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Table 7 Details of number of dogs, 95 % CI affected cases, AED doses and serum levels, treatment period and adverse effects

From: Antiepileptic drugs’ tolerability and safety – a systematic review and meta-analysis of adverse effects in dogs

Studies

AED

No of dogs

Prevalence

95 % CI affected cases

Doses of AEDs

Serum levels of AEDs

Treatment period

Body system affected and adverse effects

Most common adverse effects

Adverse effect type

Govendir et al. 2005

Gaba as an adjunct to PHB and/or PBr

17

76.5 %

56.3 %–96.6 %

Gaba: median, 35; range, 32–40 mg/kg PO SID.

PHB: median, 8; range, 6–26 mg/kg PO SID.

PBr: median, 24; range, 14–56 mg/kg PO SID.

Gabapentin: NA

PHB and PBr: within normal reference values

4 m

Neurological (sedation, ataxia), GI (PP, pancreatitis, chronic hepatoxicity), ClinPath (increased ALP, triglycerides), PU, PD

ataxia, sedation

I

Platt et al. 2006

Gaba as an adjunct to PHB and PBr

11

54.5 %

25.1 %–83.9 %

mean, 10.9; range, 9.3–13.6 mg/kg PO TID

median, 6.8; mean, 8.4; range, 2.2–20.7 mg/l

3 m

Neurological (ataxia, sedation)

ataxia, sedation

I

Dewey et al. 2009

Pregabalin as an adjunct to PHB and PBr

11

91 %

74.1 %–107.9 %

Pregabalin: 2 mg/kg PO TID. The dose was increased by 1 mg/kg PO TID each w until 3 or 4 mg/kg PO TID.

PHB and PBr: NA but were within normal reference values

Pregabalin: median, 7.3; mean, 6.4; range 2–11 μg/ml

PHB: median, 27.1; mean, 27.7; range 19.8–40 μg/ml

PBr: median, 1,6; mean, 1.9; range, 0.2–2.81 mg/ml

3 m

Neurological (ataxia, sedation), ClinPath (increased ALP, ALT)

PU, PD, PP were also recorded but were associated to the combination therapy with PHB and PBr

ataxia, sedation

I

Ruehlmann et al. 2001

Felbamate as an adjunct to PHB

6

33.3 %

−4.4 %–71.0 %

Felbamate: median, 63 (initial dose) and 77 (final dose); range, 62–220 mg/kg PO SID.

PHB: 3.75 mg/kg PO BID (discontinued 2 m after felbamate initiation)

median, 35; mean, 13–55 mg/l

median, 9 m

Haematological (leucopenia, lymphopenia, thrombocytopenia), keratoconjunctivitis sicca

leucopenia, lymphopenia, thrombocytopenia

I

McGee et al. 1998

Felbamate

NA

NA

NA

Sub-chronic group: 250, 500, and 1000 mg/kg PO SID

Chronic group: 100 and 300 mg/kg PO SID

range, 16.5–79 μg/ml

Sub-chronic group: 3 m

chronic group: 12 m

Sub-chronic group: Neurological (ataxia, sedation, tremors), GI (vomiting, salivation), ClinPath (increased ALT)

Chronic group: Neurological (ataxia, limb rigidity, tremors), GI (vomiting, salivation), ClinPath (increased ALT, ALP)

Sub-chronic group: ataxia, sedation, tremors, vomiting, salivation, increased ALT.

Chronic group: ataxia, limb rigidity, convulsions, vomiting, salivation, increased ALT, ALP.

I

Dayrell-Hart et al. 1996

Felbamate as an adjunct to PHB and PBr

16

25 %

3.8 %–46.2 %

NA

NA

NA

GI (chronic hepatotoxicity)

chronic hepatotoxicity

I

Bunch et al. 1985

Phenytoin (monotherapy or as an adjunct to Prim)

Monotherapy: 8

Adjunctive therapy: 8

Monotherapy: 0 %

Adjunctive therapy: 37 %

Monotherapy: 0 %

Adjunct therapy:−1 %–16.7 %

NA

NA

NA

Monotherapy: None

Adjunctive therapy: GI (anorexia, emaciation), ClinPath (increased ALP, ALT, bilirubin, bile acids, γ-GT, decreased albumin)

These dogs were eventually euthanised.

Monotherapy: NA

Adjunctive therapy: anorexia, increased ALP, ALT, bilirubin, bile acids, γ-GT, decreased albumin

I

Bunch et al. 1984

Phenytoin (monotherapy or as an adjunct to other AED(s))

Monotherapy: 7

Adjunctive therapy: 19

NA

ΝΑ

Phenytoin: mean, 21+/− 11 mg/kg PO SID

Prim: mean, 33+/−19 mg/kg PO SID.

