Table 1 Clinical reports of CNZ/FNZ-associated MD
From: Cinnarizine- and flunarizine-associated movement disorder: a literature review
Reference | Country/year | N cases | Age | Sex | Suspected drug | Drug dose (mg) | Time from drug-start to symptoms | Time from withdrawal to recovery | Follow-up | Important clinical history and clinical management |
|---|---|---|---|---|---|---|---|---|---|---|
Parkinsonism | ||||||||||
 Mello-Souza | Brazil 1984 | 5 | NA | NA | FNZ | NA | NA | NA | NA |  |
 MartÃ-Masso et al. | Spain 1985 | 11 | 65–83 | NA | CNZ | 150 | 6–36 months | NA | NA |  |
 Chouza et al. | Uruguay 1986 | 12 | 70 | F | FNZ | 10–20 mg | 9 months | NA | No | CH: PKN +orofacial DKN +severe AKT +moderate DPS. Even after 20 months of drug withdrawal, she was still with severe AKT. CM: Drug withdrawal |
70 | F | FNZ | 20 | 6 months | NR | CR | CH: PKN +mild DPS. CM: Drug withdrawal | |||
45 | F | FNZ | 20–40 | 2 months | NR | CR | CH: PKN +moderate DPS | |||
56 | M | FNZ | 20 | 1 month | NR | CR | CH: PKN +mild DPS. CM: Drug withdrawal | |||
66 | F | FNZ | 20–40 | Several months | NR | CR | CH: PKN +severe DPS. CM: Drug withdrawal | |||
63 | M | FNZ | 20 | 13 months | NR | CR | CH: PKN +rabbit syndrome (DKN) +mild DPS. CM: Drug withdrawal | |||
55 | F | FNZ | 10 | 15 months | NR | CR | CH: PKN +moderate DPS. CM: Drug withdrawal | |||
71 | F | FNZ | 20 | 12 months | NR | CR | CH: PKN +orofacial DKN +mild DPS. CM: Drug withdrawal | |||
72 | F | FNZ | 40 | 1 month | NR | CR | CH: PKN +mild AKT +moderate DPS. CM: Drug withdrawal | |||
65 | M | FNZ | 10 | NR | NR | CR | CH: PKN +moderate DPS. CM: Drug withdrawal | |||
66 | F | FNZ | 40 | 1 month | NR | CR | CH: PKN +rabbit syndrome (DKN) +moderate DPS. CM: Drug withdrawal | |||
73 | F | FNZ | 20 | 3 months | NR | CR | CH: Only PKN. CM: Drug withdrawal | |||
 D’Alessandro et al. | Italy 1986 | 6 | 67 | F | FNZ | 10 | NR | 6 months | CR | CH: PKN +DPS. CM: Drug withdrawal |
72 | M | FNZ | 20 | NR | 3 months | CR | CH: PKN +DPS. CM: Drug withdrawal and amitriptyline started | |||
72 | M | FNZ | 10 | NR | NA | No | CH: PKN +DPS. CM: Drug withdrawal and amineptine started | |||
77 | F | FNZ | 20 | NR | 3 months | CR | CH: PKN +DPS. CM: Drug withdrawal and amitriptyline started | |||
77 | F | FNZ | 10 | NR | 3 months | CR | CH: PKN +DPS. CM: Drug withdrawal and amitriptyline started | |||
82 | M | FNZ | 10 | NR | NA | No | CH: PKN +DPS. CM: Drug withdrawal | |||
 Laporte and Capella | Spain 1986 | 14 | 78 | M | CNZ | NR | 4.5 years | NR | NR | CH: All had some tremor or bradykinesia; two individuals had to worsen PD. CM: Drug withdrawal |
46 | F | CNZ | 45 | 5 days | NR | No | ||||
48 | F | CNZ | NR | 14 months | NR | NR | ||||
68 | M | CNZ | 150 | 2 days | NR | CR | ||||
73 | M | CNZ | 150 | NR | NR | CR | ||||
69 | F | CNZ | 150 | NR | NR | No | ||||
64 | F | CNZ | 60–180 | 1 year | NR | No | ||||
68 | M | CNZ | 150 | 2 days | NR | CR | ||||
64 | F | FNZ | 10 | 28 days | NR | CR | ||||
42 | M | FNZ | 10 | 4 months | NR | CR | ||||
48 | F | FNZ | 20 | 11 days | NR | No | ||||
60 | F | FNZ | 10 | 6 weeks | NR | CR | ||||
68 | M | FNZ | 10 | 1 year | NR | CR | ||||
69 | F | FNZ | 10 | 8 months | NR | No | ||||
 Meyboom et al. | Netherlands 1986 | 1 | 68 | M | FNZ | 10 | NR | Several months | CR | CH: PKN +AKT +mild DPS. CM: Drug withdrawal |
 MartÃ-Masso et al. | Spain 1987 | 4 | 62.5 (mean) | NA | CNZ | 150 | 58 days | NR | NA | CH: Randomized trial of CNZ in 10 patients with PD. After 1 month, 40% (4/10) had to withdraw from the study due to the worsening of bradykinesia and tremor |
 Michele et al. | Italy 1987 | 10 | 61–77 | NA | FNZ | NA | NA | NA | NA | Discusses the range of symptoms of PKN +DPS associated with dosages of FNZ |
