Zynquista - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Zynquista 200 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 200 mg sotagliflozin.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Oval, blue, film-coated tablet printed with “2456” on one side in black ink (tablet length: 14.2 mm, tablet width: 8.7 mm).

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Zynquista is indicated as an adjunct to insulin therapy to improve glycaemic control in adults with type 1 diabetes mellitus with a Body Mass Index (BMI) > 27 kg/m2, who have failed to achieve adequate glycaemic control despite optimal insulin therapy.

4.2 Posology and method of administration

Therapy with Zynquista should be initiated and supervised by a physician experienced in the management of type 1 diabetes mellitus.

Posology

The recommended dose is 200 mg sotagliflozin once daily before the first meal of the day. After at least three months, if additional glycaemic control is needed, in patients tolerating sotagliflozin 200 mg, the dose may be increased to 400 mg once daily.

Before initiating treatment with sotagliflozin 200 mg and before increasing dose to sotagliflozin 400 mg:

• – Risk factors for diabetic ketoacidosis (DKA) should be assessed and ketone levels should be evaluated as normal. If ketones are elevated (blood beta-hydroxybutyrate (BHB) reading is greater than 0.6 mmol/L or urine ketones one plus (+)) treatment with sotagliflozin should not be initiated nor the dose should be increased to sotagliflozin 400 mg until the ketone levels are normal (see sections 4.4).

• – It is recommended that patients obtain several baseline blood or urine ketone levels over one to two weeks prior to initiation of sotagliflozin therapy, and, patients should become familiar with how their behaviours and circumstances affect their ketone levels.

• – Patients must be able to perform self-management of the day-to-day aspects of their disease including self-monitoring of glucose and ketones.

• – Patients should be informed, in a dedicated education session, on the risk of DKA, how to recognize DKA risk factors, signs or symptoms, how and when to monitor ketone levels and what actions to take when ketone levels are elevated (see section 4.4).

• – Correction of volume depletion prior to initiation of sotagliflozin is recommended in patients

with this condition (see section 4.4).

Sotagliflozin must only be administered as an adjunct to insulin. In order to avoid hypoglycaemia with the first dose of sotagliflozin a 20% reduction in the first mealtime bolus insulin may be considered. Subsequent bolus doses should be adjusted individually based on blood glucose results. No reduction in basal insulin is recommended when initiating sotagliflozin. Subsequently, basal insulin should be adjusted based on blood glucose results. When needed, insulin dose reduction should be done cautiously to avoid ketosis and DKA.

Ketone monitoring during treatment:

During the initial one to two weeks of treatment with sotagliflozin, ketones should be monitored on a regular basis. After starting therapy, the frequency of ketone level testing (either blood or urine) should be individualized, according to the patient's lifestyle and/or risk factors (see section 4.4). Patients should be informed about what actions to take if ketone levels are elevated. The recommended actions are listed in Table 1. Measurement of blood ketone levels is preferred over urine.

Table 1: Actions to take in case of elevated ketone levels

Clinical stage	Blood Ketone (betahydroxybu­tyrate)	Urine Ketone	Actions
Ketonaemia or Ketonuria	0.6–1.5 mmol/L	Trace or Small +	The patient may need to take extra rapid-acting insulin and drink water. Extra carbohydrates should be taken if the glucose levels are normal or low. Ketone levels should be measured again after two hours. Check glucose levels frequently to avoid hyperglycaemia or hypoglycaemia. The patient should immediately seek medical advice and stop taking sotagliflozin if levels persist and symptoms present.
Impending DKA	> 1.5–3.0 mmol/L	Moderate ++	The patient should immediately seek medical advice and stop taking sotagliflozin. The patient may need to take extra rapid acting insulin and drink water. Extra carbohydrates should be taken if the glucose levels are normal or low. Ketone levels should be measured again after two hours. Check glucose levels frequently to avoid hyperglycaemia or

			hypoglycaemia.
Probable DKA	> 3.0 mmol/L	Large to very large +++ / ++++	The patient should go to emergency department without delay and stop taking sotagliflozin. The patient may need to take extra rapid-acting insulin and drink water. Extra carbohydrates should be taken if the glucose levels are normal or low.

