Metformin and Ertugliflozin

A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g., every 3-6 months.

Initiation of this medicinal product is not recommended in patients with a GFR less than 45 mL/min.

Because the glycaemic lowering efficacy of ertugliflozin is reduced in patients with moderate renal impairment and likely absent in patients with severe renal impairment, if further glycaemic control is needed, the addition of other anti-hyperglycaemic agents should be considered.

The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin in patients with GFR <60 mL/min.

If no adequate strength of ertugliflozin/metformin combination is available, individual monocomponents should be used instead of the fixed-dose combination.

There are no data from the use of ertugliflozin/metformin in pregnant women.

A limited amount of data suggests the use of metformin in pregnant women is not associated with an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or post-natal development.

There are limited data from the use of ertugliflozin in pregnant women. Based on results from animal studies, ertugliflozin may affect renal development and maturation. Therefore, ertugliflozin/metformin should not be used during pregnancy.

There is no information regarding the presence of ertugliflozin in human milk, the effects on the breast-fed infant, or the effects on milk production. Metformin is present in human breast milk. Ertugliflozin and metformin are present in the milk of lactating rats. Ertugliflozin caused effects in the offspring of lactating rats.

Pharmacologically mediated effects were observed in juvenile rats treated with ertugliflozin. Since human kidney maturation occurs in utero and during the first 2 years of life when exposure from breast-feeding may occur, a risk to newborns/infants cannot be excluded. Ertugliflozin/metformin should not be used during breast-feeding.

Fertility

The effect of ertugliflozin/metformin on fertility in humans has not been studied. No effects of ertugliflozin or metformin on fertility were observed in animal studies.

Ertugliflozin/metformin combination has no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia when ertugliflozin/metformin is used in combination with insulin or an insulin secretagogue and to the elevated risk of adverse reactions related to volume depletion, such as postural dizziness.

Summary of the safety profile

Ertugliflozin and metformin

The safety of concomitantly administered ertugliflozin and metformin has been evaluated in 1 083 patients with type 2 diabetes mellitus treated for 26 weeks in a pool of two placebo-controlled trials: as ertugliflozin add on therapy to metformin and as ertugliflozin add-on therapy to sitagliptin and metformin. The incidence and type of adverse reactions in these two trials were similar to the adverse reactions seen with the individual monotherapies ertugliflozin and metformin as described below in Table 1.

Ertugliflozin

The safety and tolerability of ertugliflozin were assessed in 7 placebo- or active comparator-controlled studies with a total of 3 409 patients with type 2 diabetes mellitus treated with ertugliflozin 5 mg or 15 mg. In addition, the safety and tolerability of ertugliflozin in patients with type 2 diabetes and established atherosclerotic cardiovascular disease were assessed in VERTIS CV with a total of 5 493 patients treated with ertugliflozin 5 mg or 15 mg and a mean duration of exposure of 2.9 years.

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. 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 urinary tract infections, vulvovaginal mycotic infection, and other female genital mycotic infections. Serious DKA occurred rarely.

Tabulated list of adverse reactions

Adverse reactions listed below are classified according to frequency and system organ class (SOC), within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness 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).

Table 1. Adverse reactions from placebo- and active comparator-controlled clinical trials and post-marketing experience:

¹ Adverse reaction with ertugliflozin.
² Adverse reaction with metformin.
^† See subsections below for additional information.
^§ Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.
^¶ Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.
^# Includes: thirst and polydipsia.
^Þ Mean percent changes from baseline for ertugliflozin 5 mg and 15 mg versus placebo, respectively, were low-density lipoprotein cholesterol (LDL-C) 5.8% and 8.4% versus 3.2%; total cholesterol 2.8% and 5.7% versus 1.1%; however, high-density lipoprotein cholesterol (HDL-C) 6.2% and 7.6% versus 1.9%. Median percent changes from baseline for ertugliflozin 5 mg and 15 mg versus placebo, respectively, were triglycerides -3.9% and -1.7% versus 4.5%.
^ß The proportion of subjects having at least 1 increase in haemoglobin >2.0 g/dL was higher in the ertugliflozin 5 mg and 15 mg groups (4.7% and 4.1%, respectively) compared to the placebo group (0.6%).
^à The proportion of subjects having any occurrence of blood urea nitrogen (BUN) values ≥50% increase and value >ULN was numerically higher in the ertugliflozin 5 mg group and higher in the 15 mg group (7.9% and 9.8%, respectively) relative to the placebo group (5.1%).

Description of selected adverse reactions

Ertugliflozin

Volume depletion

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. 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

In the pool of placebo-controlled studies, the incidence of documented hypoglycaemia was increased for ertugliflozin 5 mg and 15 mg (5% 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 the VERTIS CV sub-studies, when ertugliflozin was added to insulin with or without metformin, the incidences of documented hypoglycaemia were 39.4%, 38.9% and 37.5% for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively. When ertugliflozin was added to a sulphonylurea, the incidences of hypoglycaemia were 7.3%, 9.3% and 4.2% for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively. When ertugliflozin was added to metformin and a sulphonylurea, the incidences of hypoglycaemia were 20%, 26.5% and 14.5% for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively.

In patients with moderate renal impairment taking insulins, sulphonylurea, or meglitinides as background medicinal products, documented hypoglycaemia was 36%, 27% and 36% for ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively.

Diabetic ketoacidosis

In VERTIS CV, ketoacidosis was identified in 19 (0.3%) ertugliflozin-treated patients and in 2 (0.1%) placebo treated patients. Across 7 other phase 3 clinical trials in the ertugliflozin development program, ketoacidosis was identified in 3 (0.1%) ertugliflozin-treated patients and 0 (0%) of comparator-treated patients.

Blood creatinine increased/Glomerular filtration rate decreased and renal-related events

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.

In VERTIS CV, treatment with ertugliflozin was associated with an initial decrease in mean eGFR (at Week 6, -2.7, -3.8 and -0.4 mL/min/1.73 m² in the ertugliflozin 5 mg, ertugliflozin 15 mg and placebo groups, respectively) followed by a return toward baseline. Long-term, continued treatment with ertugliflozin was associated with a slower decline in eGFR compared to placebo (up to week 260).

In VERTIS CV, the incidences of renal-related adverse reactions (e.g., acute kidney injury, renal impairment, acute prerenal failure) were 4.2%, 4.3% and 4.7% in patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo respectively in the overall population and were 9.7%, 10% and 10.2% in patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo respectively in patients with an eGFR from 30 to less than 60 mL/min/1.73 m².

Genital mycotic infections

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% 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.

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.

Urinary tract infections

In VERTIS CV, urinary tract infections occurred in 12.2%, 12% and 10.2% of patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively. The incidences of serious urinary tract infections were 0.9%, 0.4%, and 0.8% with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively.

Across 7 other phase 3 clinical trials in the ertugliflozin development program, the incidences of urinary tract infections were 4% and 4.1% for ertugliflozin 5 mg and 15 mg groups and 3.9% for placebo. Most of the events were mild or moderate, and no serious cases were reported.