Other AEDs: NA

NA

range, 6–120 m

GI (chronic hepatoxicity), ClinPath (increased ALP, ALT, AST, bile acids)

Chronic hepatoxicity, increased ALP, ALT, AST, bile acids

I

Meyer and Noonan 1981

Phenytoin

6

100 %

100 %

13–19 mg/kg PO TID

NA

3 m

ClinPath (increased ALP, ALT)

increased ALP and ALT

I

Sturtevant et al. 1977

Phenytoin

2

100 %

100 %

22 mg/kg PO TID

NA

1 m

ClinPath (increased ALP, ALT)

increased ALP and ALT

I

Bunch et al. 1982

Phenytoin as an adjunct to Prim

3

NA

NA

Case 1: Prim: 250 mg PO BID; Phenytoin: NA.

Case 2: Prim: 750 mg PO BID Phenytoin: 100–233 mg PO TID

Case 3: Prim: NA PHB: 150 mg PO SID Phenytoin: 750 mg PO SID 1000 mg PO SID

NA

Case 1: 48 m.

Case 2: 30 m

Case 3: 36 m

GI (chronic hepatoxicity)

chronic hepatoxicity

I

Weiss et al. 2002

Phenytoin

1

NA

NA

NA

NA

NA

Blood dyscrasias (myelofibrosis)

NA

II

Bunch et al. 1987

Phenytoin as an adjunct to PHB and/or Prim

3

NA

NA

Case 1: Phenytoin: 5 mg/kg PO BID, then increased up to 15 mg/kg PO TID. PHB: 0.8 mg/kg PO BID, then increased up to 13 mg/kg PO BID

Case 2: Phenytoin: 7.5 mg/kg PO BID, then increased up to 15 mg/kg PO TID. PHB: 1.1 mg/kg PO BID, then increased up to 4.5 mg/kg PO TID. Prim: 18.5 mg/kg PO TID

Case 3: Phenytoin: 5 mg/kg PO SID, then increased up to 21 mg/kg PO BID. PHB: 3 mg/kg PO BID.

Prim: 13 mg/kg PO SID, then increased up to 26 mg/kg PO BID

Case 1: NA

Case 2: NA

Case 3: NA

Case 1: 27 months

Case 2: 15 months

Case 3: 8 months

GI (hepatotoxicity)

NA

II

Nash et al. 1977

Phenytoin

1

NA

NA

100 mg in total

NA

1 d

Idiosyncrasic hepatitis

NA

II

Bunch et al. 1990

Phenytoin

8

0 %

0 %

40 mg/kg PO TID

NA

13.5 m

No adverse effects

NA

NA

Nafe 1981

Valproate (monotherapy or as an adjunct to PHB and/or Prim and/or phenytoin)

Monotherapy: NA

Adjunctive therapy: 57

Monotherapy: NA

Adjunctive therapy: 2 %

Monotherapy: NA

Adjunctive therapy:−1.7 %–5.1 %

Sodium Valproate: Monotherapy: 200 mg/kg. Adjunctive therapy: range, 25–40 mg/kg PO SID.

PHB, Prim and Phenytoin: NA.

NA

mean, 4.9; range, 1–8 m

Neurological (ataxia, sedation), dermatological (alopecia), GI (vomiting)

Sedation, alopecia

I

Kiviranta et al. 2013

TPM

10

NA

NA

TPM: Initially 2 mg/kg PO BID for 0.5 m, then 5 mg/kg PO BID for 2 m, and then 10 mg/kg PO BID for 2 m and then 10 PO TID for 2 m.

PHB, PBr and LEV: NA but were within normal reference values

NA

2–6 m

Neurological (sedation, ataxia), ClinPath (increased ALP, ALT), weight lose

sedation, ataxia, increased ALP, ALT

I

  1. Abbreviations: AED(s) anti-epileptic drug(s), BID bis in die (twice daily), Chloraz Chlorazepate, CSF cerebrospinal fluid, CL confidence level, Gaba Gabapentin, IE idiopathic epilepsy, LEV Levetiracetam, m month(s), NA Not Available, PHB phenobarbital, PD polydipsia, PU polyuria, PP polyphagia, PBr potassium bromide, Prim primidone, PO per os, SID semel in die (once daily), TID ter in die (three times daily), TPM Topiramate, w week(s), y year(s)