Missed dose

If a dose is missed, it should be taken as soon as the patient remembers the missed dose. A double dose should not be taken on the same day.

Special populations

Elderly

No dosage adjustment is recommended based on age.

In patients 65 years and older, renal function and an increased risk for volume depletion should be taken into account (see sections 4.4 and 4.8). Due to the limited therapeutic experience in patients aged 75 years and older, initiation of sotagliflozin therapy is not recommended.

Renal impairment

Assessment of renal function is recommended prior to initiation of sotagliflozin and periodically thereafter (see section 4.4).

Initiation of sotagliflozin is not recommended when eGFR is less than 60 ml/min/1.73 m2 and should be discontinued if eGFR is persistently less than 45 mL/min/1.73 m2 (see sections 4.4 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 sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is recommended in patients with mild hepatic impairment. Sotagliflozin is not recommended in patients with moderate and severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of sotagliflozin in children and adolescents has not yet been established. No data are available.

Method of administration

Oral use.

Sotagliflozin should be taken once daily before the first meal of the day.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Diabetic ketoacidosis

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 initiating sotagliflozin

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 with low insulin needs.

• – Patient not on optimal insulin dose or who have recent issues with noncompliance or recurrent errors with insulin dosing and who are unlikely to maintain adequate insulin dosing.

• – Patients with recent or recurrent history of DKA (e.g.1 episode in the past 3 months or more than 1 episode in the past 6 months).

• – Patients with increased insulin requirements due to acute medical illness or surgery.

• – Patients with elevated ketones levels (BHB reading is greater than 0.6 mmol/L or urine ketones one plus (+)). If ketones are elevated (BHB reading is greater than 0.6 mmol/L), treatment with sotagliflozin should not be started until the ketone levels are normal (see section 4.2).

• – Patients unable or unwilling to monitor ketones.

• – Patients who insist on maintaining caloric restriction, carbohydrate restriction or ketogenic diet or who chronically under-dose insulin (e.g. in order to remain in a lipolytic state).

• – Patients with excessive alcohol consumption or who use illicit drugs.

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:

• – with access to ketone testing materials and immediate access to a clinician if blood or urine ketones are elevated.

• – who are able to monitor ketone levels and are educated in when it is most appropriate to do so.

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:

• – how to recognize the risk factors which can predispose to ketosis and DKA (including, but not limited to, recent or recurrent history of DKA, missed or reduced insulin doses, decreased caloric intake or severe dehydration, vigorous exercise, intercurrent illness, surgery, alcohol abuse, and in patients using an insulin infusion pump, insulin infusion interruption),

• – how to recognize DKA signs or symptoms, emphasizing that DKA could occur even when blood glucose levels are below 14 mmol/L (250 mg/dL),

• – when to discontinue sotagliflozin therapy (see section 4.2), – what actions to take when ketosis/DKA is suspected.

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.

Management of DKA risk

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.

During treatment with sotagliflozin

• – The patient should remain on optimal insulin dosing.

• – When needed to prevent hypoglycaemia, insulin dose reduction should be done cautiously to avoid ketosis and DKA (see section 4.2).

• – Consider discontinuing sotagliflozin if adequate insulinisation cannot be achieved on treatment.

Treatment with sotagliflozin should be stopped in patients who are hospitalized for major surgical procedures or acute serious medical illnesses.

Ketone monitoring during treatment

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).

Management of DKA

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 impairment

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:

• – Prior to initiation of sotagliflozin and monitored periodically, at least yearly, thereafter (see

section 4.2).

• – Prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter.

• – More frequent, at least 2 to 4 times per year, renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2.

Hepatic impairment

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).

Hypotension/ volume depletion

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.

Genital mycotic infections

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.

Urinary tract infections

Temporary interruption of sotagliflozin should be considered when treating pyelonephritis and urosepsis.

Elderly patients

Elderly may be at an increased risk of volume depletion (see section 4.2).

Lower limb amputations

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.

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 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.

