5.0) 6 (14.3) 7 (17.1) 7 (15.2) 4 (9.5) Dyspnoea exertional 2 (5.0) 3 (7.1) 1 (2.4) 3 (6.5) 0 (0.0) Epistaxis 3 (7.5) 1 (2.4) 3 (7.3) 2 (4.3) 1 (2.4) Haemoptysis 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Increased viscosity of bronchial secretion 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Nasal congestion 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 1 (2.4) Nasal dryness 1 (2.5) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

(50)

- 612 -

n (%) n (%) n (%) n (%) n (%)

mediastinal disorders 13 (32.5) 22 (52.4) 18 (43.9) 19 (41.3) 16 (38.1) Nocturnal dyspnoea 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Oropharyngeal pain 2 (5.0) 1 (2.4) 3 (7.3) 5 (10.9) 2 (4.8) Painful respiration 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Pleural effusion 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Productive cough 1 (2.5) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Rhinitis allergic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Rhinorrhoea 0 (0.0) 0 (0.0) 1 (2.4) 2 (4.3) 0 (0.0) Throat irritation 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

congestion 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Vocal cord inflammation 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

(51)

- 613 -

n (%) n (%) n (%) n (%) n (%)

mediastinal disorders 13 (32.5) 22 (52.4) 18 (43.9) 19 (41.3) 16 (38.1)

Yawning 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0)

tissue disorders 23 (57.5) 26 (61.9) 26 (63.4) 33 (71.7) 21 (50.0) Alopecia 6 (15.0) 4 (9.5) 8 (19.5) 8 (17.4) 3 (7.1) Blister 0 (0.0) 2 (4.8) 0 (0.0) 0 (0.0) 0 (0.0) Chloasma 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 1 (2.4) Dermal cyst 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Dermatitis 2 (5.0) 2 (4.8) 4 (9.8) 3 (6.5) 0 (0.0) Dermatitis allergic 1 (2.5) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Dermatomyositis 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Drug eruption 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

(52)

- 614 -

n (%) n (%) n (%) n (%) n (%)

tissue disorders 23 (57.5) 26 (61.9) 26 (63.4) 33 (71.7) 21 (50.0) Dry skin 8 (20.0) 5 (11.9) 5 (12.2) 7 (15.2) 6 (14.3) Ecchymosis 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Eczema 2 (5.0) 3 (7.1) 4 (9.8) 5 (10.9) 5 (11.9) Erythema 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Hair disorder 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Hyperhidrosis 0 (0.0) 2 (4.8) 3 (7.3) 1 (2.2) 1 (2.4) Hyperkeratosis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Increased tendency to bruise 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Madarosis 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Nail discolouration 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Nail disorder 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) Night sweats 0 (0.0) 0 (0.0) 2 (4.9) 0 (0.0) 0 (0.0)

(53)

- 615 -

n (%) n (%) n (%) n (%) n (%)

tissue disorders 23 (57.5) 26 (61.9) 26 (63.4) 33 (71.7) 21 (50.0) Onychoclasis 0 (0.0) 0 (0.0) 0 (0.0) 2 (4.3) 0 (0.0) Pain of skin 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 1 (2.4) Papule 1 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Photosensitivity reaction 0 (0.0) 3 (7.1) 0 (0.0) 0 (0.0) 0 (0.0) Pruritus 14 (35.0) 13 (31.0) 12 (29.3) 14 (30.4) 9 (21.4) Pruritus generalised 2 (5.0) 2 (4.8) 1 (2.4) 1 (2.2) 2 (4.8) Purpura 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Rash 6 (15.0) 6 (14.3) 6 (14.6) 14 (30.4) 8 (19.0) Rash erythematous 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (4.8) Rash papular 0 (0.0) 2 (4.8) 1 (2.4) 0 (0.0) 1 (2.4) Rash pruritic 0 (0.0) 0 (0.0) 1 (2.4) 2 (4.3) 0 (0.0) Seborrhoeic dermatitis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4)