 Micheli et al. | Argentina 1987 | 11 | 69 | M | FNZ | 10 | 1 month | 3 months | CR | CM: Drug withdrawal |
68 | F | CNZ | 225 | 4 years | 5 months | CR | CM: Drug withdrawal | |||
82 | F | FNZ | 11.5 | 1 year | 15 days | CR | CH: PKN +DPS. CM: Drug withdrawal | |||
73 | F | CNZ | 150 | 30 days | 17 days | CR | CH: PKN +DPS. CM: Drug withdrawal | |||
74 | F | CNZ | 150 | 4 years | 20 days | CR | CH: PKN +DPS. CM: Drug withdrawal | |||
61 | F | FNZ | 11.5 | 3 months | 5 months | CR | CH: PKN +DPS +AKT +orofacial DKN. CM: Drug withdrawal | |||
71 | F | FNZ | 10 | 3 months | 1 month | CR | CM: Drug withdrawal | |||
73 | F | CNZ | 225 | 3 months | 3 months | CR | CM: Drug withdrawal | |||
74 | M | FNZ+CNZ | 10 + 150 | 7 months–1 year | 1 month | CR | CH: PKN +DPS. CM: Drug withdrawal | |||
82 | F | FNZ | 10 | 7 months | 24 days | CR | CM: Drug withdrawal | |||
67 | F | FNZ | 10 | 16 months | 6 months | CR | CH: PKN +DPS. CM: Drug withdrawal | |||
 di Rosa et al. | Italy 1987 | 42 | Elderly | NA | FNZ | NR | Months | 12 weeks | NA | CM: Drug withdrawal |
 Bakchine et al. | France 1988 | 1 | 68 | F | FNZ | 10 | 10 weeks | 3 months | CR | CH: PKN +AKT +orofacial DKN +DPS. CM: Drug withdrawal |
 Benvenuti et al. | Italy 1988 | 27 | 74 (mean) | 19F + 8M | FNZ | 10 | 14 months (mean) | < 6 months (96%) | CR | CM: Drug withdrawal |
 Capella et al. | Spain 1988 | 39 | 78 (mean) | 24F + 13M | CNZ | 156 (mean) | 14.67 (mean) | < 6 months (90%) | CR | CH: 3 patients were taking other drugs (sulpiride, thiethylperazine, dimenhydrinate, thioridazine); 8 were with a combination CNZ+FNZ 10 mg; 4 patients had DPS symptoms. CM: Drug withdrawal |
 Lugaresi et al. | Italy 1988 | 10 | 72 | M | FNZ | 10 | 40 months | NR | NR | CM: Drug withdrawal |
56 | F | FNZ | 10 | 5 months | NR | NR | CM: Drug withdrawal | |||
63 | F | FNZ | 10 | Some months | NR | NR | CM: Drug withdrawal | |||
52 | F | FNZ | 10 | 5 months | NR | NR | CM: Drug withdrawal | |||
72 | M | FNZ | 10 | Some months | NR | NR | CM: Drug withdrawal | |||
63 | F | FNZ | 10 | 5 months | NR | NR | CM: Drug withdrawal | |||
61 | F | FNZ | 20 | 8 months | NR | NR | CM: Drug withdrawal | |||
70 | M | FNZ | 5 | 6 months | NR | NR | CM: Drug withdrawal | |||
73 | F | FNZ | 5 | 9 months | NR | NR | CM: Drug withdrawal | |||
93 | M | FNZ | 10 | 4 months | NR | NR | CM: Drug withdrawal | |||
 de Marco | Italy 1988 | 1 | Yong adult | M | FNZ | NA | NA | NA | NA |  |
 Martinez-Lage | Spain 1988 | 1 | 35.48 (mean) | NR | FNZ | 10 | NA | NA | NA |  |
 Moretti and Lucantoni | Italy 1988 | 24 | 71.1 (mean) | 14F + 10M | FNZ | 10 | 4.2 months (mean) | < 4 months (50%) | NA | CH: 10 individuals had PKN +DPS |
 Fontanari | Brazil 1989 | 8 | 62 | F | FNZ | 10 | 6 months | 3 months | CR | CM: Drug withdrawal |
65 | F | FNZ | 10 | 5 months | 5 months | CR | CM: Drug withdrawal | |||
68 | F | FNZ | 10 | 3 months | 4 months | CR | CM: Drug withdrawal | |||
62 | F | FNZ | 10 | 24 months | NR | NR | CH: PKN +orofacial DKN. CM: drug withdrawal | |||
63 | F | FNZ | 10 | 18 months | 3 months | CR | CM: Drug withdrawal | |||
55 | F | FNZ | 10 | 4 months | NR | CR | CM: Drug withdrawal | |||
60 | F | FNZ | 10 | 3 months | 6 months | CR | CM: Drug withdrawal | |||
63 | F | FNZ | 10 | 6 months | 6 months | CR | CM: Drug withdrawal | |||
 Kuzuhara et al. | Japan 1989 | 31 | Adult | 20F + 7M | FNZ | 10 | 6.1 months (mean) | < 6 months (90%) | CR | CH: Attempts with levodopa, anticholinergic drugs, and bromocriptine had been ineffective until FNZ withdrawal. 16 individuals had PKN+DPS and 5 PKN+AKT |
 Mangone et al. | Argentina 1989 | 21 | 68.5 (mean) | 16 F + 5 M | FNZ/CNR | NR | 15.7 months (mean) | 2.6 months | CR | CM: Drug withdrawal |