Urine laboratory assessments

Due to its mechanism of action, patients taking sotagliflozin will test positive for glucose in their urine.

Drug/Laboratory test interference

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 medicinal products that inhibit SGLT2. Alternative methods should be used to monitor glycaemic control.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on sotagliflozin

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.

Effects o f sotagliflozin on other medicinal products

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 BCRP-substrates (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

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).

4.6 Fertility, pregnancy and lactation

Pregnancy

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.

Breast-feeding

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.

Fertility

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).

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions were genital mycotic infections, diabetic ketoacidosis and diarrhoea.

Tabulated list of adverse reactions

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

System Organ class	Frequency of occurrence
	Very common	Common	Uncommon
Infections and infestations	Female genital mycotic infections , a, 1	Male genital mycotic infections , b, 1 urinary tract infections*’ 1
Metabolism and nutrition disorders		Diabetic ketoacidosis*’ 1
Vascular disorders		Volume depletion, c, 1
Gastrointestinal disorders		Diarrhoea, flatulence
Renal and urinary disorders		Increased urinationd, blood creatinine increased/ glomerular filtration decreased1
Investigations		Blood ketone body increased, serum lipids increasede, haematocrit increasedf
See section 4.4 t 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. dAdverse events grouping, including urine output increased, polydipsia, micturition urgency, nocturia, pollakiuria and polyuria eMean 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%. fThe 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%)

Description of selected adverse reactions

Diabetic ketoacidosis

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).

Volume depletion

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).

Genital mycotic infections

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.

Urinary tract infections

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.

Blood creatinine increased/Glo­merular filtration decreased and renal-related events 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 placebo-controlled 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/1.73 m2)	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 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

4.9 Overdose

Multiple doses of 800 mg once daily were administrated in healthy volunteers and these doses were well tolerated.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status.

The removal of sotagliflozin by haemodialysis has not been studied.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, sodium-glucose co-transporter 2 (SGLT2) inhibitors, ATC code: A10BK06

Mechanism of action

Sotagliflozin is a dual inhibitor of sodium glucose cotransporter type 1 (SGLT1) and SGLT2. Local intestinal inhibition of SGLT1, the major transporter for glucose absorption, delays and reduces glucose absorption in the proximal intestine, resulting in a blunting and delay of postprandial hyperglycaemia. SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. By inhibiting SGLT2, sotagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Pharmacodynamic effects

Urinary glucose excretion

In a 12-week dose ranging study, consistent with SGLT2 inhibition, 24-h placebo corrected change from baseline Urinary Glucose Excretion (UGE) increased by 57.7 grams (p<0.001) and 70.5 grams (p<0.001) in patients with type 1 diabetes taking 200 mg and 400 mg sotagliflozin respectively, which is consistent with SGLT2 inhibition.

Post prandial glucose reduction

In a 12 week dose ranging study, consistent with SGLT1 inhibition, placebo corrected change from baseline 2-hour post prandial glucose (PPG), measured after a standardised mixed meal, was reduced by 1.52 mmol/L (p=0.15) and 2.73 mmol/L (p=0.006) in patients taking 200 mg and 400 mg sotagliflozin respectively, which is consistent with SGLT1 inhibition.

Clinical efficacy and safety

The efficacy and safety of sotagliflozin in patients with type 1 diabetes not adequately controlled on their current insulin therapy was evaluated in three double-blind, placebo-controlled studies. In InTandem1 (study 1) and in InTandem2 (study 2) sotagliflozin was used as add on to optimised insulin and in InTandem3 (Study 3) sotagliflozin was used as add on to any existing insulin regimen in patients not on HbA1c goal.

Study 1 and study 2

On a background of optimised insulin, the efficacy and safety of sotagliflozin 200 mg or 400 mg once daily versus insulin alone were evaluated in two double-blind, placebo controlled studies (study 1 and 2) performed in 1575 patients with type 1 diabetes on insulin pump or multiple daily injection therapy. Each study was of 52 weeks duration, with primary and key secondary endpoints at 24 weeks. Beginning 6 weeks prior to randomization, insulin dose was adjusted (optimised) to achieve the following glycaemic goals fasting/prepran­dial, self-monitored blood glucose (SMBG) 4.4–7.2 mmol/L and 2-hour/peak postprandial SMBG glucose <10 mmol/L.

