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Table 3 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 treated

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

Boothe et al. 2012

PBr

23

78.5 %

61.7 %–95.3 %

mean, 30.6; range, 26–35 mg/kg PO BID

mean, 1.9 +/− 0.6; range, 0.9–3.3 mg/ml

approximately 6 m

Neurological (ataxia, hyperactivity, sedation), GI (vomiting, diarrhoea, PP), PU, PD

sedation, hyperactivity, ataxia, PD, PU

I

Pearce 1990

PBr as an adjunct to PHB

10

40 %

9.6 %–70.4 %

PBr: 22 mg/kg PO SID (dose increases occurred)

PHB: median, 3.3; mean, 3.8 mg/kg PO BID (dose was reduced by a mean of 50 % in 7/10 dogs during the PBr treatment)

PBr: mean, 810; range, 500–1625 mg/l

PHB: mean, 29.7; range, 17–45 ug/ml

median, 7; mean, 7.8 m

Neurological (ataxia, sedation, hyperactivity), PU, PD

ataxia, letargy, PU, PD

I

March et al. 2002

PBr

6

20 %

−12.0 %−52.0 %

30 mg⁄kg PO BID

median, 245; range, 178–269 mg/dL

3.9 m

(adverse effects occurred after this period when dose adjustments occurred (NA))

Neurological (ataxia, paraparesis, hyperactivity)

ataxia, paraparesis

I

Rossmeisl et al. 2009

PBr as an adjunct to PHB and/or other AEDs

1298

2 %

1.2 %–2.8 %

PBr: 44.9+/−1.7 mg/kg PO SID

PHB: 6.3+/−0.4 mg/kg PO SID

PBr: 3.7+/−0.3 mg/ml

PHB: 31.4+/−1.2 μg/dl

NA

Neurological (sedation, ataxia, paraparesis, tetraparesis)

sedation, ataxia, paraparesis, tetraparesis

I

Dayrell-Hart B et al. 1996

PBr

238

10.9 %

6.9 %–14.9 %

NA

21 affected dogs had >2.3 mg/ml and 5 affected dogs had <0.5 mg/ml

NA

Neurological (ataxia, sedation)

ataxia, sedation

I

Podell and Fenner 1993

PBr as an adjunct to PHB and/or other AEDs

23

78 %

61.1 %–94.9 %

PBr: mean, 20.75; range, 13–40 PO BID

PHB: NA

PBr: 161 mg/dl

PHB: 37.8 mcg/ml

mean, 15; range, 4–33 m

Neurological (ataxia, sedation), GI (PP), ClinPath (increased serum chloride), PU, PD

PU, PD, PP, sedation

I

Chang et al. 2006

PBr (monotherapy or as an adjunct to PHB)

Monotherapry: 4

Adjunctive Therapy: 10

Monotherapry: 62.5 %

Adjunctive Therapy: 95 %

Monotherapy: 15.0–110.0 %

Adjunctive therapy: 81 %–109 %

NA

NA

median, 18; range, 3–72 m

Neurological (ataxia, hyperactivity), Dermatological (pruritus), GI (PP),

The adjunctive therapy group had also PU, PD and vomiting/diarhoea

Ataxia, hyperactivity, pruritus, PP

I

Yohn et al. 1992

PBr as an adjunct to PHB

1

NA

NA

NA

2.7 mg/ml

1 m

Neurological (sedation, ataxia, paraparesis, anisocoria)

NA

I

Kantowitz et al. 1999

PBr (monotherapy or as an adjunct to PHB)

Monotherapry: 15

Adjunctive therapy: 8

NA

NA

NA

Monotherapy: median, 1985; range, 500–3419 mg/dL

Adjunctive therapy: PBr: median, 1399; range, 584–2438 mg/dL. PHB: median, 22.4; range, 10.9–40 μg/ml

Monotherapy: median, 14.5; range, 3–37 m

Adjunctive therapy: PBr: median, 5; range, 3–72 m. PHB: median, 22; range, 3–96 m

Monotherapy: Normal

Adjunctive therapy: Endocrine (decreased total T4, free T4)

NA

I

Srivastava et al. 2013

PBr as an adjunct to PHB

6

100 %

100 %

PBr: 30 mg/kg PO SID

PHB: Initially 2.5 mg/kg, then 5 mg/kg PO SID.

NA

mean, 11.50+/− 1.23; range, 8–15 m (on PHB).

Then, PBr started and 3 m later a reduction of 50 % in the dose of PHB was performed. After 6 m, PHB was completely withdrawn.

Neurological (ataxia), GI (hepatoxicity, anorexia, PP), ClinPath (increased ALT, ALP, AST, bile acids), PU, PD

(polyphagia, PU, PD appeared after 1–1.5 years of PBr therapy)

PU, PD, PP

I

Shaw et al. 1996

PBr as an adjunct to PHB

1

NA

NA

PBr: 20 mg/kg PO SID

PHB: 3.75 mg/kg PO BID

PBr: 1100 mg/l.

