STEGLUJAN Film-coated tablet Ref.[107097] Active ingredients: Ertugliflozin Sitagliptin Sitagliptin and Ertugliflozin

Source: European Medicines Agency (EU)  Revision Year: 2023  Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

General

Steglujan should not be used in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis (DKA) in these patients.

Acute pancreatitis

Use ofdipeptidyl peptidase-4 (DPP-4) inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Steglujan and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Steglujan should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

Hypotension/Volume depletion

Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction. Therefore, symptomatic hypotension may occur after initiating Steglujan (see section 4.8), particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m² or CrCl less than 60 mL/min), elderly patients (≥ 65 years), patients on diuretics, or patients on anti-hypertensive therapy with a history of hypotension. Before initiating Steglujan, volume status should be assessed and corrected if indicated. Monitor for signs and symptoms after initiating therapy.

Due to its mechanism of action, ertugliflozin induces an osmotic diuresis and increases serum creatinine and decreases eGFR. Increases in serum creatinine and decreases in eGFR were greater in patients with moderate renal impairment (see section 4.8).

In case of conditions that may lead to fluid loss (e.g., gastrointestinal illness), careful monitoring of volume status (e.g., physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended for patients receiving Steglujan. Temporary interruption of treatment with Steglujan should be considered until the fluid loss is corrected.

Diabetic ketoacidosis

Rare cases of DKA, including life-threatening and fatal cases, have been reported in clinical trials and post-marketing in patients treated with sodium glucose co-transporter-2 (SGLT2) inhibitors, including ertugliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/L (250 mg/dL). It is not known if DKA is more likely to occur with higher doses of ertugliflozin.

The risk of DKA must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level. In patients where DKA is suspected or diagnosed, treatment with Steglujan should be discontinued immediately.

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with Steglujan may be restarted when the ketone values are normal and the patient’s condition has stabilised.

Before initiating Steglujan, factors in the patient history that may predispose to ketoacidosis should be considered.

Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g., type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery, or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.

Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.

The safety and efficacy of Steglujan in patients with type 1 diabetes have not been established and Steglujan should not be used for treatment of patients with type 1 diabetes. Limited data from clinical trials suggest that DKA occurs with common frequency when patients with type 1 diabetes are treated with SGLT2 inhibitors.

Lower limb amputations

In a long-term cardiovascular outcomes study VERTIS CV (eValuation of ERTugliflozin effIcacy and Safety, CardioVascular), a study in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease, non-traumatic lower limb amputations (primarily of the toe) were reported with an incidence of 2% (0.57 subjects with event per 100 patient-years), 2.1% (0.60 subjects with event per 100 patient-years) and 1.6% (0.47 subjects with event per 100 patient-years) for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo groups. The event rates of lower limb amputations were 0.75 and 0.96 versus 0.74 events per 100 patient-years for ertugliflozin 5 mg and ertugliflozin 15 mg versus placebo, respectively. An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term clinical studies in type 2 diabetes mellitus with SGLT2 inhibitors. It is not known whether this constitutes a class effect. It is important to counsel patients with diabetes on routine preventative foot care.

Renal impairment

The efficacy of ertugliflozin for glycaemic control is dependent on renal function, and glycaemic efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see section 4.2).

Steglujan should not be initiated in patients with an eGFR below 45 mL/min/1.73 m² or CrCl below 45 mL/min. Steglujan should be discontinued when eGFR is persistently below 45 mL/min/1.73 m² or CrCl is persistently below 45 mL/min due to a reduction of efficacy.

Monitoring of renal function is recommended as follows:

  • Prior to Steglujan initiation and periodically during treatment (see section 4.2).
  • More frequently in patients with an eGFR below 60 mL/min/1.73 m² or a CrCl below 60 mL/min.

Hypoglycaemia with concomitant use with insulin and insulin secretagogues

Ertugliflozin may increase the risk of hypoglycaemia when used in combination with insulin and/or an insulin secretagogue, which are known to cause hypoglycaemia (see section 4.8). Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimise the risk of hypoglycaemia when used in combination with Steglujan (see sections 4.2 and 4.5).

Genital mycotic infections

Ertugliflozin increases the risk of genital mycotic infections. In trials with SGLT2 inhibitors, patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections (see section 4.8). Patients should be monitored and treated appropriately.

