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Table 1 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 PHB 20 78.5 % 60.5 %–96.5 % mean, 4.11+/−1.1; range, 3.9–4.9 mg/kg PO BID mean, 27+/−6; range, 12.4–36 μg/mL 6 m Neurological (ataxia, hyperactivity, sedation), GI (vomiting, diarrhea, PP), PU, PD, ClinPath (increased ALP, decreased albumin) ataxia, sedation, increased serum ALP, decreased albumin I
Heynold et al. 1997 PHB 37 35 % 19.6 %–50.4 % mean, 2.5 mg/kg PO BID range, 15–40 μg/ml mean, 50; range, 8–108 m Neurological (ataxia, sedation, aggression), GI (PP), Dermatological (itching) sedation I
Löscher et al. 2013 PHB 8 NA NA range, 10–40 mg/kg PO SID 14.7 μg/ml 2.5 m Neurological (sedation, ataxia), PU, PD sedation, ataxia, PU, PD I
Gaskill et al. 2000 PHB 22 32 % 12.5 %–51.5 % At 3 w: mean, 3.6+/−1.3; range, 1.3–6.0 mg/kg
At 6 m: mean, 3.7+/−1.4; range, 1.3–8.3 mg/kg
At 12 m: mean, 3.7+/−1.6; range, 1.3–8.3 mg/kg PO SID
At 3 w: mean, 58.6+/−15.0; range, 33–85 mmol/L
At 6 m: 62.5+/−25.7; range, 8–120 mmol/L.
At 12 m: mean, 62.2+/−23.51; range, 11–116 mmol/L
12 m Endocrine (decreased total T4 levels, increased TSH levels, normal TSH stimulation test) euthyroid sick syndrome I
Steinberg 2004 PHB (monotherapy prior to the addition of other AEDs) 14 26.6 % 4.8 %–52.1 % NA PHB: mean, 32.1+/−14.4 μg/ml. median, 17; range, 3.3–58.5 m GI (chronic hepatotoxicity) chronic hepatotoxicity I
von Klopmann et al. 2006 PHB 34 68 % 52.3 %–83.7 % NA NA NA Endocrine (decreased total T4 levels, normal TSH levels, normal TSH stimulation test) euthyroid sick syndrome I
Chang et al. 2006 PHB 11 92.5 % 76.9 %–108.1 % NA NA median, 18; range, 3–72 m Neurological (ataxia, hyperactivity, sedation), GI (vomiting, diarrhea, PP), Dermatological (itching), PU, PD PD, PU, PP, sedation, hyperactivity I
Tipold et al. 2014 PHB 110 57.3 % 48.1 %–66.5 % range, 2–6 mg/kg PO BID <45 μg/mL 5 m Neurological (sedation), GI (PP, diarrhea), PU, PD, ClinPath (increased ALP, γ-GT, ALT and GLDH) sedation, PP, PU, PD I
Fredso et al. 2015 PHB 6 93 % 70 %–114 % median, 2.7; mean, 3; range 2.2–3 mg/kg PO BID median, 77; mean, 77.3; range 55–111 μmol/L 2–12 m Neurological (sedation, ataxia, hyperactivity, disobedience), GI (PP), PU, PD PD, PP I
Schwartz-Porsche et al. 1985 PHB 15 93 % 80.1 %–105.9 % range, 5–17 mg/kg PO SID range, 19–57 μg/ml mean, 15; range, 7.3–32 m Neurological (sedation, ataxia), GI (PP), PD, ClinPath (ALT, ALP, GLDH) ataxia, sedation, PP, PD I
Gaskill et al. 2005 PHB 12 NA NA median, 5; range, 2.1–12.9 mg/kg PO SID mean, 22.8; range, 9.7–44.2 μg/ml median, 20.4; range, 4–78 m ClinPath (increased ALT, ALP) increased ALT, ALP I
Farnbach et al. 1984 PHB 42 2.4 % −2.2 %−7.2 % range, 0.3–19.9 mg/kg PO SID mean, 24.3; range, 6.5–81.3 μg/ml NA Neurological (hyperactivity) hyperactivity I
