1 Name of Medicine
Sitagliptin phosphate monohydrate.
2 Qualitative and Quantitative Composition
Januvia is available for oral use as film coated tablets containing sitagliptin phosphate monohydrate equivalent to 25, 50 or 100 mg of free base.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Januvia 25 mg. A pink, round, film coated tablet with "221" on one side and plain on the other.
Januvia 50 mg. A light beige, round, film coated tablet with "112" on one side and plain on the other.
Januvia 100 mg. A beige, round, film coated tablet with "277" on one side and plain on the other.
4 Clinical Particulars
4.9 Overdose
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).
During controlled clinical trials in healthy subjects, single doses of up to 800 mg Januvia were generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg Januvia (see Section 5.1 Pharmacodynamic Properties, Cardiac electrophysiology). There is no experience with doses above 800 mg in humans. In phase I multiple dose studies, there were no dose related clinical adverse reactions observed with Januvia with doses of up to 400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g. remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.
Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5% of the dose was removed over a 3 to 4 hour haemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.
5 Pharmacological Properties
5.3 Preclinical Safety Data
Genotoxicity. Sitagliptin was not mutagenic or clastogenic in a battery of genetic toxicology studies, including the Ames bacterial mutagenicity assay, a chromosome aberration assay in Chinese hamster ovary cells, an in vitro rat hepatocyte DNA alkaline elution assay (an assay which measures the compound's ability to induce single strand breaks in DNA), and an in vivo mouse micronucleus assay.
Carcinogenicity. A two year carcinogenicity study was conducted in rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of focal eosinophilic cellular alterations in the liver in both sexes at 150 mg/kg/day and at 500 mg/kg/day. There was an increased incidence of basophilic cellular alterations in females at 500 mg/kg/day. Eosinophilic and basophilic cellular alterations are regarded as preneoplastic lesions. There was an increase in hepatic adenomas and carcinomas in males, and hepatic carcinomas in females at 500 mg/kg/day. Systemic exposure in rats at 150 and 500 mg/kg/day are 19 and 58 times, respectively, that of humans at 100 mg/day. The no observed effect level for induction of hepatic neoplasia in rats was 150 mg/kg/day, producing exposure approximately 19-fold higher than the human exposure at the 100 mg/day clinical dose. The increased incidence of hepatic tumours was likely secondary to chronic hepatic toxicity at this high dose. The clinical significance of these findings for humans is unknown.
In a two year carcinogenicity study conducted in mice, sitagliptin did not increase tumour incidence at oral doses up to 500 mg/kg/day (approximately 68 times human exposure at the clinical dose of 100 mg/day).
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Januvia (sitagliptin phosphate monohydrate) is an orally active inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme for the treatment of type 2 diabetes. Sitagliptin differs in chemical structure and pharmacological action from GLP-1 analogues, insulin, sulfonylureas or meglitinides, biguanides, peroxisome proliferators-activated receptor gamma (PPARγ) agonists, alpha-glucosidase inhibitors, and amylin analogues.
Chemical structure. The chemical name of sitagliptin phosphate monohydrate is 7-[(3R)-3-amino-1-oxo-4- (2,4,5-trifluorophenyl)butyl]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)- 1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate.
The empirical formula is C16H15F6N5O.H3PO4.H2O and the molecular weight is 523.32. The structural formula is:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSSIPHMO.gif Sitagliptin phosphate monohydrate is a white to off white, crystalline, nonhygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone and acetonitrile; and insoluble in isopropanol and isopropyl acetate. The pH of a saturated water solution of sitagliptin phosphate monohydrate is 4.4. The partition coefficient is 1.8 and the pKa is 7.7.
CAS number. The CAS Registry Number is 654671-77-9.
7 Medicine Schedule (Poisons Standard)
Prescription Only Medicine (Schedule 4).
Summary Table of Changes
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