PHB: 20.4 μg/ml

Approximately 21 m

After PBr initiation: Neurological (sedation, ataxia)

NA

I

Paull et al. 2003

PBr

5

60 %

17.1 %–102.9 %

Initially 100 mg/kg PO BID for 2 days. Then,

30 mg/kg PO SID for 180 days.

range, 88–300 mg/dL (only one dog was >300 mg/dl)

6 m

Endocrine (Euthyroid sick syndrome with decreased TT4 and normal TSH)

Placebo group had the same results

NA

I

Stabile et al. 2014

PBr as an adjunct to PHB

1

NA

NA

PBr: Initially, 400 mg/kg divided in six daily doses for four days. Then, 14 mg/kg PO BID

PHB: Initially, 2.7 mg/kg, then 5 mg/kg and finally 6.4 mg/kg PO BID.

PBr: 15.9 mg/ml; PHB: 23.7 μg/ml

≥26 m

Neurological (sedation, ataxia, generalised appendicular repetitive myoclonus), ClinPath (pseudohyperchlormia, increased ALP)

NA

I & II

Gaskill and Kimber 2010

PBr

32

85.9 %

73.8 %–98.0 %

NA

NA

12 m

Neurological (ataxia, sedation, hyperactivity, aggression), GI (PP, anorexia, vomiting, diarrhoea, pancreatitis), Dermatological (skin problems), ClinPath (increased ALP, ALT, amylase, lipase), PU, PD

vomiting, sedation, PP, PU, PD

I & II

Volk et al. 2008

PBr as an adjunct to PHB (prior to addition of other AEDs)

14

100 %

100 %

PBr and PHB: NA but were within normal reference values

PBr: 1.7+/−0.4 mg/ml

PHB: 35.5+/−6.3 μg/ml

≥2–6 m

Neurological (ataxia, aggression), GI (PP, vomiting, pancreatitis), ClinPath (increased ALT, ALP) PU, PD

increased ALT, ALP, ataxia, aggression

I & II

Gaskill et al. 2000

PBr as an adjunct to PHB

Clinical trial: 6

Case series: 19

Clinical trial: 50 %

Case series: 37 %

Clinical trial: 10.0 %–90.0 %

Case series: 15.3 %–58.7 % (pancreatitis); 47.5 %–89.3 % (increased enzymes only)

Clinical trial: NA

Case series: NA

Clinical trial: NA

Case series: PBr: range, 12.5-37.5 mmol/L; PHB: range, 54–190 imol/L

Clinical trial: approximately 1 year

Case series: NA

GI (pancreatitis, increased amylase and/or lipase activities)

pancreatitis, increased amylase and/or lipase activities

II

Steinmetz et al. 2012

PBr as an adjunct to PHB

1

NA

NA

101.19 mg/kg SID PO (added at the beginning of the 4th year)

PHB: 4.9 mg/kg BID PO

PBr: 45 mmol/l

PHB: 168.52 μmol/l

48 m (adverse effect occurred after the 48 m)

Neurological (neuromyopathy with generalised low motor signs)

NA

II

Mackay and Mitchell 1998

PBr as an adjunct to PHB

1

NA

NA

PBr: Initially 200 mg/kg PO BID for 3 days, then 30 mg/kg PO SID

PHB: 5 mg/kg PO BID.

PBr: NA.

PHB: 126 umol/L

3 d

(signs started 3 d after the loading dose of PBr was initiated)

ClinPath (artifactual hyperchloraemia and negative anion gap), Neurological (pacing, disorientation), GI (vomiting)

The Neurological and GI signs were attributed to hypercloraemia

NA

II

Boynosky and Stokking 2014

PBr as an adjunct to PHB

2

NA

NA

Initially 40 mg/kg PO SID, then 60 mg/kg PO SID (case 1) or 86 mg/kg PO SID (case 2)

Case 1: 2.9 mg/mL; Case 2: initially 0.8, then 3 mg/ml (after 7.5 months of treatment)

12 m

[adverse effects occured 3 (case 1) and 8 (case 2) m after the dose increase]

Dermatological (panicculitis) accompanied by sedation and anorexia

NA

II

Steiner et al. 2008

PBr (monotherapy or as an adjunct to PHB)

Monotherapy: 98

Adjunctive therapy: 121

14 %

Monotherapy: 8.2 %–22.4 %

Adjunctive: 5.9 %–17.3 %

NA

range, 0.5–4.2 mg/ml (majority of dogs; range, 1–2 mg/ml)

NA

ClinPath (increased cPLI)

NA

II

Bizzeti et al. 2006

PBr as an adjunct to PHB

7

43 %

6.1 %–79.4 %

NA

NA

NA

Pancreatitis, ClinPath (increased amylase, lipase,cPLI)

NA

II

  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)