(54)

- 616 -

n (%) n (%) n (%) n (%) n (%)

tissue disorders 23 (57.5) 26 (61.9) 26 (63.4) 33 (71.7) 21 (50.0) Skin exfoliation 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Skin fissures 1 (2.5) 2 (4.8) 0 (0.0) 1 (2.2) 0 (0.0) Skin induration 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0) Skin ulcer 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Swelling face 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Trichorrhexis 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Urticaria 0 (0.0) 1 (2.4) 0 (0.0) 1 (2.2) 1 (2.4) Urticaria physical 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) Vitiligo 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Xeroderma 0 (0.0) 1 (2.4) 1 (2.4) 2 (4.3) 0 (0.0) Vascular disorders 0 (0.0) 3 (7.1) 4 (9.8) 5 (10.9) 1 (2.4)

(55)

- 617 -

n (%) n (%) n (%) n (%) n (%) Vascular disorders 0 (0.0) 3 (7.1) 4 (9.8) 5 (10.9) 1 (2.4) Flushing 0 (0.0) 0 (0.0) 0 (0.0) 2 (4.3) 0 (0.0) Haematoma 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.2) 0 (0.0) Hot flush 0 (0.0) 1 (2.4) 1 (2.4) 1 (2.2) 0 (0.0) Hypertension 0 (0.0) 1 (2.4) 2 (4.9) 0 (0.0) 1 (2.4) Orthostatic hypotension 0 (0.0) 0 (0.0) 1 (2.4) 1 (2.2) 0 (0.0) Varicose vein 0 (0.0) 1 (2.4) 0 (0.0) 0 (0.0) 0 (0.0)

Every patient is counted a single time for each applicable row and column.

A system organ class or specific adverse event appears on this report only if its incidence in one or more of the columns meets the incidence criterion in the report title, after rounding.

(56)

- 618 -

With one or more

drug-related adverse events Overall 15 (78.9) 15 (83.3) 18 (90.0) 15 (83.3) 17 (89.5)

MK 4 (21.1) 3 (16.7) 5 (25.0) 3 (16.7) 6 (31.6)

P+R 15 (78.9) 13 (72.2) 14 (70.0) 12 (66.7) 15 (78.9)

MK+P+R 8 (42.1) 8 (44.4) 11 (55.0) 12 (66.7) 8 (42.1)

Blood and lymphatic

system disorders Overall 3 (15.8) 2 (11.1) 2 (10.0) 0 (0.0) 4 (21.1)

P+R 3 (15.8) 2 (11.1) 1 (5.0) 0 (0.0) 4 (21.1)

MK+P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Anaemia Overall 2 (10.5) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

(57)

- 619 -

Leukopenia Overall 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Neutropenia Overall 1 (5.3) 1 (5.6) 2 (10.0) 0 (0.0) 2 (10.5) P+R 1 (5.3) 1 (5.6) 1 (5.0) 0 (0.0) 2 (10.5) MK+P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Pancytopenia Overall 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Cardiac disorders Overall 1 (5.3) 0 (0.0) 1 (5.0) 0 (0.0) 1 (5.3)

P+R 1 (5.3) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Angina pectoris Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

(58)

- 620 -

Palpitations Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 1 (5.3) P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) MK+P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Tachycardia Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Eye disorders Overall 4 (21.1) 3 (16.7) 2 (10.0) 1 (5.6) 2 (10.5)

P+R 3 (15.8) 2 (11.1) 2 (10.0) 1 (5.6) 2 (10.5)

MK+P+R 2 (10.5) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Dry eye Overall 1 (5.3) 1 (5.6) 0 (0.0) 1 (5.6) 1 (5.3)

P+R 0 (0.0) 1 (5.6) 0 (0.0) 1 (5.6) 1 (5.3)

MK+P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

(59)

- 621 -

Eye irritation P+R 1 (5.3) 0 (0.0) 1 (5.0) 0 (0.0) 1 (5.3)

MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Eye pain Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Eye pruritus Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

MK+P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Eye swelling Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Photopsia Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

(60)

- 622 -

Vision blurred P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Xerophthalmia Overall 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0)

P+R 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0)

Gastrointestinal disorders Overall 12 (63.2) 11 (61.1) 13 (65.0) 9 (50.0) 11 (57.9)

MK 2 (10.5) 2 (11.1) 5 (25.0) 2 (11.1) 5 (26.3)

P+R 6 (31.6) 3 (16.7) 5 (25.0) 2 (11.1) 4 (21.1)

MK+P+R 6 (31.6) 7 (38.9) 8 (40.0) 7 (38.9) 6 (31.6)

Abdominal discomfort Overall 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0)

Abdominal pain Overall 0 (0.0) 0 (0.0) 1 (5.0) 1 (5.6) 0 (0.0)

P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

(61)

- 623 -

Abdominal pain upper Overall 1 (5.3) 1 (5.6) 2 (10.0) 1 (5.6) 1 (5.3)

MK 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) P+R 1 (5.3) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0) MK+P+R 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 1 (5.3) Constipation Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Diarrhoea Overall 4 (21.1) 1 (5.6) 6 (30.0) 2 (11.1) 3 (15.8) MK 1 (5.3) 0 (0.0) 1 (5.0) 0 (0.0) 1 (5.3) P+R 1 (5.3) 0 (0.0) 3 (15.0) 0 (0.0) 1 (5.3) MK+P+R 2 (10.5) 1 (5.6) 2 (10.0) 2 (11.1) 1 (5.3)

Dry mouth Overall 0 (0.0) 1 (5.6) 2 (10.0) 2 (11.1) 1 (5.3)

MK 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

(62)

- 624 -

Dry mouth MK+P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Dyspepsia Overall 4 (21.1) 3 (16.7) 0 (0.0) 1 (5.6) 3 (15.8) MK 1 (5.3) 2 (11.1) 0 (0.0) 0 (0.0) 2 (10.5) P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) MK+P+R 2 (10.5) 1 (5.6) 0 (0.0) 1 (5.6) 0 (0.0) Flatulence Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) Gastrooesophageal

reflux disease Overall 1 (5.3) 2 (11.1) 0 (0.0) 1 (5.6) 0 (0.0)

P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

MK+P+R 1 (5.3) 1 (5.6) 0 (0.0) 1 (5.6) 0 (0.0)

(63)

- 625 -

Glossodynia MK+P+R 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

Lip dry Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

MK+P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Nausea Overall 5 (26.3) 4 (22.2) 7 (35.0) 6 (33.3) 6 (31.6)

MK 0 (0.0) 0 (0.0) 3 (15.0) 1 (5.6) 1 (5.3)

P+R 3 (15.8) 2 (11.1) 1 (5.0) 1 (5.6) 2 (10.5)

MK+P+R 2 (10.5) 2 (11.1) 4 (20.0) 4 (22.2) 3 (15.8)

Oesophageal pain Overall 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Stomatitis Overall 1 (5.3) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

(64)

- 626 -

Vomiting Overall 0 (0.0) 0 (0.0) 6 (30.0) 3 (16.7) 2 (10.5) MK 0 (0.0) 0 (0.0) 3 (15.0) 1 (5.6) 1 (5.3) P+R 0 (0.0) 0 (0.0) 2 (10.0) 0 (0.0) 0 (0.0) MK+P+R 0 (0.0) 0 (0.0) 2 (10.0) 2 (11.1) 1 (5.3)

General disorders and administration site conditions Overall 10 (52.6) 8 (44.4) 11 (55.0) 10 (55.6) 10 (52.6) MK 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) P+R 9 (47.4) 7 (38.9) 11 (55.0) 9 (50.0) 9 (47.4) MK+P+R 3 (15.8) 1 (5.6) 1 (5.0) 1 (5.6) 1 (5.3) Asthenia Overall 2 (10.5) 1 (5.6) 2 (10.0) 3 (16.7) 1 (5.3) P+R 1 (5.3) 1 (5.6) 2 (10.0) 3 (16.7) 1 (5.3) MK+P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

