Carcinogenicity

Long-term studies in animals performed to evaluate carcinogenic potential of SUBLOCADE have not been conducted. However, the carcinogenic potential of the active drug substance in SUBLOCADE, buprenorphine, has been evaluated in Sprague-Dawley rats and CD-1 mice.

In the carcinogenicity study conducted in Sprague-Dawley rats, buprenorphine was administered in the diet at doses of 0.6, 5.5, and 56 mg/kg/day (approximately 0.5, 5, and 50 times the recommended human monthly subcutaneous dose of 300 mg of buprenorphine) for 27 months. A statistically significant dose-related increase in Leydig cell tumors occurred. In an 86 week study in CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (approximately 45 times the recommended human monthly subcutaneous dose of 300 mg of buprenorphine).

N-methyl-2-pyrrolidone [NMP], an excipient in SUBLOCADE, produced an increase in hepatocellular adenomas and carcinomas in male and female mice at 6 and 8 times the maximum daily dose (MDD) of NMP via SUBLOCADE. The clinical significance of these findings is unclear. No tumors were noted at 1 and 1.3 times the MDD. In 2-year inhalation and dietary studies in rats, NMP did not result in evidence of carcinogenicity.

Mutagenicity

No evidence of mutagenic potential for subcutaneous SUBLOCADE was found in in vivosubcutaneous micronucleus test using rats' marrow. 

Mutagenic potential for buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both prokaryotic and eukaryotic systems. Results were negative in yeast ( S. cerevisiae) for recombinant, gene convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, negative for clastogenicity in CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse lymphoma L5178Y assay. 

Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame shift mutation at a high dose (5 mg/plate) in a third study. Results were positive in the Green-Tweets ( E. coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for both in vivoand in vitroincorporation of [3H]thymidine, and positive in unscheduled DNA synthesis (UDS) test using testicular cells from mice. 

Impairment of Fertility

In a fertility study in rats, SUBLOCADE or ATRIGEL ®was administered every 28 days for 3 months (males) or once before mating and once on GD 7; female mating, fertility, and fecundity indices were unaffected by the subcutaneous administration of SUBLOCADE up to 900 mg/kg buprenorphine (approximately 38 times the maximum recommended human dose [MRHD] of 300 mg on an AUC basis). However, higher mean post-implantation loss was observed with SUBLOCADE at 900 mg/kg buprenorphine and at an equivalent level of ATRIGEL ®alone, which correlated with higher mean number of resorptions and reduced mean number of viable fetuses/litter size. Mean gravid uterine weight and mean final body weight were lower with SUBLOCADE at 900 mg/kg buprenorphine and an equivalent level of ATRIGEL ®alone, and correlated with higher mean number of resorptions and lower fetal body weights. The NOAEL for female fertility was 900 mg/kg and the NOAEL for female-mediated developmental parameters was 600 mg/kg (approximately 25 times the MRHD on an AUC basis). 

Male fertility and reproduction indices were lower as evidenced by abnormal sperm parameters (low motility, low mean number of sperm, and higher percentage of abnormal sperm) with SUBLOCADE at 600 mg/kg and with an equivalent level of ATRIGEL ®. The NOAEL for male fertility parameters, including sperm analysis, and male-mediated developmental parameters was 300 mg/kg (approximately 32 times the MRHD on an AUC basis).