Adverse reactions : תופעות לוואי

4.8   Undesirable effects

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 (see section 5.1). The incidence and type of adverse reactions in these two trials were similar to the adverse reactions seen with ertugliflozin. There were no additional adverse reactions identified in the pooling of these two placebo-controlled trials that included metformin relative to the three placebo-controlled studies with ertugliflozin (see below).

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 (see section 5.1) 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 (see section 5.1). 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” for frequencies and see section 4.4.

Tabulated list of adverse reactions
Adverse reactions listed below 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).


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

System Organ Class                                    Adverse Reaction Frequency
Infections and infestations
Very common                                           Vulvovaginal mycotic infection and other female genital mycotic infections*,†,1
Urinary tract infections†,1
Common
Balanitis candida and other male genital mycotic infections*,†,1
Not known
Necrotising fasciitis of the perineum (Fournier’s gangrene)*
Metabolism and nutrition disorders
Common                                                Hypoglycaemia*,†,1 
Rare                                                  Diabetic ketoacidosis*,†,1 
Very rare                                             Lactic acidosis*,2, Vitamin B12 deficiency‡,2 
Nervous system disorders
Common                                                Taste disturbance2 
Vascular disorders
Common                                                Volume depletion*,†,1 Gastrointestinal disorders
Very common                                           Gastrointestinal symptoms§,2 
Hepatobiliary disorders
Very rare                                             Liver function test abnormal2, Hepatitis2 Skin and subcutaneous tissue disorders
Very rare                                             Erythema2, Pruritus2, Urticaria2 
Renal and urinary disorders
Common                                                Increased urination¶,1 
Uncommon                                              Dysuria1, Blood creatinine increased/Glomerular filtration rate decreased†,1
Reproductive system and breast disorders
Common                                                Vulvovaginal pruritus1 
General disorders and administration site conditions
Common                                               Thirst#,1


Investigations
Common                                                Serum lipids changedÞ,1, Haemoglobin increasedß,1, BUN increasedà,1
1 Adverse reaction with ertugliflozin.
2 Adverse reaction with metformin.
* See section 4.4.
† See subsections below for additional information.
‡ Long-term treatment with metformin has been associated with a decrease in vitamin B absorption, which may very 12 rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anaemia).
§ 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 LDL-C 5.8%  and 8.4% versus 3.2%; total cholesterol 2.8% and 5.7% versus 1.1%; however, 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 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

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 sections 4.2 and 4.4). 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 hypoglycaemia 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 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 20.0%, 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 medication, documented hypoglycaemia was 36%, 27% and 36% for ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively (see sections 4.2, 4.4, and 4.5).

Diabetic ketoacidosis (ertugliflozin)
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 (see section 4.4).

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 section 4.4).

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 section 4.4).

Urinary tract infections (ertugliflozin)
In VERTIS CV, urinary tract infections occurred in 12.2%, 12.0% 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 4.0% 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.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form:
/https://sideeffects.health.gov.il