1 Name of Medicine
Teduglutide.
2 Qualitative and Quantitative Composition
Revestive contains teduglutide powder and solvent for solution for injection. Each single-use vial contains 5 mg of teduglutide as a white lyophilised powder. The solvent is water for injections. After reconstitution, each vial contains 5 mg teduglutide in 0.5 mL of solution, corresponding to a concentration of 10 mg/mL.
The active ingredient teduglutide (rDNA origin) is a 33 amino acid glucagon-like peptide-2 (GLP-2) analogue manufactured using a strain of Escherichia coli modified by recombinant DNA technology.
See Section 6.7 Physicochemical Properties for the chemical composition and structural formula.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Powder for solution for injection.
4 Clinical Particulars
4.9 Overdose
The maximum dose of Revestive studied during clinical development was 80 mg/day for 8 days. No unexpected systemic adverse reactions were seen. In the event of overdose, the patient should be carefully monitored by the medical professional.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia), or the National Poisons Centre on 0800 POISON (0800 764766) in New Zealand.
5 Pharmacological Properties
5.3 Preclinical Safety Data
Genotoxicity. Teduglutide was negative in the Ames test, chromosomal aberration test in Chinese hamster ovary cells, and in an in vivo mouse micronucleus assay. The genotoxic potential of teduglutide is considered to be low.
Carcinogenicity. In a 2-year rat carcinogenicity study with subcutaneous doses of 3, 10 and 35 mg/kg/day, treatment related benign neoplasms included tumours of the bile duct epithelium in 1 out of 44 males at 10 mg/kg and 4 out of 48 males and 1 out of 48 females at 35 mg/kg, associated with respective exposures (plasma AUC) approximately 32-fold and 155-fold clinical exposure at the recommended dose. Adenomas of the jejunal mucosa were observed in 5 out of 50 males at 155-fold clinical exposure, and jejunal adenocarcinoma and jejunal adenoma were observed in 1 out of 50 males at 3 mg/kg (approximately 10-fold clinical exposure). These tumours were not observed in females at exposures up to 97-fold clinical exposure.
In a 2-year mouse subcutaneous carcinogenicity study, treatment related benign neoplasms of the gallbladder developed in 5 out of 71, 2 out of 70 and 6 out of 70 males dosed at 1, 3.5 and 12.5 mg/kg/day respectively, associated with respective exposures (plasma AUC) approximately 12-, 45- and 186-fold clinical exposure at the recommended dose. Four out of 68 males and 1 out of 69 females dosed at 12.5 mg/kg developed a jejunal adenocarcinoma.
There is limited evidence that sub-therapeutic doses of teduglutide may accelerate tumour growth in rodent models of chemically-induced intestinal neoplasia. The human clinical relevance of rodent models of chemically-induced intestinal neoplasia is uncertain.
Juvenile animal toxicity data. In a juvenile toxicity study, teduglutide was administered twice daily to juvenile Gottingen minipigs at subcutaneous doses of 1, 5, and 25 mg/kg/day, from nursing to weaning (from post-natal day 7 and continuing for 90 days), followed by a 13 week recovery period. Exposures (AUC) at these doses were 24-, 50-, and 340-fold the paediatric clinical exposure for ages 1 to 11 years at 0.05 mg/kg, respectively, and 20-, 42-, and 283-fold the paediatric clinical exposure for ages 12 to 17 years at 0.05 mg/kg, respectively.
In juvenile animals, teduglutide had the same pharmacological effect and toxicological target organ findings (intestinotrophic effects, gall bladder mucosal hyperplasia, bile duct mucosal hyperplasia, injection site reactions) as those observed in normal healthy adults of other species and were partially resolved following a 13 week recovery period. There were no new or unique toxicities that suggested a specific risk in the paediatric population.
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Molecular formula: C164H252N44O55S.
Chemical structure. The chemical composition of teduglutide is L-histidyl-L-glycyl-L-aspartyl-L-glycyl- L-seryl-L-phenylalanyl-L-seryl-L- aspartyl-L-glutamyl-L-methionyl-L-asparaginyl-L -threonyl-L-isoleucyl-L-leucyl-L-aspartyl-L -asparaginyl-L-leucyl-L-alanyl-L-alanyl-L-arginyl-L -aspartyl-L-phenylalanyl-L-isoleucyl-L -asparaginyl-L-tryptophanyl-L-leucyl-L -isoleucyl-L-glutaminyl-L-threonyl-L-lysyl-L -isoleucyl-L-threonyl-L-aspartic acid.
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSTEDUGL.gif CAS registry number. 197922-42-2.
Molecular weight: 3752 Daltons.
7 Medicine Schedule (Poisons Standard)
Prescription Medicine.
Summary Table of Changes
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/REVESTST.gif