(65)

- 627 -

Chest pain Overall 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

MK+P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Chills Overall 2 (10.5) 1 (5.6) 1 (5.0) 0 (0.0) 3 (15.8) P+R 2 (10.5) 0 (0.0) 1 (5.0) 0 (0.0) 3 (15.8) MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) Discomfort Overall 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) MK 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) Fatigue Overall 6 (31.6) 3 (16.7) 6 (30.0) 2 (11.1) 1 (5.3) P+R 4 (21.1) 3 (16.7) 5 (25.0) 2 (11.1) 1 (5.3) MK+P+R 2 (10.5) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Feeling cold Overall 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

(66)

- 628 -

Feeling of body

temperature change Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Influenza like illness Overall 4 (21.1) 4 (22.2) 4 (20.0) 4 (22.2) 5 (26.3)

P+R 4 (21.1) 4 (22.2) 4 (20.0) 3 (16.7) 5 (26.3)

MK+P+R 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

Injection site erythema Overall 0 (0.0) 1 (5.6) 2 (10.0) 1 (5.6) 0 (0.0)

P+R 0 (0.0) 1 (5.6) 2 (10.0) 1 (5.6) 0 (0.0)

Injection site reaction Overall 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0)

P+R 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0)

Irritability Overall 2 (10.5) 2 (11.1) 1 (5.0) 0 (0.0) 1 (5.3)

(67)

- 629 -

Pain Overall 0 (0.0) 0 (0.0) 3 (15.0) 0 (0.0) 0 (0.0) P+R 0 (0.0) 0 (0.0) 2 (10.0) 0 (0.0) 0 (0.0) MK+P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Pyrexia Overall 1 (5.3) 0 (0.0) 1 (5.0) 1 (5.6) 3 (15.8) P+R 1 (5.3) 0 (0.0) 1 (5.0) 1 (5.6) 3 (15.8)

Infections and infestations Overall 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 1 (5.3)

P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 1 (5.3)

MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Bronchitis Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Herpes virus infection Overall 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

(68)

- 630 -

Viral infection Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) Investigations Overall 2 (10.5) 3 (16.7) 3 (15.0) 2 (11.1) 2 (10.5) P+R 1 (5.3) 2 (11.1) 2 (10.0) 2 (11.1) 2 (10.5) MK+P+R 1 (5.3) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0) Blood bilirubin increased Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) MK+P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) Body temperature increased Overall 1 (5.3) 1 (5.6) 0 (0.0) 1 (5.6) 1 (5.3) P+R 1 (5.3) 1 (5.6) 0 (0.0) 1 (5.6) 1 (5.3)

Haemoglobin decreased Overall 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

(69)

- 631 -

Neutrophil count decreased Overall 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0) P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0) MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Weight decreased Overall 1 (5.3) 0 (0.0) 2 (10.0) 0 (0.0) 0 (0.0)

P+R 0 (0.0) 0 (0.0) 2 (10.0) 0 (0.0) 0 (0.0)

MK+P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

decreased Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 1 (5.3)

P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 1 (5.3)

disorders Overall 2 (10.5) 3 (16.7) 5 (25.0) 1 (5.6) 1 (5.3)

P+R 2 (10.5) 2 (11.1) 4 (20.0) 0 (0.0) 0 (0.0)

(70)

- 632 -

Decreased appetite Overall 2 (10.5) 3 (16.7) 5 (25.0) 1 (5.6) 1 (5.3)

P+R 2 (10.5) 2 (11.1) 4 (20.0) 0 (0.0) 0 (0.0)

MK+P+R 1 (5.3) 1 (5.6) 1 (5.0) 1 (5.6) 1 (5.3)

