Acute toxicity
Acute toxicity studies performed with Octreotide in the guinea-pig showed that LD50 is 72 mg/kg by IV and 470 mg/kg subcutaneously . In the mouse, LD50 was 18 mg/kg ( IV). Octreotide acetate was well tolerated by dogs that received up to 1 mg/kg by IV bolus.
Toxicity after repeated administration
A 26 weeks toxicity study in dogs, with IV doses up to 0.5 mg/kg, bid, showed progressive changes in acidophilic pituitary cells that contain prolactin. Further investigations showed that this variation was within the physiologic range and apparently not related to Octreotide administration. No significant changes were seen in plasma level of hormones. Rhesus monkey females receiving 0.5mg/kg bid for 3 weeks did not show pituitary changes nor changes in plasma levels of GH, prolactin or glucose.
Local tolerance
While acidic vehicle produced inflammation and fibroplasias in mouse after repeated injections, no evidence of Octreotide acetate causing hypersensitivity reactions was found in the guinea-pig model after intradermal administration.
In a toxicology study on predominantly male rats, sarcomas were observed at the subcutaneous injection site after 52 weeks, but only with the highest dose (around forty times the maximum dose used in humans). In a 52-week toxicology study in dogs, no hyperplastic or neoplastic lesions were observed at the subcutaneous injection site. No cases of tumour formation at the injection site have been reported in patients treated with Octreotide for periods of up to 15 years. All of the available information to date indicates that the results obtained in rats are species-specific and are not relevant for the use of the drug in humans.
Mutagenicity
Octreotide and/or its metabolites were without mutagenic potential in standard in vitro tests. An increase of chromosomic changes in V79 Chinese hamster cells was seen, in vitro, although only with high and cytotoxic concentrations. In human lymphocytes incubated with Octreotide acetate in vitro the chromosomal changes were not increased. Blastogenic activity in vivo (micronuclei test in guinea pigs) was not observed
Carcinogenicity
Studies with mice treated with SC Octreotide in daily doses up to 1.25 mg/kg of body weight, the presence of fibrosarcomas, after 52, 104 and 113/116 weeks was observed in some animals, mainly males. Local tumours in control group of mice also appeared, however the tumours were related to disorganized fibroplasias produced by irritant effects of the acid vehicle. In guinea-pigs that received daily SC injections of Octreotide in doses up to 2 mg/kg for 98 weeks, neoplastic lesions were not observed.
The mouse carcinogenicity study also revealed endometrial carcinomas, statistically significant for the highest SC dose of 1.25 mg/kg/day. This observation was associated with an increase in endometritis, a reduced number of luteal bodies, a reduction of breast adenomas and the presence of luminal dilation and glandular uterus, suggesting a hormonal imbalance. The available data indicates that the observed hormone-dependent tumours in mice are species specific and therefore not relevant for humans.
Reproduction toxicity
The fertility study as well as the studies of pre-, peri- and post-natal effects in rats did not reveal adverse events on the reproductive ability or on foetal development with doses up to 1 mg/kg/day SC. Some delay of offspring growth, which was transient and may be due the GH inhibition due to the excessive pharmacodynamic activity, was observed
Preclinical data reveal no specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Studies in animals showed transient growth retardation of offspring, possibly due to the pharmacodynamic action of Octreotide, but there was no evidence of foetotoxic, teratogenic, or other reproductive effects.Acute and repeated dose toxicology, genotoxicity, carcinogenicity and reproductive toxicology studies in animals revealed no specific safety concerns for humans.
Reproduction studies in animals revealed no evidence of teratogenic, embryo/foetal or other reproduction effects due to octreotide at parental doses of up to 1 mg/kg/day. Some retardation of physiological growth was noted in the offspring of rats which was transient and attributable to GH inhibition brought about by excessive pharmacodynamic activity (see section 4.6).
No specific studies were conducted in juvenile rats. In the pre- and post-natal developmental studies, reduced growth and maturation was observed in the F1 offspring of dams given octreotide during the entire pregnancy and lactation period. Delayed descent of the testes was observed for male F1 offspring, but fertility of the affected F1 male pups remained normal. Thus, the abovementioned observations were transient and considered to be the consequence of GH inhibition.
Carcinogenicity/Chronic toxicity
In rats receiving octreotide acetate at daily doses up to 1.25 mg/kg body weight, fibrosarcomas were observed, predominantly in a number of male animals, at the s.c. injection site after 52, 104 and 113/116 weeks. Local tumours also occurred in the control rats, however development of these tumours were attributed to disordered fibroplasia produced by sustained irritant effects at the injection sites, enhanced by the acidic lactic acid/mannitol vehicle. This non-specific tissue reaction appeared to be particular to rats. Neoplastic lesions were not observed either in mice receiving daily s.c. injections of octreotide at doses up to 2 mg/kg for 98 weeks, or in dogs treated with daily s.c. doses of the drug for 52 weeks.