2 | 68.5 (mean) | 2F | FNZ/CNR | NR | NA | NA | NA | CH: Worsening of PD symptoms | ||
 Micheli et al. | Argentina 1989 | 81 | 69.7 (mean) | 69F + 31M | 51FNZ/31CNZ/8CNZ+FNZ | 13.4/154.4 (mean) | 32.1/14.1 months (mean) | 80.5/105 days (mean) | CR | CH: 46 individuals had PKN +DPS. CM: Drug withdrawal |
 Mukai et al. | Japan | 1 | Adult | NA | FNZ | NA | NA | NA | NA | CH: Showed slightly decreased signal intensity of the putamen on brain MRI |
 Sa and Heinisch | Brazil 1989 | 19 | 75 | M | FNZ | 20 | 10 months | 30 days | CR | CM: Previous of FNZ withdrawal was attempted anticholinergic and levodopa without success |
62 | F | FNZ | 20 | 2 months | 4 months | CR | CM: Previous of FNZ withdrawal was attempted anticholinergic and levodopa without success | |||
71 | M | FNZ | 20 | 9 months | 30 days | CR |  | |||
76 | F | FNZ | 10 | 2 months | 60 days | CR | CM: Previous of FNZ withdrawal was attempted anticholinergic without success | |||
72 | F | FNZ | 10 | 1 year | 6 months | CR | CM: Previous of FNZ withdrawal was attempted levodopa without success | |||
65 | F | FNZ | 10 | 8 months | 4 months | CR |  | |||
37 | F | FNZ | 20 | 8 months | 4 months | CR | CH: PKN +DPS | |||
67 | F | FNZ | 10 | 7 months | 3 months | CR | CM: Previous of FNZ withdrawal was attempted anticholinergic without success | |||
64 | F | FNZ | 10 | 5 months | 60 days | CR | CH: PKN +DPS. CM: Previous of FNZ withdrawal was attempted anticholinergic and imipramine without success | |||
54 | F | FNZ | 10 | 6 months | 3 months | CR | CM: Previous of FNZ withdrawal was attempted anticholinergic and imipramine without success | |||
69 | F | FNZ | 10 | 1 year | 50 days | CR | CH: PKN +DPS | |||
47 | F | FNZ | 10 | 15 days | 7 days | CR | CH: PKN +DPS | |||
72 | F | FNZ | 10 | 11 months | 30 days | CR | CH: PKN +DPS | |||
72 | F | FNZ | 10 | NR | 60 days | CR | CM: Previous of FNZ withdrawal was attempted anticholinergic and levodopa without success | |||
68 | F | FNZ | 10 | NR | 60 days | CR | CM: Previous of FNZ withdrawal was attempted anticholinergic without success | |||
76 | F | FNZ | 10 | 11 months | 10 months | CR | CM: Previous of FNZ withdrawal was attempted anticholinergic without success | |||
74 | F | FNZ | 40 | 5 months | 60 days | CR | CH: PKN +DPS. CM: Previous of FNZ withdrawal was attempted levodopa without success | |||
NR | F | FNZ | 20 | 7 days | 20 days | CR | CH: PKN +DPS | |||
66 | F | FNZ | 40 | 3 months | 60 days | CR | CH: PKN +DPS. CM: Previous of FNZ withdrawal was attempted imipramine without success | |||
 Trevisol-Bittencourt | Brazil 1990 | 1 | 72 | M | FNZ | 10 | 8 months | 30 days | CR | CM: Drug withdrawal and biperiden started |
 Fontanari | Brazil 1990 | 1 | Adult | F | FNZ | NR | NR | NR | No | CH: She had PKN due to FNZ; the drug was removed, and she started to developing choreoathetotic DKN. Anticholinergics and levodopa did not ameliorate the DKN symptoms |
 Gimenez-Roldan and Mateo | Spain 1991 | 24 | 70.6 (mean) | 15F + 9M | CNZ | 181.3 (mean) | 4.2 years (mean) | NR | NR |  |
 Garcia-Ruiz et al. | Spain 1992 | 32 | 72.6 (mean) | 26F + 6M | 4FNZ/27CNZ/1FNZ+CNZ | 8.75/122.5 (mean) | 15 months (mean) | NR | NR | CH: Only 3 patients had a full recovery. 44% had PKN +DPS. Patients younger than 73 years recovered better than older individuals |
 Morgante et al. | Italy 1992 | 4 | Adult | NR | FNZ | NR | NR | NR | NR | CH 1 individual FNZ +alpha methyldopa; 3 only FNZ |
 Negrotti et al. | Italy 1992 | 25 | Adult | NR | FNZ/CNZ | NR | NR | NR | NR | CH: In the CNZ/FNZ-induced PKN there was a positive family history for PD or essential tremor with a greater percentage than the general population |
 Amancio et al. | Brazil 1993 | 1 | Adult | NR | FNZ | NR | NR | NR | NR |  |