Gaskill and Kimber 2010 PHB 30 80 % 65.7 %–94.3 % NA NA 12 m Neurological (ataxia, sedation, hyperactivity, aggression), GI (PP, anorexia, vomiting, diarrhoea), Dermatological (skin problems), ClinPath (increased ALP, ALT, lipase), PU, PD PP, PU, PD, vomiting, skin problems, hyperactivity I
Aitken et al. 2003 PHB 95 40 % 30.1 %–49.8 % <2–> 10 mg/kg PO SID <65–> 120 μmol/l <3–> 12 m ClinPath (increased ALT, ALP, γ-GT, GLDH, cholesterol, bile acids) increased ALP, ALT, GLDH I
Dayrell-Hart et al. 1991 PHB 18 NA NA median, 10.4; range, 3.1–27 mg/kg PO SID mean, 49.7; range, 16–60 μg/ml (12 dogs had >40) median, 39; range, 5–82 m GI (hepatotoxicity)
(also all dogs were ataxic and sedated)
NA I
Andrik et al. 2010 PHB 30 (15 epileptic and 15 non-epileptic) NA NA Epileptic dogs: 2 mg/kg PO BID (increased if necessary)
Non-epileptic dogs: Initially at 2 mg/kg PO SID, then increased at 8 mg/kg PO SID
NA Epileptic dogs: range, 12–60 m
Non-epileptic dogs: 5 m
GI (chronic hepatotoxicity), ClinPath (increased ALP, ALT, AST, total bilirubin, decreased albumin and total protein) increased ALT, ALP I
Litchfield et al. 1972 PHB 4 NA NA range, 5–40 mg/kg IV SID NA 0.5 m ClinPath (increased ALP) NA I
Foster et al. 2000 PHB Experimental dogs: 6
Epileptic dogs: 10
70 % Experimental dogs: 0 %
Epileptic dogs: 41.6 %–98.4 %
Experimental dogs: mean, 6 mg/kg; range, 5.9–6.4 mg/kg PO SID
Epileptic dogs: range, 3.9–14.4 mg/kg PO SID
Experimental dogs: mean, 63+/−15, range, <65–194 μmol/L
Epileptic dogs: mean, 110; range, 72–171 μmol/L
Experimental dogs: 3 m
Epileptic dogs: range, 14–92 m
ClinPath (increased ALP, ALT, cholesterol) increased ALP I
Gaskil et al. 1999 PHB 78 40 % 28.8 %–50.6 % median 4; range, 1–16.4 mg/kg PO SID median, 17.6; range, 4–70 μg/ml median, 12.5; range, 0.3–96 Endocrine (decreased total T4, free T4, increased TSH)
Also, ClinPath abnormalities were reported, i.e. increased ALT, ALP, AST, γ-GT, fasting bile acids and cholesterol, but no further details are provided.
eythyroid sick syndrome I
Muller et al. 2000 PHB 12 91.6 % 100 % or 50.5 %–99.5 % mean, 5; range, 4.8–6.6 mg/kg PO BID range, 20–40 μg/mL 7.1 m Endocrine (decreased total T4, free T4, increased TSH, cholesterol and total T3), Neurological (sedation for the first 3 days)
No significant PHB’s effect on either of the adrenal function tests
euthyroid sick syndrome I
Muller et al. 2000 PHB 12 87.5 % 75.9 %–107.3 % mean, 5; range, 4.8–6.6 mg/kg PO BID range, 20–40 μg/ml 7.1 m ClinPath (increased ALP, ALT, γ-GT, decreased albumin), Neurological (sedation for the first 3 days) increased ALP, ALT, γ-GT I
Kantrowitz et al. 1999 PHB 55 NA NA NA median, 25.3; range, 8.0–74.3 μg/ml median, 7 m; range, 1–120 m Endocrine (decreased T4, increased TSH) eythyroid sick syndrome I
Chauvet et al. 1995 PHB 5 100 % 100 % NA range, 20–47 μg/ml 13 m Endocrine (increased ACTH, altered ACTH stimulation and dexamethasone supression test), ClinPath (increased ALT, ALP, decreased albumin, cholesterol), PU, PD increased ACTH, altered ACTH stimulation and dexamethasone supression test, increased ALT, ALP, decreased albumin, cholesterol I
