Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Guidehouse Germany GmbH, Albrechtstr. 10c, 10117 Berlin, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors should be used with caution in patients with increased risk of DKA. In the clinical trials (pool of two 52-week placebo-controlled trials) of sotagliflozin, the incidence of diabetic ketoacidosis (DKA) was higher in the sotagliflozin treatment group compared with the placebo group (see section 4.8).
Before starting treatment, patients should be evaluated with respect to DKA risk.
Sotagliflozin should not be initiated when patients are at a higher risk of DKA, such as:
Patients using an insulin infusion pump have a higher risk of DKA and should be experienced with pump use, common trouble-shooting strategies when interruptions of insulin delivery via pump occur (issues with insertion site, clogged tubing, empty reservoir, etc.) and use of supplemental insulin injections with pen or syringe as needed in case of pump failure. Patients should consider monitoring ketones levels three to four hours after changing pump materials. Patients using a pump should also check their ketone levels with any suspected insulin interruption, regardless of blood glucose levels. Insulin injections should be given within 2 hours of an unexplained high blood glucose value and sotagliflozin treatment should be interrupted. If ketones are high follow instructions given above in Table 1 (see section 4.2).
Sotagliflozin should only be given to patients:
During a dedicated counselling session with the patient at the time of first prescription of sotagliflozin the Patient/Carer Guide and Patient Alert card, also available via the QRcode or website, should be presented. The Patient Alert Card is also provided in the product packaging.
The patient should be informed:
It is recommended that patients obtain several baseline blood or urine ketone levels over one to two weeks period prior to initiation of sotagliflozin therapy, and patients should become familiar with the behaviours/circumstances associated with elevated ketone levels and how to address them.
The risk of diabetic ketoacidosis 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. It is possible that adverse effects occurring with sotagliflozin may be similar to presenting symptoms of DKA. Patients should be assessed for ketoacidosis immediately if these symptoms occur, by measuring the urine or blood ketones, regardless of blood glucose level. DKA episodes during sotagliflozin use can be atypical, with patients not having blood sugar levels as high as expected. This atypical presentation of DKA (i.e. normal or slightly elevated blood glucose levels) can delay diagnosis and treatment.
Treatment with sotagliflozin should be stopped in patients who are hospitalized for major surgical procedures or acute serious medical illnesses.
After initiating sotagliflozin ketones should be monitored on a regular basis during the initial one to two weeks, then the frequency of ketone level testing should be individualised, according to the patient’s lifestyle and/or risk factors. For all patients, it is recommended that ketones should be measured with changes to the normal routine, including reduced carbohydrate intake, intercurrent illness, reductions in total daily insulin dosing, physical activity and stress. Ketones should be measured repetitively when any signs or symptoms consistent with DKA or euglycaemic DKA are present. Measurement of blood ketone levels is preferred over urine.
Patients must be informed about what actions to take if ketone levels are elevated. The recommended actions are listed in Table 1 (see section 4.2).
In patients where DKA is suspected or diagnosed, treatment with sotagliflozin should be discontinued immediately.
With sotagliflozin DKA may be present with low, normal or high blood glucose levels. DKA should be treated as per standard of care. Supplemental carbohydrate may be required based on glucose levels in addition to hydration and additional rapid acting insulin (see Table 1 in section 4.2).
Restarting sotagliflozin is not recommended, unless a cause for the ketoacidosis is identified and resolved (e.g., pump malfunction, acute intercurrent illness, excessive reduction of insulin).
Renal function abnormalities (increased serum creatinine and decreased eGFR) can occur after initiating sotagliflozin (see section 4.8). Patients with hypovolemia may be more susceptible to these changes.
Sotagliflozin should not be initiated in patients with an eGFR < 60 mL/min and should be discontinued at eGFR persistently below 45 mL/min (see section 4.2 and 4.8).
Sotagliflozin should not be used in patients with severe renal impairment, end stage renal disease (ESRD) or in patients on dialysis as it has not been studied in these patients (see section 4.2).