 Cunha et al. | Brazil 1993 | 11 | 67 (mean) | 8F + 3M | FNZ/CNZ | 20/150 (mean) | 24 months (mean) | 2 months (mean) | CR | CH: 63% had PKN +DPS. |
 Galhardo et al. | Brazil 1993 | 1 | 48 | F | FNZ | 10 | 3 months | 90 days | CR | CM: FNZ withdrawal; methixene and levodopa started |
 Llau et al. | France 1994 | 16 | 65 (mean) | 10F + 6M | FNZ/CNZ | NR | 15.76 months (mean) | NA | NA |  |
 Anjaneyulu and Mohandas | India 1995 | 2 | NA | NA | FNZ | NA | NA | NA | NA |  |
 Baquero et al. | Spain 1995 | 18 | 66 (mean) | NA | FNZ/CNZ | NA | 1 year (mean) | NA | NA |  |
 Claps | Chile 1995 | > 1 | NA | NA | FNZ | NA | NA | NA | NA |  |
 Handforth et al. | USA 1995 | 1 | 37 | F | FNZ | 60 | NA | NA | NA | CH: Assessment of FNZ for the treatment of epilepsy in the USA |
 Biary et al. | Arabia 1995 | 1 | 52 | M | FNZ | 10 | 18 months | NR | NR |  |
 Jimenez-Jimenez et al. | Spain 1996 | 30 | 70 (mean) | 24F + 6M | FNZ/CNZ | NR | 60.9 months (mean) | 4.5 months (mean) | CR |  |
 Lee and Lee | Korea 1996 | 3 | 64.33 (mean) | 2F + 1M | FNZ | 10 | 3 months (mean) | 4 months | CR | CH: 2 PKN +DPS; 1 only PKN. Only one had a full recovery; others needed to take levodopa after the event |
 Martinez | Chile 1996 | > 1 | NA | NA | FNZ/CNZ | NA | NA | NA | NA |  |
 Morgante et al. | Italy 1996 | 4 | 74 | M | FNZ | 10 | NR | NR | CR | CM: Drug withdrawal |
72 | M | FNZ | 20 | NR | NR | CR | CM: Drug withdrawal | |||
93 | F | FNZ | 10 | NR | NR | No | CM: Drug withdrawal | |||
62 | M | FNZ | 10 | NR | NR | NR | CM: Drug withdrawal | |||
 Negrotti and Calzeti | Italy 1997 | 11 | 69.5 (mean) | F | 8FNZ/3CNZ | 10/150 | 7 months | NA | No | CH: 6 orofacial DKN; 3 limb DKN. No recovery. CM: Drug withdrawal |
 Cardoso et al. | Brazil 1998 | 20 | NR | NR | 8FNZ/12CNZ | NR | NR | NR | NR |  |
 Errea-Abad et al. | Spain 1998 | 19 | Elderly | 14F + 5M | 4FNZ/15CNZ | NR | NR | NR | NR |  |
 Garcia-Ruiz et al. | Spain 1998 | 36 | 71.7 (mean) | 30F + 6M | 6FNZ/29CNZ/1FNZ+CNZ | NR | NR | NR | NR | CH: Only 4 individuals had a full recovery.CM: Drug withdrawal |
 Marti-Masso and Poza | Spain 1998 | 87 | 75 (mean) | NR | 13FNZ/69CNZ/5FNZ+CNZ |  | 33 months (mean) | 5 months (mean) | CR (90%) |  |
 Orti-Pareja et al. | Spain 1999 | 7 | 75.6 (mean) | 5F + 2M | 7 CNZ | NR | 45.8 months | NR | NA | CH: PKN +orofacial DKN |
1 | 75.6 (mean) | F | 1CNZ | NR | NA | NR | NA | CH: PKN +DTN | ||
3 | 75.6 (mean) | 3F | 3CNZ | NR | NA | NR | NA | CH: PKN +AKT | ||
3 | 75.6 (mean) | 3F | 3CNZ | NR | NA | NR | NA | CH: Only PKN. CM: Drug withdrawal | ||
 Stucchi-Portocarrero et al. | Peru 1999 | 1 | 25 | F | CNZ | NA | 11 days | NA | NA | CH: PKN +AKT +DPS. CM: Drug withdrawal; benzodiazepines, propranolol, and orphenadrine were started |
 Zamora and Argote | Colombia 1999 | 9 | 65 | F | FNZ | 10 | 4 years | NA | NA | CH: Possible interaction with verapamil |
77 | F | FNZ | 10 | 1 year | NA | NA | CH: Possible interaction with verapamil | |||
65 | M | FNZ | 10 | 6 months | NA | NA |  | |||
76 | M | FNZ | 10 | 6 months | NA | NA |  | |||
51 | F | FNZ | 10 | 3 months | NA | NA | CH: PKN +DPS | |||
51 | F | FNZ | 10 | NR | NA | NA | Â | |||
57 | F | CNZ | 75 | 3 years | NA | NA |  | |||
68 | F | FNZ | 10 | 3 years | NA | NA |  | |||
62 | F | FNZ | 10 | NR | NA | NA | CH: Possible interaction with verapamil | |||
 Benito-Leon et al. | Spain 2003 | 9 | NA | NA | 8CNZ/1FNZ | NA | NA | NA | NA |  |
 Fabiani et al. | Brazil 2004 | 4 | 61.75 (mean) | 2F + 2M | 2FNZ/2CNZ | 11.2/72.1 (mean) | 16.5 months (mean) | NR | NR | CH: Only PKN. CM: Drug withdrawal |
1 | 87 | F | FNZ+CNZ | 10 + 75 | 16.5 months (mean) | NR | NR | CH: PKN +orofacial DKN +DPS | ||
1 | 76 | F | FNZ+CNZ | 10 + 75 | 16.5 months (mean) | NR | NR | CH: PKN +orofacial DKN | ||
