* All doses administered as single dose unless otherwise specified. † AUC is reported as AUC 0-∞ unless otherwise specified. ‡ Metformin hydrochloride extended-release tablets 500 mg. § Ratio of arithmetic means. ¶ Steady-state 100 mg topiramate every 12 hr + metformin 500 mg every 12 hr AUC = AUC 0-12hr.  

 

No dosing adjustments required for the following: 

Glyburide 5 mg 500 mg‡ Metformin‡ 0.98§ 0.99§ 

Furosemide 40 mg 850 mg Metformin 1.09§ 1.22§ 

Nifedipine 10 mg 850 mg Metformin 1.16 1.21 

Propranolol 40 mg 850 mg Metformin 0.90 0.94 

Ibuprofen 400 mg 850 mg Metformin 1.05§ 1.07§ 

Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin. [See Warnings and Precautions (5.1) and Drug Interactions (7.2).] 

Cimetidine 400 mg 850 mg Metformin 1.40 1.61 

Carbonic anhydrase inhibitors may cause metabolic acidosis. [See Warnings and Precautions (5.1) and Drug Interactions (7.2).] 

Topiramate 100 mg¶ 500 mg¶ Metformin 1.25¶ 1.17 

 

13 NONCLINICAL TOXICOLOGY 

 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis 

 

Ertugliflozin 

 

Carcinogenicity was eva luated in CD-1 mice and Sprague-Dawley rats. In the mouse study, ertugliflozin was administered by oral gavage at doses of 5, 15, and 40 mg/kg/day for up to 97 weeks in males and 102 weeks in females. There were no ertugliflozin-related neoplastic findings at doses up to 40 mg/kg/day (approximately 50 times human exposure at the maximum recommended human dose [MRHD] of 15 mg/day based on AUC). In the rat study, ertugliflozin was administered by oral gavage at doses of 1.5, 5, and 15 mg/kg/day for up to 92 weeks in females and 104 weeks in males. Ertugliflozin-related neoplastic findings included an increased incidence of adrenal medullary pheochromocytoma (PCC) in male rats at 15 mg/kg/day. Although the molecular mechanism remains unknown, this finding may be related to carbohydrate malabsorption leading to altered calcium homeostasis, which has been associated with PCC development in rats and has unclear relevancy to human risk. The no-observed-effect level (NOEL) for neoplasia was 5 mg/kg/day (approximately 16 times human exposure at the MRHD of 15 mg/day, based on AUC).

Metformin hydrochloride 

 

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

 

Mutagenesis 

Ertugliflozin