Patients were then maintained on optimised insulin and randomized to sotagliflozin 200 mg, sotagliflozin 400 mg or insulin alone. For the first meal on Day 1, patients were instructed to decrease their calculated (or usual) mealtime carbohydrate bolus insulin by 30%. Insulin optimisation was continued throughout the study.

In study 1, a total of 793 patients entered the study. The mean age of patients was 46 years, 8.1% were 65 years or older. Mean duration of diabetes was 24.4 years, 60% of patients were using insulin pump and 40% were using multiple daily injections. In the study 48% were male and 92% were White and 84% of randomised patients completed the study. The mean eGFR was 87 mL/min/1.73 m2 and 5.7% of patients had eGFR between 45 and 60 mL/min/1.73 m2. The mean BMI was 30 kg/m2 and 23% of patients had SBP > 130 mmHg. At screening the HbAlc was 8.21%, 8.26% and 8.20% for insulin, insulin+sotagli­flozin 200 mg and insulin+sotagli­flozin 400 mg.

In study 2, a total of 782 patients entered the study. The mean age of patients was 41 years, 4.2% were 65 years or older. Mean duration of diabetes was 18 years, 26% of patients were using insulin pump and 74% were using multiple daily injections. In the study 52% were male and 96.2% were White and 87% of randomised patients completed the study. The mean eGFR was 92 mL/min/1.73 m2 and 3.3% had eGFR between 45 and 60 mL/min/1.73 m2. The mean BMI was 28 kg/m2 and 32% of patients had SBP > 130 mmHg. At screening the HbA1c was 8.42%, 8.35% and 8.38% for insulin, insulin+sotagli­flozin 200 mg and insulin+sotagli­flozin 400 mg.

At week 24, treatment with 200 mg or 400 mg sotagliflozin provided statistically significant reductions in HbA1c (p-value <0.001) compared to insulin alone. Treatment with sotagliflozin also resulted in reduction in body weight and FPG compared with insulin alone (see Table 4).

Main results for insulin dose and Diabetes Treatment Satisfaction Questionnaire and Diabetes Distress Screening Scale are presented in Table 4.

Table 4: Results at 24-week trial with sotagliflozin in patients with type 1 diabetes mellitus inadequately controlled on insulin (Study 1 – Study 2)

	Study 1			Study 2
	Insulin	Insulin + sotagliflozi n 200 mg	Insulin + sotagliflozin 400 mg	Insulin	Insulin + sotagliflozin 200 mg	Insulin + sotagliflozin 400 mg
N	268	263	262	258	261	263
HbAlc (%)
Baseline (after 6-week insulin optimisation), mean	7.54	7.61	7.56	7.79	7.74	7.71
At Week 24, mean	7.50	7.17	7.O8	7.79	7.36	7.35
Change from baseline, LS mean	-O.O7	–0.43	-O.48	-O.O2	-O.39	-O.37
Difference from insulin alone, LS mean [95%CI]	N/A	-O.36 [-0.45, -O.27]	-O.41 [-0.50, -O.32]	N/A	-O.37 [-0.48, -O.25]	-O.35 [-0.47, -O.24]
HbAlc < 7.0% at week 24, n (%)	61 (22.8)	97 (36.9)	123(46.9)	39 (15.1)	87 (33.3)	89 (33.8)
Body Weight (kg)
Baseline, mean	87.30	86.96	86.50	81.08	81.93	81.97
Change from baseline, LS mean	O.78	–1.57	–2.67	0.11	–1.88	–2.47
Difference from insulin alone, LS mean [95%CI]	N/A	–2.35 [-2.85, –1.85]	–3.45 [-3.95, –2.94]	N/A	–1.98 [-2.53, –1.44]	–2.58 [-3.12, –2.O4]
Bolus insulin dose (units/day)
Baseline, mean	31.72	30.27	30.75	32.08	31.12	31.89
% Change from baseline, LS mean	3.89	–1.8O	–8.78	5.9O	–7.O4	–10.47
% Difference from insulin alone, adjusted mean [95%CI]	N/A	–5.7 [-12.82, 1.42]	–12.67 [-19.79, –5.55]	N/A	–12.9 [-20.50, –5.38]	–16.3 [-23.90, –8.83]
Diabetes Treatment Satisfaction Questionnaire
Baseline, mean	28.9	28.4	29.2	28.2	28.3	28.4
Difference from placebo, LS mean [95%CI]	N/A	2.5 [1.7, 3.3]	2.5 [1.8, 3.3]	N/A	2.0 [1.3, 2.7]	1.7 [1.O, 2.4]
Diabetes Distress Screening Scale
Baseline score, mean	5.0	5.1	4.9	5.3	5.6	5.5
Difference	N/A	–0.7*	–0.8*	N/A	-O.3	-O.4