Urinary tract infections

Urinary glucose excretion may be associated with an increased risk of urinary tract infections (see section 4.8). Temporary interruption of ertugliflozin should be considered when treating pyelonephritis or urosepsis.

Necrotising fasciitis of the perineum (Fournier’s gangrene)

Post-marketing cases of necrotising fasciitis of the perineum, (also known as Fournier’s gangrene), have been reported in female and male patients taking SGLT2 inhibitors. This is a rare but serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment.

Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either urogenital infection or perineal abscess may precede necrotising fasciitis. If Fournier’s gangrene is suspected, Steglujan should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.

Hypersensitivity reactions

Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported (see section 4.8). These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, Steglujan should be discontinued. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated.

Bullous pemphigoid

There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, Steglujan should be discontinued.

Elderly patients

Elderly patients may be at an increased risk of volume depletion and renal impairment. Patients 65 years and older treated with ertugliflozin, had a higher incidence of adverse reactions related to volume depletion compared to younger patients. In a long-term cardiovascular outcomes study VERTIS CV, safety and efficacy were similar for patients age 65 years and older compared to patients younger than 65 (see sections 4.2 and 4.8).

Cardiac failure

There is no experience in clinical studies with Steglujan in New York Heart Association (NYHA) class IV.

Urine laboratory assessments

Due to the mechanism of action of ertugliflozin, patients taking Steglujan will test positive for glucose in their urine. Alternative methods should be used to monitor glycaemic control.

Interference with 1,5-anhydroglucitol (1,5-AG) assay

Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Alternative methods should be used to monitor glycaemic control.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacokinetic drug interaction studies with Steglujan have not been performed; however, such studies have been conducted with ertugliflozin and sitagliptin, the individual active substances of Steglujan.

Ertugliflozin

Pharmacodynamic interactions

Diuretics

Ertugliflozin may add to the diuretic effect of diuretics and may increase the risk of dehydration and hypotension (see section 4.4).

Insulin and insulin secretagogues

Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Ertugliflozin may increase the risk of hypoglycaemia when used in combination with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with Steglujan (see sections 4.2, 4.4, and 4.8).

Pharmacokinetic interactions

Effects of other medicinal products on the pharmacokinetics of ertugliflozin

Metabolism by UGT1A9 and UGT2B7 is the primary clearance mechanism for ertugliflozin.

Interaction studies conducted in healthy subjects, using a single dose design, suggest that the pharmacokinetics of ertugliflozin are not altered by sitagliptin, metformin, glimepiride, or simvastatin.

Multiple-dose administration of rifampicin (a uridine 5'-diphospho-glucuronosyltransferase [UGT] and cytochrome P450 [CYP] inducer) decreases ertugliflozin area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax) by 39% and 15%, respectively. This decrease in exposure is not considered clinically relevant and therefore, no dose adjustment is recommended. A clinically relevant effect with other inducers (e.g., carbamazepine, phenytoin, phenobarbital) is not expected.

The impact of UGT inhibitors on the pharmacokinetics of ertugliflozin has not been studied clinically, but potential increase in ertugliflozin exposure due to UGT inhibition is not considered to be clinically relevant.

Effects of ertugliflozin on the pharmacokinetics of other medicinal products

Interaction studies conducted in healthy volunteers suggest that ertugliflozin had no clinically relevant effect on the pharmacokinetics of sitagliptin, metformin, and glimepiride.

Coadministration of simvastatin with ertugliflozin resulted in a 24% and 19% increase in AUC and Cmax of simvastatin, respectively, and 30% and 16% increase in AUC and Cmax of simvastatin acid, respectively. The mechanism for the small increases in simvastatin and simvastatin acid is unknown and is not perpetrated through organic anion transporting polypeptide (OATP) inhibition by ertugliflozin. These increases are not considered to be clinically meaningful.

Sitagliptin

Pharmacokinetic interactions

Effects of other medicinal products on sitagliptin

Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. In vitro studies indicate that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8.

Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or ESRD. For this reason, it is possible that potent CYP3A4 inhibitors (i.e., ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD.

Interaction studies conducted in patients with type 2 diabetes or healthy volunteers suggest that metformin and ciclosporin had no clinically relevant effect on the pharmacokinetics of sitagliptin.