5 | 66 (mean) | 5F | 3CNZ/1FNZ/1CNZ+FNZ | 11.2/72.1 (mean) | 16.5 months (mean) | NR | NR | CH: PKN +DPS | ||
 Trevisol-Bittencourt et al. | Brazil 2005 | 3 | 73.2 (mean) | F | CNZ/FNZ | NR | NR | NR | NR |  |
 Barbosa et al. | Brazil 2006 | 13 | 73.5 (mean) | NR | 7FNZ/6CNZ | NR | NR | NR | NR |  |
 Louter and Tromp | Netherlands 2009 | 1 | Adult | NR | CNZ | NR | NR | NR | CR | CM: Drug withdrawal |
 Ma et al. | Korea 2009 | 6 | 71.5 (mean) | NR | FNZ | NR | 6.3 months (mean) | NR | NR |  |
 Mattos et al. | Brazil 2009 | 1 | 74 | F | FNZ | 10 | 1 year | 10 months | CR | CH: Progressive supranuclear palsy like syndrome. CM: Drug withdrawal; levodopa, tolcapone, and memantine were started |
 Munhoz et al. | Brazil 2010 | 47 | 60.8 (mean) | NA | 34FNZ/13CNZ | NA | NA | NA | NA |  |
 Masmoudi et al. | France 2011 | 1 | 80 | F | FNZ | 10 | Months | NR | No | CH: PKN +orofacial DKN; possible interaction with trimetazidine; she did not recover the DKN |
 Arias | Colombia 2012 | 2 | 35 | F | FNZ | 20 | NR | 10 weeks | CR | CH: PKN +DPS. CM: Drug withdrawal |
28 | M | FNZ | 20 | 6 weeks | 10 weeks | CR | CH: PKN +DPS. CM: Drug withdrawal | |||
 Pioner et al. | Brazil 2012 | 1 | 56 | F | CNZ | 25 | NR | NR | CR | CM: Drug withdrawal |
 Kim et al. | Korea 2013 | 6 | 65 | F | FNZ | 10 | 12 months | NR | NR | CH: PKN. CM: Drug withdrawal |
62 | M | FNZ | 10 | 1 month | NR | NR | CH: PKN. CM: Drug withdrawal | |||
84 | F | FNZ | 10 | 3 months | NR | NR | CH: PKN. CM: Drug withdrawal | |||
70 | F | FNZ | 10 | 48 months | NR | NR | CH: PKN. CM: Drug withdrawal | |||
58 | F | FNZ | 10 | 1 month | NR | NR | CH: PKN +oromandibular DTN | |||
66 | F | FNZ | 10 | 3 months | NR | NR | CH: PKN. CM: Drug withdrawal | |||
 Gotardelo et al. | Brazil 2014 | 1 | 72 | F | FNZ | 10 | Years | 2 months | CR | CM: Drug withdrawal; biperiden started |
 Miguel et al. | Portugal 2014 | 30 | 73.3 (mean) | 22F + 8M | FNZ/CNZ | NR | NR | NR | CR (43%) | CH: 43% recovered only with withdrawal; the others needed a dopaminergic treatment for improving the symptoms |
 Chary and Krishnan | India 2016 | 1 | 37 | F | FNZ | 15 | 1 month | 1 week | CR | CH: PKN +DPS. CM: Drug withdrawal; trihexyphenidyl started |
 Munhoz et al. | Brazil 2016 | 58 | 74.1 (mean) | NR | 38FNZ/20CNZ | 9.1/45 (mean) | 6 months | NR | NR |  |
 Nistico et al. | Italy 2016 | 2 | 64.19 (mean) | 2F | FNZ | NR | NR | NR | NR |  |
 Sung et al. | Korea 2016 | 1 | 70.85 (mean) | 1F | CNZ | NR | NR | NR | NR |  |
Dyskinesia | ||||||||||
 Micheli et al. | Argentina 1987 | 2 | 64 | F | FNZ | 10 | 3 months | 2 months | CR | CH: Orofacial DKN (probably rabbit syndrome). CM: Drug withdrawal |
62 | F | FNZ | 10 | 2 years | NA | No | CH: Orofacial DKN +DPS. CM: Drug withdrawal, but without symptoms resolution | |||
 Gabellini et al. | Italy 1989 | 1 | 62 | F | FNZ | 10 | 1 year | 3 weeks | CR | CH: Transient tongue tremor. CM: Drug withdrawal |
 Mangone et al. | Argentina 1989 | 6 | 68.5 (mean) | 5F + 1 M | FNZ/CNR | NR | NR | 2 months | NR | CH: Orofacial DKN. CM: Drug withdrawal |
1 | 68.5 (mean) | 1F | FNZ/CNR | NR | NR | 2 months | CR | CH: Rabbit syndrome + AKT. CM: Drug withdrawal | ||
 Micheli et al. | Argentina 1989 | 9 | 74 | F | FNZ | 10 | 36 months | NA | No | CH: Orofacial DKN +AKT. CM: Drug withdrawal |
59 | M | CNZ | 225 | 36 months | 2 weeks | CR | CH: Orofacial DKN +PKN +DPS. CM: Drug withdrawal | |||
62 | F | CNZ | 150 | 24 months | 1 month | CR | CH: Orofacial DKN. CM: Drug withdrawal | |||
64 | F | FNZ | 10 | 4 months | 1 month | CR | CH: Orofacial DKN +PKN. CM: Drug withdrawal | |||
61 | F | FNZ | 11.5 | 3 months | 5 months | CR | CH: Orofacial DKN +AKT +PKN +DPS. CM: Drug withdrawal | |||
70 | F | FNZ+CNZ | 25/10 mg | 24 months | NA | No | CH: Orofacial DKN +AKT. CM: Drug withdrawal | |||