Musculoskeletal and

connective tissue disorders Overall 3 (15.8) 5 (27.8) 2 (10.0) 3 (16.7) 2 (10.5)

MK 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) P+R 3 (15.8) 3 (16.7) 2 (10.0) 2 (11.1) 2 (10.5) MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 1 (5.6) 0 (0.0) Arthralgia Overall 0 (0.0) 3 (16.7) 2 (10.0) 1 (5.6) 0 (0.0) MK 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) P+R 0 (0.0) 2 (11.1) 2 (10.0) 1 (5.6) 0 (0.0)

Back pain Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 2 (10.5)

(71)

- 633 -

Muscular weakness Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Musculoskeletal chest

pain Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Musculoskeletal pain Overall 0 (0.0) 2 (11.1) 0 (0.0) 2 (11.1) 0 (0.0)

P+R 0 (0.0) 1 (5.6) 0 (0.0) 1 (5.6) 0 (0.0)

MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 1 (5.6) 0 (0.0)

Myalgia Overall 2 (10.5) 0 (0.0) 1 (5.0) 1 (5.6) 0 (0.0)

P+R 2 (10.5) 0 (0.0) 1 (5.0) 1 (5.6) 0 (0.0)

Pain in extremity Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

(72)

- 634 -

Nervous system disorders Overall 6 (31.6) 5 (27.8) 9 (45.0) 10 (55.6) 5 (26.3)

MK 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

P+R 4 (21.1) 2 (11.1) 7 (35.0) 3 (16.7) 2 (10.5)

MK+P+R 2 (10.5) 3 (16.7) 2 (10.0) 7 (38.9) 2 (10.5)

Disturbance in attention Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) Dizziness Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) Dysgeusia Overall 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 1 (5.3) MK 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) P+R 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0) Headache Overall 6 (31.6) 3 (16.7) 8 (40.0) 7 (38.9) 2 (10.5)

(73)

- 635 -

Headache P+R 4 (21.1) 1 (5.6) 7 (35.0) 2 (11.1) 0 (0.0) MK+P+R 2 (10.5) 2 (11.1) 1 (5.0) 5 (27.8) 2 (10.5) Hyperaesthesia Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Memory impairment Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Migraine Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Paraesthesia Overall 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

(74)

- 636 -

Restless legs syndrome P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Somnolence Overall 0 (0.0) 0 (0.0) 0 (0.0) 2 (11.1) 1 (5.3)

P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

MK+P+R 0 (0.0) 0 (0.0) 0 (0.0) 2 (11.1) 0 (0.0)

Psychiatric disorders Overall 5 (26.3) 5 (27.8) 2 (10.0) 5 (27.8) 4 (21.1)

P+R 3 (15.8) 4 (22.2) 2 (10.0) 4 (22.2) 3 (15.8)

MK+P+R 3 (15.8) 2 (11.1) 0 (0.0) 1 (5.6) 1 (5.3)

Abnormal dreams Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Anxiety Overall 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

(75)

- 637 -

Depressed mood Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Depression Overall 2 (10.5) 1 (5.6) 1 (5.0) 1 (5.6) 0 (0.0)

P+R 2 (10.5) 0 (0.0) 1 (5.0) 1 (5.6) 0 (0.0)

MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Initial insomnia Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

MK+P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Insomnia Overall 2 (10.5) 4 (22.2) 1 (5.0) 3 (16.7) 2 (10.5)

P+R 1 (5.3) 4 (22.2) 1 (5.0) 2 (11.1) 2 (10.5)

MK+P+R 1 (5.3) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

Libido decreased Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

(76)

- 638 -

Mood swings Overall 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

P+R 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

Nervousness Overall 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

MK+P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Restlessness Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

MK+P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Sleep disorder Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Renal and urinary

disorders Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

(77)

- 639 -

Pollakiuria MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

breast disorders Overall 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 0 (0.0)