	Study 1			Study 2
	Insulin	Insulin + sotagliflozi n 200 mg	Insulin + sotagliflozin 400 mg	Insulin	Insulin + sotagliflozin 200 mg	Insulin + sotagliflozin 400 mg
from placebo, LS mean [95%CI]		[-0.9, –0.4]	[-1.0, –0.5]		[-0.6, –0.0]	[-0.7, –0.2]
Basal insulin dose (units/day)
Baseline, mean	35.06	34.84	33.39	29.76	29.18	29.50
% Change from baseline, LS mean	3.77	–1.73	–5.35	1.66	–4.16	–3.01
% Difference from insulin alone, LS mean [95% CI]	N/A	–5.51* [-8.71, –2.30]	–9.12* [-12.32, –5.91]	N/A	–5.82 [-10.04, –1.59]	–4.67 [-8.88, –0.47]
N: all randomised and treated patients Post-Baseline LS means, LS mean differences, 95% CLs, and p-values for each individual study were obtained from accounting for missing data p <0.001 p 0.12 Î p=0.034

No differences in HbA1c decrease could be detected across subgroups including age, gender, race, geographic region, baseline BMI, age at diagnosis, baseline HbA1c, eGFR, duration of disease and insulin delivery method.

In studies 1 and 2 combined, patient 24-week completion rates were 89.5% among insulin alone patients, and 91.4% and 90.7% among patients receiving 200 mg and 400 mg of sotagliflozin, respectively. The 52-week completion rates were 84.2%, 86.6%, and 85.3% respectively.

Efficacy over a 52-week period

At the end of 24 weeks the reduction in HbA1c was –0.36% and –0.38% and at 52 weeks it was –0.23% and –0.32% with sotagliflozin 200mg and 400 mg, respectively. The proportion of patients with A1C <7.0% at 24 weeks was 19.0% for placebo, 35.1% for sotagliflozin 200mg, 40.4% for sotagliflozin 400mg and at 52 weeks was 18.3%, 28.6% and 31.6% for placebo, sotagliflozin 200 mg and 400 mg respectively.

At the end of 52 weeks the reduction in body weight, mean daily bolus insulin dose, FPG were sustained compared to insulin alone.

CGM substudy: 2-hr PPG and time in range

From study 1 and study 2, 278 subjects participated in a blinded continuous glucose monitoring (CGM) sub-study (see Table 5).

Table 5: Results of CGM sub study at week 24 (Pooled data, study 1 and study 2)

Characteristic	Insulin	Insulin + sotagliflozin 200 mg	Insulin + sotagliflozin 400 mg
N	93	89	96
Percent Time in range 3.9–10.0 mmol/L
Baseline (after 6-week insulin optimisation) , LS mean	52.30	52.19	50.66
Change from baseline, LS mean	–1.26	4.09	10.45
Difference from insulin alone, LS mean % (p-value)	N/A	5.35 (0.026)	11.71 (<0.001)
2-hour postprandial glucose following a standardized mixed meal, mmol/L
Baseline (after 6-week insulin optimisation), mean	12.76	11.75	11.64
Change from baseline, LS mean	–0.44	–2.37	–2.71
Difference from insulin alone, LS mean (p-value)	N/A	–1.93 (0.004)	–2.27 (<0.001)
* 5.35% more time in range, correspond to 1.3 hours 11.71% more time in range, correspond to 2.8 hours

Study 3

InTandem 3 (study 3) was a 24-week duration study performed on a background of existing insulin regimen in type 1 diabetes patients with screening HbAlc >7.0% to <11.0%, to evaluate efficacy and safety of sotagliflozin 400 mg once daily versus insulin alone.