68 | F | FNZ | 10 | 48 months | 5 months | CR | CH: Orofacial DKN +PKN +DPS. CM: Drug withdrawal | |||
64 | F | FNZ | 10 | 24 months | NA | No | CH: Orofacial DKN +AKT +DPS. CM: Drug withdrawal | |||
84 | M | CNZ | 150 | 4 months | NA | No | CH: Orofacial DKN +PKN. CM: Drug withdrawal | |||
 Jimenez-Jimenez et al. | Spain 1996 | 2 | 70 (mean) | 2F | FNZ/CNR | NR | 60.9 months (mean) | 4.5 months (mean) | CR |  |
 Orti-Pareja et al. | Spain 1999 | 1 | 75.6 (mean) | F | FNZ | NA | 45.8 months | NA | NA |  |
 Fabiani et al. | Brazil 2004 | 1 | 72 | M | FNZ | 10 | 16.5 months (mean) | NR | NR |  |
Akathisia | ||||||||||
 Micheli et al. | Argentina 1987 | 1 | 54 | M | CNZ | 75 | 4 h | 1 day | CR | CM: Drug withdrawal |
 Micheli et al. | Argentina 1989 | 4 | 70 | F | FNZ | 30 | 48 months | 2 months | CR | CH: AKT +bruxism + PKN. CM: Drug withdrawal |
49 | F | FNZ | 20 | 8 months | 2 months | CR | CH: AKT +PKN +DPS. CM: Drug withdrawal | |||
66 | F | FNZ | 10 | 18 months | 2 months | CR | CH: AKT +PKN +DPS. CM: Drug withdrawal | |||
74 | M | FNZ | 20 | 18 months | 8 months | CR | CH: AKT +PKN +DPS. CM: Drug withdrawal | |||
 Garcia and Uriarte | Spain 1991 | 1 | Adult | NA | FNZ | NA | NA | NA | NA |  |
 Anand and Thiagarajan | India 1993 | 1 | Adult | NA | FNZ | NA | NA | NA | NA | CH: AKT +DPS |
 Jimenez-Jimenez et al. | Spain 1996 | 2 | 70 (mean) | 2F | FNZ/CNR | NR | 60.9 months (mean) | 4.5 months (mean) | CR |  |
Dystonia | ||||||||||
 Micheli et al. | Argentina 1987 | 1 | 37 | M | FNZ+CNZ | 10 + 150 | 3 days | NA | NA | CH: Cervical DTN. CM: FNZ+CNZ was maintained |
 Mangone et al. | Argentina 1989 | 6 | 68.5 (mean) | 1F + 5M | FNZ/CNR | NR | NR | NR | CR | CH: Acute DTN that resolved after drug withdrawal |
 Micheli et al. | Argentina 1989 | 1 | 67 | F | FNZ+CNZ | 20 + 150 | 18 months | NA | No | CH: Blepharospasm + oromandibular DTN. CM: Drug withdrawal |
 Biary et al. | Arabia 1995 | 1 | 31 | F | FNZ | 10 | 3 months | NR | NR | CH: Cervical DTN |
 Jimenez-Jimenez et al. | Spain 1996 | 2 | 70 (mean) | 2F | FNZ/CNR | NR | 60.9 months (mean) | 4.5 months (mean) | CR |  |
 Koukoulis et al. | Spain 1997 | 1 | 30 | F | FNZ | 10 | 2 months | 1 month | CR | CH: Blepharospasm. CM: Drug withdrawal |
 Fabiani et al. | Brazil 2004 | 1 | 61 | F | FNZ+CNZ | 11.2/72.1 (mean) | 16.5 months (mean) | NA | NA |  |
 Alonso-Navarro and Jimenez-Jimenez | Spain 2006 | 1 | 53 | F | CNZ | 40 | 6 years | 1 year | CR | CH: Blepharospasm; she also had a history of DTN with thiethylperazine and sulpiride. CM: Drug withdrawal |
 Mathews et al. | India 2017 | 1 | 17 | F | CNZ | 25 | Single-dose | 1.5 days | CR | CH: Oromandibular and cervical DTN; possible interaction between CNZ and prochlorperazine. CM: Drug withdrawal; diphenhydramine started |
 Gallop et al. | UK 2019 | 1 | 10.5 (mean) | F | FNZ | 5 mg | NA | NA | NA | CH: Worsening of DTN; Sturge-Weber syndrome |
Myoclonus | ||||||||||
 Turner et al. | Israel 2006 | 1 | 2.5 | F | CNZ | Overdose | NA | NA | NA | CH: Possible MCL (twitching in both hands) |
 Lopez-Castellanos et al. | El Salvador 2017 | 4 | 58 | M | FNZ+CNZ | NR | 1 week | 3 days | CR | CH: Multifocal MCL. CM: Drug withdrawal |
66 | F | FNZ | NR | 20 years | 1 month | CR | CH: Multifocal MCL. CM: Drug withdrawal | |||
70 | F | CNZ | NR | 8 years | NA | No | CH: Multifocal MCL. CM: Drug withdrawal | |||
69 | M | CNZ | NR | 3 years | 5 years | CR | CH: Multifocal MCL. CM: Drug withdrawal | |||
Cases not clearly defined | ||||||||||
 MartÃ-Masso | Spain 1986 | > 1 | PKN | Case series showing that the worsening of PD is reversible with CNZ, but the MD may last several days or even weeks | ||||||
