Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Segluromet should not be used in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis (DKA) in these patients.
Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.
In case of dehydration (severe vomiting, diarrhoea, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a healthcare professional is recommended.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and non-steroidal anti-inflammatory drugs [NSAIDs]) should be initiated with caution in metformintreated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).
Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (<7.35), increased plasma lactate levels (>5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.
Intravascular administration of iodinated contrast agents may lead to contrast-induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Segluromet should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.5).
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).
Segluromet should not be initiated in patients with a GFR below 45 mL/min. Segluromet should be discontinued when GFR is persistently below 45 mL/min.
GFR should be assessed before treatment initiation and regularly thereafter (see section 4.2). More frequent renal function monitoring is recommended in patients with a GFR below 60 mL/min. Metformin is contraindicated in patients with GFR <30 mL/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).
Segluromet must be discontinued at the time of surgery under general, spinal, or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.
Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction. Therefore, symptomatic hypotension may occur after initiating Segluromet (see section 4.8), particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m² or a creatinine clearance (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 Segluromet, 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 ertugliflozin. Temporary interruption of treatment should be considered until the fluid loss is corrected.
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 Segluromet 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 Segluromet may be restarted when the ketone values are normal and the patient’s condition has stabilised.
Before initiating Segluromet, 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 Segluromet in patients with type 1 diabetes have not been established and Segluromet 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.
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.
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). Therefore, a lower dose of insulin or insulin secretagogue may be required to minimise the risk of hypoglycaemia when used in combination with Segluromet (see sections 4.2 and 4.5).
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 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.
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, Segluromet should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.
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. The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than 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). Assess renal function more frequently in elderly patients.
There is no experience in clinical studies with ertugliflozin in New York Heart Association (NYHA) class IV.
Due to the mechanism of action of ertugliflozin, patients taking Segluromet will test positive for glucose in their urine. Alternative methods should be used to monitor glycaemic control.
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 medicines containing an SGLT2 inhibitor. Alternative methods should be used to monitor glycaemic control.
Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contraindicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
Pharmacokinetic drug interaction studies with Segluromet have not been performed; however, such studies have been conducted with ertugliflozin and metformin, the individual active substances of Segluromet.
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, 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 Segluromet (see sections 4.2, 4.4, and 4.8).
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.
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 polypeptides (OATP) inhibition by ertugliflozin. These increases are not considered to be clinically meaningful.
Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.
Segluromet must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.4).
Some medicinal products can adversely affect renal function, which may increase the risk of lactic acidosis, e.g., NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.
Metformin is a substrate of both transporters OCT1 and OCT2.
Coadministration of metformin with
Caution is therefore advised, especially in patients with renal impairment, when these medicinal products are coadministered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin.
Glucocorticoids (given by systemic and local administration), beta 2 agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.
There are no data from the use of Segluromet 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 (see section 5.3).
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, Segluromet 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 (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. Segluromet should not be used during breast-feeding.
The effect of Segluromet on fertility in humans has not been studied. No effects of ertugliflozin or metformin on fertility were observed in animal studies (see section 5.3).
Segluromet has no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia when Segluromet 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).
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 the individual monotherapies ertugliflozin and metformin as described below in Table 1.
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.
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).
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 common | Urinary tract infections†,1 Vulvovaginal mycotic infection and other female genital mycotic 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, Vitamin B12 decrease/deficiency,2 |
| Rare | DKA*,†,1 |
| Very rare | Lactic acidosis*,2 |
| Nervous system disorders | |
| Common | Taste disturbance2 |
| Vascular disorders | |
| Common | Volume depletion*,†,1 |
| Gastrointestinal disorders | |
| Very common | Gastrointestinal symptoms§,2 |
| Hepatobiliary disorders | |
| Very rare | Hepatitis2, Liver function test abnormal2 |
| 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.
§ 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%).
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.
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).
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).
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.
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).
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.
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.
Not applicable.
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