Table 2.
Toxicology*
| Nonproprietary name | Neonatal HIE dose (based on animal studies with hypothermia) | Trade name under which toxicology performed | Toxicology: species, dose range, and route | Juvenile toxicology | Significant toxicology results |
|---|---|---|---|---|---|
| Recombinant erythropoietin/epoetin alfa | 1000 U/kg intravenous on PNDs 1, 2, 3, and 7 | Epogen® (Amgen®, USA)/Epoetin Hospira® (Hospira Inc.®, USA) | 1500 U/kg (human equivalent dose of 833 U/kg) intravenous three times weekly for 13 weeks in dogs with recovery for 4 weeks. No single-dose toxicity studies reported | No studies | Hypoactivity, loss of limb function (1 male), discoloration of the faeces, reduced faecal output, dehydration, red gums and/or discoloration (yellow) of the teeth; 3 of 4 recovery remained thin throughout 4-week recovery period |
| Melatonin | 10 mg/kg intravenous on PNDs 1 and 2 | Circadin®(Neurim Pharmaceuticals®, Israel)/Slenyto®(Neurim Pharmaceuticals®, Israel) | Only single-dose toxicity studies using intravenous route reported. Dose range not reported | No studies | The intravenous lethal dose (LD50) is 180 to 472 mg/kg in mice and 356 mg/kg in rats (human equivalent dose: 15 to 58 mg/kg). The higher doses led to sedation, lethargy, impairment of righting, placing and flexor reflexes, marked reduction in body temperature, and respiratory distress preceding death |
| Cannabidiol | 0.3 mg/kg intravenous on PND 1. Further dose-ranging studies are required | Epidyolex® (GW Pharmaceuticals®, UK) | See juvenile toxicology | Subcutaneous doses of 0 or 15 mg/kg on postnatal days 4–6 followed by oral administration of 0, 100, 150, or 250 mg/kg on PNDs 7–77 in rats | Increased body weight, delayed male sexual maturation, neurobehavioural effects, increased bone mineral density, and liver hepatocyte vacuolation. The lowest dose causing developmental toxicity was 15 mg/kg subcutaneous (human equivalent dose of 1 mg/kg) in juvenile rats |
| Exenatide/exendin-4 |
Dose-ranging studies are required Anticipated 90 μg/kg 12 hourly intravenous (equivalent) |
Byetta® (AstraZeneca®, UK) | Subcutaneous doses of 100, 300, 1000, 3000, and 5000 μg/kg in monkeys | No studies | No mortality or signs of serious toxicity at any dose. Doses ≥ 5000 μg/kg (human equivalent dose of 1600 μg/kg) caused decreased food consumption |
| Allopurinol sodium | Dose-ranging studies are required | Aloprim® (Mylan Institutional®, USA) | No dose-ranging toxicology reported | No studies | In mice, the minimal lethal dose is 45 mg/kg intravenous (human equivalent dose of 3.65 mg/kg). Hypoactivity was observed with these doses. In rats, the minimum lethal dose is 100 mg/kg intravenous (human equivalent dose of 16 mg/kg) |
*Source: EMA and FDA; human equivalent dose was calculated according to FDA guidance [118]