 Giannaula et al. | Argentina 1986 | 27 | EPS | Report of 27 individuals that developed PKN +DPS after CNZ/FNZ use | ||||||
 Amery | Belgium 1987 | > 1 | EPS | Reports about EPS following the use of FNZ | ||||||
 Baldrati et al. | Italy 1987 | 1 | Tremor | A young female presented with unilateral postural tremor after 10 mg FNZ for 2 months. Later, 4 months, she developed DPS. No signs of PKN were observed | ||||||
 Herskovits and Mangone | Argentina 1987 | > 1 | EPS | EPS following the use of CNZ/FNZ | ||||||
 Assmann et al. | Netherlands 1988 | > 1 | EPS | EPS following the use of FNZ | ||||||
 di Rosa | Italy 1988 | > 1 | EPS | EPS following the use of FNZ | ||||||
 Rostin | France 1988 | > 1 | EPS | Assessment of the efficacy of FNZ to the prophylactic treatment of migraine | ||||||
 Hefner and Fischer | Germany 1989 | > 1 | PKN | Worsening of PD symptoms with FNZ | ||||||
 Jongerius and van Gool | Netherlands 1989 | > 1 | EPS | EPS following the use of FNZ | ||||||
 Mangone et al. | Argentina 1989 | 8 | Tremor | The symptoms started within 15 months of the beginning of the FNZ/CNZ and recovery in two months after drug withdrawal | ||||||
 Petri | Netherlands 1989 | > 1 | EPS | EPS following the use of FNZ | ||||||
 Centozone et al. | Italy 1990 | 1 | Tremor | Assessment of the efficacy of FNZ to the prophylactic treatment of migraine | ||||||
 Micheli et al. | Argentina 1990 | 2 | Bradykinesia | Assessment of the efficacy of FNZ to the management of Tourette’s syndrome | ||||||
 Senard et al. | France 1990 | 6 | EPS | Report of 5F + 1M with 71.5 years (mean) who were n use of FNZ 11.66 mg when the EPS occurred. The EPS appeared after 7.0 (mean) months and disappeared after 2.2 (mean) months respectively | ||||||
 Wilder-Smith et al. | Switzerland 1991 | 1 | Tremor | Assessment of the efficacy of CNZ as an antiemetic for platin chemotherapy, possible interaction with metoclopramide and lorazepam | ||||||
1 | AKT | |||||||||
 Curran and Lang | Canada 1993 | 3 | Tremor | Assessment of the efficacy of FNZ in 10 patients with essential tremor. 3 individuals developed worsening of the symptoms | ||||||
 Beghi et al. | Italy1994 | > 1 | PKN | Pharmaco-epidemiological study about the prevalence of PKN in Italy. Exposure to FNZ, neuroleptics was observed in 8 patients | ||||||
 Brucke et al. | Austria 1995 | NA | EPS | SPECT assessment in 26 individuals under FNZ/CNZ. It was observed that older age and long-term treatment are predisposing factors for EPS | ||||||
 MartÃ-Masso | Spain 1996 | > 1 | PKN | Determine the prevalence of DIP in general neurology practice. During 1981–1988, the drug most often implicated was CNZ, though its relative impact decreased after | ||||||
 Vecchio et al. | Italy 1996 | 3 | Tremor | Assessment of the efficacy of FNZ in 12 patients with essential tremor. 3 individuals had worsening of tremor, in the others nothing change | ||||||
 Verspeelt et al. | Germany 1996 | 43 | EPS | Assessment of the efficacy of FNZ in vestibular vertigo and migraine | ||||||
 Orti-Pareja et al. | Spain 1999 | 2 | Tremor | Reports of tremor following the use of CNZ (1) or FNZ (1) | ||||||
 Vazquez-Alen et al. | Spain 2000 | > 1 | PKN | To determine demographic changes in an outpatient clinic in Spain about MD. It was observed a 40% decrease of the PKN during 1991–1998; the authors hypothesized that this occurred because of a reduction in prescriptions of CNZ/FNZ and flupentixol | ||||||
 Schillevoort et al. | Netherlands 2002 | > 1 | PKN | Data obtained from the PHARMO-database 1986–1998. CNZ/FNZ users were more likely to receive antiparkinsonian medication than non-users. Also, the use of antiparkinsonian medication was already elevated with CNZ/FNZ low doses and increased with increasing dose and duration of use | ||||||
