Long-term animal studies have not been conducted to eva luate the carcinogenic potential of Immune Globulin Infusion 10% (Human) or its effect on fertility.

An in vitro mutagenicity test was performed for Immune Globulin Infusion 10% (Human) and there was no evidence of mutagenicity observed.

Recombinant Human Hyaluronidase

Hyaluronidases are found in most tissues of the body. Long-term animal studies to eva luate the carcinogenic or mutagenic potential of recombinant human hyaluronidase have not been conducted.

No adverse effects on fertility were observed in mice, rabbits and cynomolgus monkeys exposed to antibodies that bind to recombinant human hyaluronidase and species-specific hyaluronidase. Reversible infertility has been observed in male and female guinea pigs immunized to produce antibodies to hyaluronidase. However, antibodies to hyaluronidase did not influence reproduction following immunization of mice, rabbits, sheep, or cynomolgus monkeys. The effects of antibodies that bind to recombinant human hyaluronidase on human fertility are unknown.

13.2 Animal Toxicology and/or Pharmacology Developmental studies in mice demonstrated that administration of recombinant human hyaluronidase did not produce teratogenicity or signs of maternal toxicity at doses up to 18 mg/kg (2.2 x 106 U/kg), which is 28,800 times higher than the typical monthly human dose. Maternal doses of 9 and 18 mg/kg were associated with reduced fetal weight and an increased number of fetal resorptions. No adverse effects on fetal development were observed at a maternal dose of 3 mg/kg (360,000 U/kg), which is 4800 times higher than the typical monthly human dose.

In a peri-and post-natal reproduction study, female mice were dosed daily with recombinant human hyaluronidase from implantation through lactation and weaning. There were no adverse effects on gestation, parturition, lactation and maternal behavior or on the development of the male or female offspring of the treated female mice in terms of sexual maturation, learning and memory of offspring, or their ability to produce another generation of offspring at doses up to 9 mg/kg (1.1 x106 Unit/kg) which is 14,400 times higher than the typical monthly human dose.

14 CLINICAL STUDIES

A prospective, open-label, non-controlled, multi-center trial was conducted in the US to determine the efficacy, tolerability and pharmacokinetics (PK) of HYQVIA in subjects with PI. Two cohorts of subjects were enrolled. Thirty-one subjects had been treated intravenously for three months and then subcutaneously each week at 137% of the intravenous dose for approximately one year before transitioning to the HYQVIA trial. The remaining subjects also were treated intravenously for 3 months and then immediately began treatment with HYQVIA in the trial.

One week after the last intravenous or subcutaneous infusion, each subject began subcutaneous treatment with HYQVIA. After placing the subcutaneous needle set, the hyaluronidase of HYQVIA was infused through the needle set followed within 10 minutes by the immune globulin of HYQVIA at 108% of the intravenous dose. Dosing began with a 1-week equivalent dose. One week later, a 2-week dose was administered, followed 2 weeks later with a 3-week dose. For those subjects who were on a 4-week dose interval prior to entering the trial, 3 weeks later the 4-week dose was administered. This ramp-up period allowed subjects to b