Monitoring of renal function is recommended as follows:
There is limited experience in clinical trials in patients with moderate and severe hepatic impairment. Sotagliflozin is not recommended in patients with moderate and severe hepatic impairment, as sotagliflozin exposure is increased in these patients (see sections 4.2 and 5.2).
Based on the mode of action of sodium glucose co-transporter 2 (SGLT-2) inhibitors, by increasing urinary glucose excretion (UGE), sotagliflozin induces an osmotic diuresis which may reduce intravascular volume and decrease blood pressure (see sections 4.8 and 5.1). Sotagliflozin may cause intravascular volume contraction (see section 4.8). Symptomatic hypotension may occur after initiating sotagliflozin particularly in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics. Before initiating sotagliflozin, volume contraction should be assessed and volume status should be corrected if indicated. Patients should be monitored for signs and symptoms of hypotension after initiating therapy.
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 sotagliflozin. Temporary interruption of treatment with sotagliflozin should be considered until the fluid loss is corrected.
Consistent with the mechanism of SGLT2 inhibition with increased UGE, sotagliflozin increases the risk for genital mycotic infections as reported in clinical trials (see section 4.8). Patients with a history of chronic or recurrent genital mycotic infections are more likely to develop genital mycotic infections. Patients should be monitored and treated as appropriate.
Temporary interruption of sotagliflozin should be considered when treating pyelonephritis and urosepsis.
Elderly may be at an increased risk of volume depletion (see section 4.2).
An increase in cases of lower limb amputation (primarily of the toe) has been observed in ongoing long-term, clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect. Like for all diabetic patients it is important to counsel patients on routine preventative footcare.
Post-marketing cases of necrotising fasciitis of the perineum, (also known as Fournier’s gangrene), have been reported in female and male patients taking other 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 uro-genital infection or perineal abscess may precede necrotizing fasciitis. If Fournier’s gangrene is suspected, sotagliflozin should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.
Due to its mechanism of action, patients taking sotagliflozin will test positive for glucose in their urine.
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 medicinal products that inhibit SGLT2. Alternative methods should be used to monitor glycaemic control.
The coadministration of a multiple dosing regimen of rifampicin, an inducer of various UGT and CYP metabolizing enzymes, with a single dose of 400 mg sotagliflozin resulted in a decrease in the AUC0-inf (60%) and Cmax (40%) of sotagliflozin. This decrease in exposure to sotagliflozin may decrease efficacy. If an enzyme inducer (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) must be co-administered with sotagliflozin, consider frequent monitoring of glucose level.
Interaction studies in healthy volunteers showed that metformin, metoprolol, midazolam, rosuvastatin and oral contraceptives had no clinically relevant effect on the pharmacokinetics of sotagliflozin.
There is an increase in AUC0-inf and Cmax of digoxin (27% and 52% respectively) when coadministered with sotagliflozin 400mg, due to inhibition of P-gp by sotagliflozin. Patients taking sotagliflozin with concomitant digoxin should be monitored appropriately.
An increase in total exposure and Cmax of rosuvastatin of ca 1.2- and 1.4-fold, respectively, was demonstrated when co-administered with sotagliflozin and is not deemed clinically relevant. However, the mechanism behind the limited increase in exposure is not completely elucidated as sotagliflozin and M19 (sotagliflozin 3-O-glucuronide) are characterized as BCRP inhibitors in vitro and M19 also as an inhibitor OATP1B3 and OAT3. Rosuvastatin is a known OATP, BCRP and OAT3 substrate. It cannot be ruled out that sotagliflozin may interact with other sensitive OAT3, OATP- and/or BCRPsubstrates (e.g.: fexofenadine, paclitaxel, bosentan, methotrexate, furosemide, benzylpenicillin) resulting in potentially larger increases of exposure than seen for rosuvastatin. It should be evaluated if additional safety monitoring is needed when using these substrates.
Based on in-vitro data, induction of CYP2C9, CYP2B6 and CYP1A2 cannot be ruled out. Substrates of these enzymes should be monitored for decreases in efficacy.
Interaction studies conducted in healthy volunteers show that sotagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, metoprolol, midazolam and oral contraceptives.