Balazs et al. 1978 PHB 4 100 % 100 % 40 mg/kg PO SID NA 1.8 m ClinPath (increased ALP) increased ALP I
Conning and Litchfield 1971 PHB NA NA NA NA NA NA ClinPath (increased ALP) increased ALP I
Sturtevant et al. 1977 PHB 2 100 % 100 % 4.4 mg/kg PO TID NA 1 m ClinPath (Increased ALT, ALP) increased ALT and ALP I
Thrift et al. 2010 PHB 1 NA NA 6.4 mg/kg PO BID NA 2 m ClinPath (anemia, increased ALT, ALP, AST) idiosyncrasic anemia I & II
Kube et al. 2006 PHB 1 NA NA Initially 5 mg/kg PO BID for 4 days, then 3 mg/kg PO BID NA 2 m Dyskinesia (twitching episodes) NA II
Steiner et al. 2008 PHB 118 14.4 % 8.1 %–20.7 % NA Unclear NA ClinPath (Increased cPLI) NA II
Gaskill et al. 2000 PHB 88 9 % 3.0 %–15.0 % NA range, 39–130 mol/L 16 m GI (pancreatitis, increased amylase and/or lipase activities) increased amylase and/or lipase activities II
March et al. 2004 PHB 11 NA NA mean, 12.4+/−5.7; range, 3.8–19.8 mg/kg PO SID mean, 43.5+/−15.1; range, 22.8–66 μg/ml median, 6; range, 20.4–132 m Dermatological (superficial necrolytic dermatitis) NA II
Weiss 2005 PHB 3 NA NA NA NA NA Blood dyscrasias (bone marrow necrosis-myelofibrosis) NA II
Jacobs et al. 1998 PHB 2 NA NA Case 1: 2.2 mg/kg PO BID; Case 2: 4.4 mg/kg PO BID NA Case 1: 5 m; Case 2: 3 m Blood dyscrasias (neutropenia, thrombocytopenia), ClinPath (increase ALP) NA II
Weiss et al. 2002 PHB 1 NA NA NA NA NA Blood dyscrasias (myelofibrosis) NA II
Bevier et al. 2010 PHB 1 NA NA NA NA NA Dermatological (superficial necrolytic dermatitis) NA II
Bersan et al. 2014 PHB 16 NA NA median, 3; mean, 2.75+/−0.43; range, 1.60–7.25 mg/kg PO BID median, 19; mean, 22.4+/−5.5; range, 13.2–30.5 μg/ml median, 69.5; mean, 72.1+/−sd 45.8; range, 14–157 m Blood dyscrasias (anemia and/or thrombocytopenia and/or neutropenia and/or pancytopenia) anemia, pancytopenia II
Volk et al. 2008 (case series) PHB (monotherapy prior to the addition of other AEDs) 8 NA NA NA but was within normal reference values NA Approximately 2–3 m Blood dyscrasias (bone marrow suppression) NA II
Habock and Pakozdy 2012 PHB 37 22 % 16.8 %–57.2 % NA NA >1 m Blood dyscrasias (anemia and/or thrombocytopenia and/or neutropenia and/or pancytopenia) NA II
Von Klopmann et al. 2006 PHB 1 NA NA 2 mg/kg PO BID NA   Blood dyscrasias (pancytopenia) NA II
Bizzeti et al. 2006 PHB 7 14.4 % −11.6 %−40.2 % NA NA NA Pancreatitis, ClinPath (Increased amylase, lipase, cPLI) NA II
Mathis et al. 2014 PHB 1 NA NA 2.1 mg/kg PO BID 27.5 μg/dL 6 m Blood dyscrasias (bone marrow supression) NA II
Daminet et al. 1999 PHB 9 0 % 0 % Initially 1.8–3 for one week, then 2.7–4.5 mg/kg PO BID range, 65–150 pmol/L 0.8 m No adverse effects NA NA
Dyer et al. 1994 PHB 6 0 % 0 % 5 mg/kg PO BID range, 18–37 μg/ml 2 m No PHB’s effect on endogenous ACTH and ACTH stimulation test NA NA
  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)