P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Erectile dysfunction Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Menstrual disorder Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

mediastinal disorders Overall 2 (10.5) 2 (11.1) 1 (5.0) 3 (16.7) 2 (10.5)

(78)

- 640 -

mediastinal disorders MK+P+R 0 (0.0) 1 (5.6) 1 (5.0) 0 (0.0) 1 (5.3)

Cough Overall 0 (0.0) 1 (5.6) 0 (0.0) 1 (5.6) 0 (0.0)

P+R 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0)

Dry throat Overall 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

P+R 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0) Dyspnoea Overall 2 (10.5) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) P+R 2 (10.5) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) MK+P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) Epistaxis Overall 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3) P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

(79)

- 641 -

Nasal dryness Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Oropharyngeal pain Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 1 (5.3)

P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Productive cough Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Rhinorrhoea Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Throat irritation Overall 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 0 (0.0)

(80)

- 642 -

tissue disorders Overall 7 (36.8) 7 (38.9) 4 (20.0) 4 (22.2) 5 (26.3)

MK 2 (10.5) 1 (5.6) 0 (0.0) 1 (5.6) 0 (0.0)

P+R 6 (31.6) 5 (27.8) 3 (15.0) 3 (16.7) 5 (26.3)

MK+P+R 1 (5.3) 2 (11.1) 1 (5.0) 0 (0.0) 0 (0.0)

Alopecia Overall 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

P+R 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.3)

Dry skin Overall 3 (15.8) 1 (5.6) 0 (0.0) 1 (5.6) 1 (5.3)

P+R 3 (15.8) 1 (5.6) 0 (0.0) 1 (5.6) 1 (5.3)

Eczema Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 1 (5.3)

P+R 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 1 (5.3)

(81)

- 643 -

Erythema MK 1 (5.3) 1 (5.6) 0 (0.0) 1 (5.6) 0 (0.0)

Night sweats Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Pruritus Overall 3 (15.8) 2 (11.1) 0 (0.0) 1 (5.6) 1 (5.3) P+R 2 (10.5) 2 (11.1) 0 (0.0) 1 (5.6) 1 (5.3) MK+P+R 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Rash Overall 2 (10.5) 2 (11.1) 2 (10.0) 2 (11.1) 1 (5.3) P+R 1 (5.3) 0 (0.0) 2 (10.0) 2 (11.1) 1 (5.3) MK+P+R 1 (5.3) 2 (11.1) 0 (0.0) 0 (0.0) 0 (0.0)

Rash papular Overall 0 (0.0) 1 (5.6) 0 (0.0) 0 (0.0) 1 (5.3)

(82)

- 644 -

Rash vesicular Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

MK+P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Skin burning sensation Overall 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

P+R 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) 0 (0.0)

Skin reaction Overall 1 (5.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

3) ベースラインからの個々の変化量 付録 2.7.4:30 主な臨床検査値の推移 (045 試験 )( 続き ) Individual Change From Baseline in Creatinine (mg/dl) Over Time (All Patients as Treated) 24

- 563 -

in N

eutr

ophi

ls (/

mic

roL)

Cha

nge F

rom

Bas

elin

e

- 564 -

in C

reat

inine

(m

g/dL

)

Cha

nge F

rom

Bas

elin

e

- 565 -

in A

spa

rtat

e A

min

otran

sfer

ase (

IU/L

)

Cha

nge F

rom

Bas

elin

e

- 566 -

in A

lani

ne A

mino

tran

sfer

ase

(IU

/L)

Cha

nge F

rom

Bas

elin

e

- 567 -

in B

ilirub

in (m

g/dL)

Cha

nge F

rom

Bas

elin

e

- 568 -

- 569 -

- 570 -

- 571 -

- 572 -

- 573 -

- 574 -

- 575 -

- 576 -

3) ベースラインからの個々の変化量付録 2.7.4:30 主な臨床検査値の推移 (045 試験 )( 続き ) Individual Change From Baseline in Creatinine (mg/dl) Over Time (All Patients as Treated) 24