Hematological Safety of Metamizole: Retrospective Analysis of WHO and Swiss Spontaneous Safety Reports

Lea S Blaser1, Alexandra Tramonti1, Pascal Egger2, Manuel Haschke1, Stephan Krähenbühl1,Alexandra E Rätz Bravo1,3

1Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland

2Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland

3Regional Pharmacovigilance Center, University Hospital, Basel, Switzerland

Corresponding author

Stephan Krähenbühl, MD, PhD

Clinical Pharmacology & Toxicology

University Hospital

Hebelstrasse 2

CH-4031 Basel

Phone: ++41 61 265 47 15

Fax: ++ 41 265 45 60

E-mail:

Supplementary Table 1.

Age categories retrieved from international and the subgroup of Swiss individual case safety reports of metamizole-associated hematological adverse drug reactions between 1968-01/2013 and 1991-2012, respectively

Age categories at ADR diagnosis [number (%)] / Total international ICSR
(n=1319) / Total Swiss ICSR
(n=77)
< 10 years / 22 (2) / 1 (1)
10 – 19 years / 81 (6) / 2 (3)
20 – 29 years / 163 (12) / 11 (14)
30 – 39 years / 100 (8) / 6 (8)
40 – 49 years / 164 (12) / 10 (13)
50 – 59 years / 174 (13) / 9 (12)
60 – 69 years / 234 (18) / 13 (17)
70 – 79 years / 239 (18) / 15 (19)
> 80 years / 142 (11) / 10 (13)
ADR adverse drug reaction, ICSR individual case safety reports, n number

Supplementary Table 2.

Drug classes of co-suspected drugs retrieved from the subgroup of Swiss individual case safety reports of metamizole-associated hematological adverse drug reactions between 1991-2012

Drug classes of co-suspected drugs according to ATC codes [number] / Total Swiss ICSR
(n=77)
Antiinfectivesforsystemicuse / 28
Nervoussystem / 23
Cardiovascularsystem / 14
Others / 13
Antineoplastic agents and Immunomodulating agents / 10
Alimentarytractandmetabolism / 10
Musculo – skeletalsystem / 9
ICSR individual case safety reports, n number

Supplementary Table 3.

Most prevalent underlying diseases expressed asICD-10 codes among 65 Swiss metamizole-associated hematological individual case safety reports (ICSR) reported to Swissmedic between 1991-2012

Organ classes / Number (% of patients) / Diseases (number of patients)
Circulatory system / 17 (26) / Hypertension (9), cerebral disease (2), coronaryheartdisease(2), pulmonary disease (2), others (2)
Injury and external causes / 17 (26) / Fractures (11), allergies (3), concussions (3)
Musculoskeletal system / 16 (25) / Osteoporosis (4), rheumatoid arthritis (4), others(6)
Endocrine and metabolic diseases / 14 (22) / Diabetes (4), hypercholesterolemia (4), obesity (2), others(4)
Symptoms unclassified / 11 (17) / Pain (8), others (3)
Digestive system / 10 (15) / Not differentiated
Infections / 10 (15) / Bacterial infections (3), bacterial infections unspecified(4), herpes zoster (1), viral encephalitis(1), hepatitisCinfection (1)

Supplementary Table 4.

Detailed information on the seven Swiss individual case safety reports of metamizole-associated hematologic adverse drug reactions between 1991 and 2012 with fatal outcome

Age sex / Repor-ting year / Indication metamizole / Underlying diseases / Reported preferred term / Metamizole causality assessment / Daily dose, treatment duration, route of administration / Latency timeb [days] / Therapy / Co-suspected drugs / Concomitant
drugs / Death cause / Time to deatha
[days] / Labora-
tory
values
21
F / 2006 / Abdominal pain / Crohn's disease, bile stone with cholangitis or cholecystitis / Agranulocytosis / probable / 1500 mg
7 days
oral / 10 / GCSF, AB, W / Azathioprine
Mesalazine
Methotrexate (single dose of 25 mg)
Paracetamol / Pantoprazole / Septicemia unspecified / 10 / Neutro
phils
0.02 G/L
78
F / 2011 / NR / Atrial fibrillation and flutter, fracture of femur, rheumatoid arthritis / Pancytopenia, gastrointestinal hemorrhage / possible / 1500 mg
14 days
oral / 14 / GCSF, AB, W / Alendronate Esomeprazole
Etodolac
Methotrexate (10 mg/week)
Prednisolone / Atenolol
Calcium
Colecalciferol
Domperidone
Flupentixol
Lactitol
Melitracene
Morphinesulfate / Gastroin-testinal he-morrhage unspecified / 10 / Leucocytes
0.3 G/L
Thrombocytes
12 G/L
Hemoglobin
43 g/L
79
M / 2011 / Pain, not specified / Multiple fractures of ribs / Agranulocytosis / possible / 2000 mg
9 days
oral / 9 / GCSF, AB, W / - / - / Bacterial pneumonia, respiratory failure / 17 / Leucocytes
0.4G/L
84
F / 2012 / Joint pain / Rheumatoid arthritis, hyperuricemia / Pancytopenia / possible / 2000 mg
594 days
oral / 594 / GCSF, AB, W / Allopurinol
Methotrexate (7.5 mg/week)
Moxifloxacin Spironolactone
Torasemid / - / Multiple organ failure / 5 / Neutrophils
0.0 G/L
Thrombocytes
66 G/L
Hemoglobin
64 g/L
66
F / 2012 / Fever of unknown origin / Peripheral T-cell lymphoma, bacterial infection, viral encephalitis / Pancytopenia / possible / 4000 mg
4 days intravenous / 4 / AB, W / Amoxicillin
Acyclovir
Ceftriaxone
Dalteparin
Esomeprazole
Methotrexate (single dose of 5500 mg in preexisting pancytopenia) / Calciumfolinate
Escitalopram
Glucarpidase
Pantoprazole
Prednisolone / Septicemia unspecified / 13 / Leucocytes 1.62 G/L
Thrombocytes
64 G/L
Hemoglobin
84 g/L
49
F / 2012 / Unspecified renal colic / Nephrolithiasis, hypertension, hypercholesterolemia / Agranulocytosis / probable / 3500 mg
36 days
oral / 56 / GCSF, AB, tonsillectomy, W / - / Atorvastatin Candesartan / Septicemia unspecified / 3 / Neutrophils
0.01 G/L
83
F / 2012 / Low back pain / Hypertension, fracture of pelvic ring, chronic lumbar pain / Agranulocytosis / possible / 1500 mg
120 days
oral / 120 / AB, W / - / Acetylsalicylic acid (100mg)
Bisoprolol
Calcium carbonate
Colecalciferol
Eprosartan
Simvastatin / Septicemia due to gram-negative organism / 5 / Leucocytes
0.4 G/L
AB antibiotics, F female, GCSF granulocyte colony-stimulating factor, M male, NR not reported, W Withdrawal of metamizole
a Time from the diagnosis of the adverse drug reaction till death
b Time from the start of the metamizole therapy till the adverse drug reaction was diagnosed