Effects of sitagliptin on other medicinal products

In drug interaction studies, sitagliptin did not have clinically meaningful effects on the pharmacokinetics of the following: metformin, rosiglitazone, glyburide, simvastatin, warfarin, and oral contraceptives.

Digoxin

Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased on average by 11% and the plasma Cmax on average by 18%. No dose adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of Steglujan in pregnant women. 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 (see section 5.3). Therefore, Steglujan should not be used during pregnancy.

Breast-feeding

There is no information regarding the presence of Steglujan or its individual components in human milk, the effects on the breast-fed infant, or the effects on milk production. No studies in lactating animals have been conducted with the combined components of Steglujan. Ertugliflozin and sitagliptin 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 (see section 5.3). 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. Steglujan should not be used during breast-feeding.

Fertility

The effect of Steglujan on fertility in humans has not been studied. No effects of ertugliflozin or sitagliptin on fertility were observed in animal studies (see section 5.3).

4.7. Effects on ability to drive and use machines

Steglujan has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported with sitagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when Steglujan 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 (see sections 4.2, 4.4, and 4.8).

4.8. Undesirable effects

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 section 5.1). The incidence and type of adverse reactions in these three studies were similar to the adverse reactions seen with the individual monotherapies ertugliflozin and sitagliptin 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 (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 urinary tract infections, vulvovaginal mycotic infection and other female genital mycotic infections. Serious DKA occurred rarely (see section 4.4).

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 section 4.4).

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:

System organ class
Frequency
Adverse reaction
Infections and infestations
Very commonUrinary tract infections†,1
Vulvovaginal mycotic infection and other female
genital mycotic infections*†,1
CommonBalanitis candida and other male genital mycotic
infections*†,1
Not knownNecrotising fasciitis of the perineum (Fournier’s
gangrene)*
Blood and lymphatic system disorders
Rare Thrombocytopenia2
Immune system disorders
Not known Hypersensitivity reactions including anaphylactic
responses*a,2
Metabolism and nutrition disorders
CommonHypoglycaemia*†,1,2
RareDKA*†,1
Nervous system disorders
CommonHeadache2
UncommonDizziness2
Respiratory, thoracic and mediastinal disorders
Not known Interstitial lung diseasea,2
Gastrointestinal disorders
UncommonConstipation2
Not knownFatal and non-fatal haemorrhagic and necrotising
pancreatitis*a,2
Acute pancreatitis*a,b,2
Vomitinga,2
Skin and subcutaneous tissue disorders
UncommonPruritusa,2
Not knownExfoliative skin conditions including
Stevens-Johnson syndrome*a,2
Angioedema*a,2
Bullous pemphigoid*a,2
Cutaneous vasculitis*a,2
Rash*a,2
Urticaria*a,2
Musculoskeletal and connective tissue disorders
Not knownArthropathya,2
Back paina,2
Arthralgiaa,2
Myalgiaa,2
Vascular disorders
Common Volume depletion*†,1
Renal and urinary disorders
CommonIncreased urination‡,1
UncommonDysuria1, Blood creatinine increased/Glomerular
filtration rate decreased†,1
Not knownAcute renal failurea,2
Impaired renal functiona,2
Reproductive system and breast disorders
Common Vulvovaginal pruritus1
General disorders and administration site conditions
Common Thirst§,1
Investigations
Common Serum lipids changed¶,1, Haemoglobin
increased**1, BUN increased¶¶,1

1 Adverse reaction with ertugliflozin.
2 Adverse reaction with sitagliptin.
* See section 4.4.
See subsections below for additional information.
Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.
§ Includes: thirst and polydipsia.
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%.
** 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%).
¶¶ The proportion of subjects having any occurrence of blood urea nitrogen (BUN) values ≥50% increase and value >upper limit of normal (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%).
a Adverse reactions were identified through post-marketing surveillance.
b See Sitagliptin cardiovascular outcomes study (TECOS) below.

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 (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

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 (see sections 4.2, 4.4, and 4.5).

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 (see section 4.4).

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 (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

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.

Sitagliptin

In addition to the adverse reactions described in the table above, 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 haemoglobin A1c (HbA1c) and cardiovascular (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% 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 via the national reporting system listed in Appendix V.

6.2. Incompatibilities

Not applicable.

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