Insulin may increase the risk of hypoglycaemia. A lower dose of insulin may be required to minimise the risk of hypoglycaemia when used in combination with sotagliflozin (see section 4.2).
There are no data from the use of sotagliflozin in pregnant women.
Animal studies have shown that sotagliflozin crosses the placenta.
Animal studies do not indicate direct or indirect harmful effects with respect to fertility and pregnancy (see section 5.3). Pharmacologically-related reversible renal changes were observed in a rat postnatal study, corresponding to the second and third trimesters of human pregnancy (see section 5.3). Therefore, sotagliflozin is not recommended during the second and third trimesters of pregnancy. As a precautionary measure, when pregnancy is detected, treatment with sotagliflozin should be discontinued.
No data in humans are available on excretion of sotagliflozin into milk.
Available toxicological data in animals have shown excretion of sotagliflozin into milk.
A risk to the newborns/infants cannot be excluded.
Sotagliflozin should not be used during breast-feeding.
No studies on the effect on human fertility have been conducted for sotagliflozin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).
Sotagliflozin has no or negligible influence on the ability to drive and use machines.
However, patients should be alerted to the risk of hypoglycaemia as sotagliflozin is used in combination with insulin.
The most frequently reported adverse reactions were genital mycotic infections, diabetic ketoacidosis and diarrhoea.
The following adverse reactions have been identified in the pool of two 52-week placebo-controlled clinical trials described above. 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 2. Tabulated list of adverse reactions:
Very common: Female genital mycotic infections*,a,†
Common: Male genital mycotic infections*,b,†, urinary tract infections*,†
Common: Diabetic ketoacidosis*,†
Common: Volume depletion*,c, †
Common: Diarrhoea, flatulence
Common: Increased urinationd, blood creatinine increased/glomerular filtration decreased†
Common: Blood ketone body increased, serum lipids increasede , haematocrit increasedf
* See section 4.4
† See subsections below for additional information.
a Adverse event grouping, including, but not limited to, vulvovaginal mycotic infection, vaginal infection, vulvitis, vulvovaginal candidiasis, genital infection, genital candidiasis, genital infection fungal, vulvovaginitis, urogenital infection fungal.
b Adverse event grouping, including, but not limited to, balanoposthitis, genital infections fungal, balanitis candida, epididymitis.
c Adverse events grouping, including dehydration, hypovolaemia, postural dizziness, orthostatic hypotension, hypotension, syncope and presyncope when reported in context of volume depletion.
d Adverse events grouping, including urine output increased, polydipsia, micturition urgency, nocturia, pollakiuria and polyuria
e Mean percent changes from baseline for sotagliflozin 200 mg and 400 mg versus placebo, respectively, were HDL-C 3.3% and 4.2% versus 0.5%; LDL-C 5.0% and 6.1% versus 3.3%; triglycerides 5.7% and 5.4% versus 2.7%.
f The proportion of subjects that met the criteria haematocrit >50% was higher in the sotagliflozin 200 mg and 400 mg groups (6.7% and 8.2%) compared to the placebo group (2.7%).
In placebo-controlled clinical trials of sotagliflozin, patients were advised to monitor urine or blood ketones in case of suspected symptoms of DKA and seek medical advice/attention if their selfmeasured blood ketone reading was > 0.6 mmol/l. In the pooled 52-week data, the incidence of DKA was increased in a dose-dependent manner for sotagliflozin (2.9% and 3.8% for sotagliflozin 200 mg and 400 mg, respectively) compared to placebo (0.2%). The exposure-adjusted incidence rate was 3.12, 4.19 and 0.21 subjects per 100 patient-years for sotagliflozin 200 mg, sotagliflozin 400 mg and placebo. Fifteen of the 35 cases (43%) experienced DKA with glucose values in the glycaemic range 8 to 14 mmol/L. In the broader pool, including all type 1 diabetes mellitus patients in phase 2 and 3 studies, the exposure-adjusted incidence rate was 3.07, 5.29 and 0.76 subjects per 100 patient-years for sotagliflozin 200 mg, sotagliflozin 400 mg and placebo (see section 4.4).
Sotagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. Adverse reactions related to volume depletion (e.g., hypovolemia, blood pressure decreased, blood pressure systolic decreased, dehydration, hypotension, orthostatic hypotension, and syncope) were reported by 2.7%, 1.1% and 1.0% of patients treated with sotagliflozin 200mg, sotagliflozin 400 mg and placebo. Sotagliflozin may increase the risk of hypotension in patients at risk for volume contraction (see section 4.4).
The incidence of female genital infections (e.g. vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis and vulvitis) was increased in the sotagliflozin 200 mg and 400 mg group (15% and 17%, respectively) as compared to placebo (4.7%). Most of the events were mild or moderate and no serious case was reported. Discontinuation due to genital mycotic infections occurred in 1.2%, 1.1% and 0.8% of patients treated with sotagliflozin 200 mg, sotagliflozin 400 mg and placebo, respectively.
The incidence of male genital infections (e.g. balanoposthitis, genital infection fungal) was increased for sotagliflozin 200 mg (3.0%), sotagliflozin 400 mg (6.3%) compared to placebo (1.1%). All events were mild or moderate in intensity and no serious cases. Discontinuation due to genital mycotic infections occurred in 0%, 0.4% and 0.4% of patients treated with sotagliflozin 200 mg, sotagliflozin 400 mg and placebo, respectively.
The overall frequency of urinary tract infections reported were 7.1% and 5.5% for sotagliflozin 200 mg and sotagliflozin 400 mg compared to 6.1% for placebo. The incidence of UTI in female subjects was 12%, 7.0% and 11% and the incidence of UTI in male subjects was 2.3%, 4.0% and 1.8% for sotagliflozin 200 mg, sotagliflozin 400 mg and placebo, respectively. All UTI events were mild or moderate in intensity except for one severe case (male subject in the sotagliflozin 400 mg group). Two cases (2 cases of cystitis) were serious; both occurred in male subjects in the sotagliflozin 400 mg group.
Sotagliflozin was associated with decreases in mean eGFR at week 4 (-4.0% and -4.3% for sotagliflozin 200 mg and 400 mg) versus placebo (-1.3%) that were generally reversible during continuous treatment. Mean increases in serum creatinine from baseline to week 4 was 4.0%, 4.3% and 1.4% for sotagliflozin 200mg, sotagliflozin 400 mg and placebo, respectively. At week 24 and 52 the change from baseline in creatinine was equal to or less than 0.02 mg/dL for both sotagliflozin 200 and sotagliflozin 400 mg.
The incidence of renal-related events was low and similar across the groups (1.5%, 1.5% and 1.3% for sotagliflozin 200 mg, sotagliflozin 400 mg and placebo).
Table 3. Changes from baseline in serum creatinine and eGFR in the pool of two 52-week placebocontrolled studies:
| Placebo (N=526) | Sotagliflozin 200mg (N=524) | Sotagliflozin 400 mg (N=525) | ||
|---|---|---|---|---|
| Mean baseline values | N | 526 | 524 | 525 |
| Creatinine (mg/dL) | 0.85 | 0.85 | 0.85 | |
| eGFR (mL/min/1.73m 2) | 90.2 | 89.3 | 89.1 | |
| Mean change from baseline at week 4 | N | 511 | 502 | 505 |
| Creatinine (mg/dL) | 0.01 | 0.03 | 0.04 | |
| eGFR (mL/min/1.73 m²) | -1.15 | -3.57 | -3.81 | |
| Mean change from baseline at week 24 | N | 481 | 479 | 477 |
| Creatinine (mg/dL) | 0.01 | 0.02 | 0.02 | |
| eGFR (mL/min/1.73 m²) | -1.06 | -1.79 | -1.66 | |
| Mean change from baseline at week 52 | N | 374 | 392 | 380 |
| Creatinine (mg/dL) | 0.01 | 0.02 | 0.01 | |
| eGFR (mL/min/1.73 m²) | -0.70 | -2.14 | -0.57 | |
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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