For the first meal on Day 1, patients were instructed to decrease their calculated (or usual) mealtime carbohydrate bolus insulin by 30%.

The mean age of patients was 43 years, 7.2% were 65 years or older. Mean duration of diabetes was 20 years, 39% of patients were using insulin pump and 61 % were using non-pump insulin therapy. In the study 50% were male and 88 % were White and 87% of randomised patients completed the study. The mean eGFR was 92 mL/min/1.73 m2 and 5 % had eGFR between 45 and 60 mL/min/1.73 m2. The mean BMI was 28 kg/m2 and 29% had SBP > 130 mmHg.

At week 24, treatment with 400 mg sotagliflozin before the first meal of the day resulted in statistically significant more patients achieving the net benefit primary endpoint (proportion of patients with HbA1c <7.0% at week 24 and no episode of severe hypoglycaemia, and no episode of DKA from randomisation to Week 24) compared with insulin alone (28.6% versus 15.2%) (p-value<0.001) and provided statistically significant mean reductions in HbA1c (p-value <0.001).

Treatment with sotagliflozin also resulted in reduction in body weight and bolus insulin dose compared with insulin alone (see Table 6). Treatment with sotagliflozin also resulted in reduction in body weight and systolic blood pressure (in patients with baselines SBP >130 mmHg) compared with insulin alone (see Table 6). Main results regarding insulin dose are presented in Table 6.

Table 6: Efficacy results of a 24 week placebo-controlled study of sotagliflozin as add-on to insulin therapy

in patients not at HbAlc goal (Study 3): _____________­________________________­______________

Characteristic	Insulin	Insulin + sotagliflozin 400 mg
N	703	699
HbAlc (%)
Baseline, LS mean	8.21	8.26
Change from baseline, mean	–0.33	–0.79
Difference from insulin alone, LS mean [95% CI]	N/A	– 0.4 [-0.54, –0.38]
HbAlc < 7.0% at week 24, n (%)	111 (15.8)	207 (29.6)
Body Weight (kg)
Baseline, mean	81.55	82.40
Change from baseline, LS mean	0.77	–2.21
Difference from insulin alone, LS mean [95% CI]	N/A	– 2.9 [-3.31, –2.66]
Bolus insulin
Baseline, mean in units	28.72	27.34
% change from baseline, LS mean	6.62	–5.71
% difference from insulin alone, LS mean	N/A	–12.32f
Basal insulin
Baseline, mean in units/day	29.63	29.54
% change from baseline, LS mean	6.76	–3.11
% difference from insulin alone, LS mean	N/A	–9.88f
Systolic Blood Pressure in those with baseline SBP > 130 mmHg*
N	203	203
Baseline, mean in mmHg	139.9	140.5
Change from baseline, LS mean	–5.7	–9.2
Difference from insulin alone, adjusted mean [95% CI]	N/A	–3,5* [-5.7, –1.3]
Systolic blood pressure was assessed at week 16 f p <0.001 i p=0.002

Hypoglycaemia

The incidence of severe hypoglycaemia and rates of documented hypoglycaemia (overall and nocturnal) were lower on sotagliflozin compared to insulin alone in the 52-week studies, as shown in Table 7.