 MartÃ-Masso | Spain 2005 | 2 | PKN | Retrospective study about the adverse effects of trimetazidine on motor functions. 4 patients were taking CNZ two developed PKN, and the other 2 did not have any adverse event | ||||||
 Otero | Spain 2006 | 1 | EPS | Report of an infant male who developed EPS +DPS after the use of FNZ 10 mg | ||||||
 Bisol et al. | Brazil 2008 | > 1 | AKT | Assessment of the efficacy of FNZ in the management of schizophrenia and schizoaffective disorder | ||||||
 Benito-Leon et al. | Spain 2009 | > 1 | PKN | A population-based study of the PD incidence. It was observed 6 reports of possible PKN with cinnarizine, flunarizine, clebopride | ||||||
 Diaz-Corrales et al. | Spain 2009 | 2 | PKN | Assessment of SPECT in the differentiation of DIP and PD. 1 individual had DIP secondary to CNZ and other to FNZ | ||||||
 Bondon-Guitton et al. | France 2011 | 10 | PKN | Reports of DIP to a pharmacovigilance center in France from 1993 to 2009. 7 individuals had PKN with FNZ, and the other 3 with CNZ | ||||||
 Kizilay et al. | Turkey 2011 | 1 | Myokymia | Report of a young adult female who used FNZ and developed fasciculation–myokymia | ||||||
 Foubert-Samier et al. | France 2012 | NA | PKN | Assessment of the long-term risk of developing PD after past exposure to neuroleptics and neuroleptic-like drugs. Concerning phenothiazines, the association with the risk of PD was mainly due to FNZ/CNZ (RR, 3.39; 95% CI, 1.20–9.58). Without FNZ/CNZ, the association was not statistically significant for phenothiazines (RR, 1.81; 95% CI, 0.71–4.64) | ||||||
 Lin et al. | Taiwan 2016 | 280 | PKN | A population-based study assessing the risk for PKN in patients receiving FNZ/CNZ. The adjusted hazard ratio for PKN was 5.11 (CI = 3.758–6.967). Age, stroke, and diabetes mellitus were significant risk factors, but female sex and total doses of the studied drugs were not | ||||||
 Jhang et al. | Taiwan 2017 | 497 | EPS | A population-based study assessing the risk for PKN in patients receiving FNZ/CNZ. The hazard ratios of EPS for FNZ CNZ were 8.03 (CI 6.55–9.84) and 3.41 (CI 2.50–4.63) | ||||||
 Yang et al. | China 2017 | NA | PKN | A population-based study assessing the risk of PKN in patients with DM. When FNZ is present, the hazard risk ratio is (1.21, 1.08–1.35) | ||||||
 Karsan et al. | UK 2018 | 11 | EPS | Assessment of FNZ for the management of migraine. 11 individuals had possible EPS; 9 tremors and 2 with micrographia | ||||||
 Liang et al. | Taiwan 2018 | NA | PKN | Assessment of the risk of developing PKN after FNZ in patients with type 2 diabetes. The adjusted odds ratio was 2.75 (2.26–3.36) | ||||||
 Byun et al. | Korea 2019 | NA | PKN | Assessment of the prevalence of DIP and the utilization of offending drugs through an analysis of representative nationwide Korean data. From 2009 to 2015, it was observed a compound annual growth rate of 7.42% to FNZ | ||||||
 Jhang et al. | Taiwan 2019 | NA | PKN | Assessment of the risk of developing MD after FNZ. FNZ was associated with 240 PKN +48 hyperkineses. Higher exposure dose and duration, older age, history of essential tremor, and cardiovascular disease were associated with FNZ-associated MD | ||||||
 Kim et al. | Korea 2019 | NA | PKN | Assessment of the association between drug exposure and the risk of PKN using Korean population-based data. The odds ratio of FNZ when compared to those that never used it was 4.95 (2.71–9.03) | ||||||
 Lin et al. | Taiwan 2019 | NA | PKN | Assessment of the risk of developing PKN after FNZ in the database of Taiwan’s National Health Insurance Research Database. It is associated with older age, history of comorbidities, exposure to FNZ high-dose, and longer duration of exposure to FNZ | ||||||