Summary of the safety profile: Ertugliflozin and Sitagliptin: The safety of concomitantly administered ertugliflozin and sitagliptin has been evaluated in 990 patients with type 2 diabetes mellitus treated for 26 weeks in three studies; a factorial study of ertugliflozin 5 mg or 15 mg in combination with sitagliptin 100 mg once daily compared to the individual components, a placebo-controlled study of ertugliflozin 5 mg or 15 mg as add-on therapy to sitagliptin 100 mg and metformin once daily, and a placebo-controlled study of initial therapy with ertugliflozin 5 mg or 15 mg once daily in combination with sitagliptin 100 mg once daily (see Pharmacology: Pharmacodynamics under Actions). The incidence and type of adverse reactions in these three studies were similar to the adverse reactions seen with ertugliflozin and are described as follows in Table 5. There were no additional adverse reactions identified in these three trials that included sitagliptin relative to the three placebo-controlled studies with ertugliflozin (see as follows).
Ertugliflozin: Pool of placebo-controlled trials: The primary assessment of safety was conducted in a pool of three 26-week, placebo-controlled trials. Ertugliflozin was used as monotherapy in one trial and as add-on therapy in two trials (see Pharmacology: Pharmacodynamics under Actions). These data reflect exposure of 1,029 patients to ertugliflozin with a mean exposure duration of approximately 25 weeks. Patients received ertugliflozin 5 mg (N=519), ertugliflozin 15 mg (N=510), or placebo (N=515) once daily.
The most commonly reported adverse reactions across the clinical program were vulvovaginal mycotic infection and other female genital mycotic infections. Serious diabetic ketoacidosis occurred rarely. See "Description of selected adverse reactions" as follows for frequencies and see Precautions.
Sitagliptin: Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea (4.7%-13.8%) and insulin (9.6%) (see Precautions).
Tabulated list of adverse reactions: Adverse reactions listed as follows are classified according to frequency and system organ class (SOC). Frequency categories are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). (See Table 5.)
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Description of selected adverse reactions: Volume depletion (ertugliflozin): Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. In the pool of placebo-controlled studies, the incidence of adverse events related to volume depletion (dehydration, dizziness postural, presyncope, syncope, hypotension and orthostatic hypotension) was low (< 2%) and not notably different across the ertugliflozin and placebo groups. In the subgroup analyses in the broader pool of Phase 3 studies, subjects with eGFR < 60 mL/min/1.73 m2, subjects ≥ 65 years of age and subjects on diuretics had a higher incidence of volume depletion in the ertugliflozin groups relative to the comparator group (see Dosage & Administration and Precautions). In subjects with eGFR < 60 mL/min/1.73 m2, the incidence was 5.1%, 2.6% and 0.5% for ertugliflozin 5 mg, ertugliflozin 15 mg and the comparator group and for subjects with eGFR 45 to < 60 mL/min/1.73 m2, the incidence was 6.4%, 3.7% and 0% respectively.
Hypoglycaemia (ertugliflozin): In the pool of placebo-controlled studies, the incidence of documented hypoglycemia was increased for ertugliflozin 5 mg and 15 mg (5.0% and 4.5%) compared to placebo (2.9%). In this population, the incidence of severe hypoglycaemia was 0.4% in each group. When ertugliflozin was used as monotherapy, the incidence of hypoglycaemic events in the ertugliflozin groups was 2.6% in both groups and 0.7% in the placebo group. When used as add-on to metformin, the incidence of hypoglycaemic events was 7.2% in the ertugliflozin 5 mg group, 7.8% in the ertugliflozin 15 mg group and 4.3% in the placebo group.
When ertugliflozin was added to metformin and compared to sulphonylurea, the incidence of hypoglycaemia was higher for the sulphonylurea (27%) compared to ertugliflozin (5.6% and 8.2% for ertugliflozin 5 mg and 15 mg, respectively).
In patients with moderate renal impairment taking insulins, SU, or meglitinides as background medication, documented hypoglycaemia was 36%, 27% and 36% for ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively (see Dosage & Administration, Precautions, and Interactions).
Diabetic Ketoacidosis (ertugliflozin): Across the clinical program for ertugliflozin, ketoacidosis was identified in 3 of 3,409 (0.1%) ertugliflozin-treated patients and 0.0% of comparator-treated patients (see Precautions).
Blood creatinine increased/Glomerular filtration rate decreased and renal-related events (ertugliflozin): Initial increases in mean creatinine and decreases in mean eGFR in patients treated with ertugliflozin were generally transient during continuous treatment. Patients with moderate renal impairment at baseline had larger mean changes that did not return to baseline at Week 26; these changes reversed after treatment discontinuation.
Renal-related adverse reactions (e.g., acute kidney injury, renal impairment, acute prerenal failure) may occur in patients treated with ertugliflozin, particularly in patients with moderate renal impairment where the incidence of renal-related adverse reactions was 2.5%, 1.3%, and 0.6% in patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively.
Genital mycotic infections (ertugliflozin): In the pool of three placebo-controlled clinical trials, female genital mycotic infections (e.g., genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis) occurred in 9.1%, 12%, and 3.0% of females treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. In females, discontinuation due to genital mycotic infections occurred in 0.6% and 0% of patients treated with ertugliflozin and placebo, respectively (see Precautions).
In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genital infection, genital infection fungal) occurred in 3.7%, 4.2%, and 0.4% of males treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males. In males, discontinuations due to genital mycotic infections occurred in 0.2% and 0% of patients treated with ertugliflozin and placebo, respectively. In rare instances, phimosis was reported and sometimes circumcision was performed (see Precautions).
Sitagliptin: In addition to the adverse reactions described in the table previously, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5% and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis. Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with sitagliptin (not reaching the 5% level, but occurring with an incidence of > 0.5% higher with sitagliptin than that in the control group) included osteoarthritis and pain in extremity.
Some adverse reactions were observed more frequently in studies of combination use of sitagliptin with other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These included hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin), influenza (common with insulin (with or without metformin)), nausea and vomiting (common with metformin), flatulence (common with metformin or pioglitazone), constipation (common with the combination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or the combination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin), and dry mouth (uncommon with insulin (with or without metformin)).
TECOS (trial evaluating cardiovascular outcomes with sitagliptin): The cardiovascular safety study with sitagliptin (TECOS) included 7,332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and < 50 ml/min/1.73 m2), and 7,339 patients treated with placebo in the intention-to-treat population. Both treatments were added to usual care targeting regional standards for HbA1c and CV risk factors. The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo.
In the intention-to-treat population, among patients who were using insulin and/or a sulphonylurea at baseline, the incidence of severe hypoglycaemia was 2.7% in sitagliptin-treated patients and 2.5% in placebo-treated patients; among patients who were not using insulin and/or a sulphonylurea at baseline, the incidence of severe hypoglycaemia was 1.0% in sitagliptin-treated patients and 0.7% in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3% in sitagliptin-treated patients and 0.2% in placebo-treated patients.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.