Table 7: Incidence of severe hypoglycaemia and rates of documented, (overall and nocturnal)

hypoglycaemic events in the pool of two 52-week placebo-controlled clinical studies

	Insulin (N=526)	Insulin + sotagliflozin 200 mg (N=524)	Insulin + sotagliflozin 400 mg (N=525)
Incidence of severe hypoglycaemia (%)	7.4	5.7	4.4
Reduction in risk of severe hypoglycaemia compared to insulin alone (%)	–	24a	41 b
Rate of documented hypoglycaemia! (events per patient year) at thresholds of <3.1 or <3.9 mmol/L	<3.1 mmol/L: 19.0 <3.9 mmol/L: 95.6	<3.1 mmol/L: 14.9 <3.9 mmol/L: 81.3	<3.1 mmol/L: 15.0 <3.9 mmol/L: 83.7
Reduction in risk of documented hypoglycaemia, compared to insulin alone at threshold of <3.1 mmol/L (%)	–	21 c	18 c
Rate of nocturnal} documented hypoglycaemia! (events per patient year) at thresholds of <3.1 or <3.9 mmol/L	<3.1 mmol/L: 2.7 <3.9 mmol/L: 12.2	<3.1 mmol/L: 2.3 <3.9 mmol/L: 11.0	<3.1 mmol/L: 2.3 <3.9 mmol/L: 11.1
* Defined as an event consistent with hypoglycaemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). All severe hypoglycaemia presented were positively adjudicated. Defined as a documented SMBG or laboratory blood glucose value below or equal to threshold of 3.1 or 3.9 mmol/L. J Defined as event that occurred between 00:00 and 05:59 hours. a p=0.28 b p=0.04 c p<0.01

In study 3 at 24 weeks incidences of severe hypoglycaemia were 2.4% and 3.0% on placebo and sotagliflozin 400 mg, respectively and the reduction in the rate of hypoglycaemic events at 24 weeks (blood glucose <3.1 mmol/L) for sotagliflozin 400 mg was 22% (p<0.001) compared to insulin alone.

Patients with renal impairment

In the 3 Phase 3 randomized clinical studies in patients with type 1 diabetes, patients with eGFR < 45 mL/min/1.73 m2 were excluded, 79 patients exposed to sotagliflozin had an eGFR < 60 mL/min/1.73 m2 and 841 patients had an eGFR > 60 to < 90 mL/min/1.73 m2. The HbAlc reduction observed in patients with eGFR >60 to <90 mL/min/1.73 m2 was comparable to the HbAlc reduction observed in patients with eGFR >90 mL/min/1.73 m2. In patients with eGFR <60 mL/min/1.73 m2 a numerical HbAlc reduction was observed. No overall differences in safety were observed with sotagliflozin treatment as compared to insulin alone in subjects with eGFR between 45 and 60 mL/min/1.73 m2.

Fasting plasma glucose

In a pre-specified pooled analysis of study 1 and study 2, treatment with sotagliflozin as adjunct to insulin resulted in LS mean changes from baseline in FPG of –0.56 mmol/l for sotagliflozin 200 mg and –0.87 mmol/l for sotagliflozin 400 mg compared to insulin alone (0.32 mmol/l) at week 24.

In study 3 there was a significant reduction in FPG of 0.79 mmol/L (p<0.001) with sotagliflozin 400 mg at 24 weeks compared to insulin alone.

Blood pressure

In a pre-specified pooled analysis of study 1 and study 2, treatment with sotagliflozin as adjunct to insulin resulted in a reduction of SBP (-0.6 mmHg for placebo, –2.6 mmHg for sotagliflozin 200 mg and –4.1 mmHg for sotagliflozin 400 mg) at week 12. Pooled analysis of change in SBP in patients with baseline SBP >130 mmHg showed greater reduction in SBP at week 12 (-5.4 mmHg for placebo, –9.0 mmHg for sotagliflozin 200 mg and –10.7 mmHg for sotagliflozin 400 mg).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Zynquista in one or more subsets of the paediatric population in type 1 diabetes mellitus (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics (PK) of sotagliflozin has been characterized in healthy subjects and in diabetic patients. No clinically relevant differences were noted between the two populations.

Absorption

The median Tmax ranged from 1.25 to 3 hours, over a single-dose range of 400 to 2000 mg. Following administration of multiple doses (400 and 800 mg dose), the median Tmax values ranged from 2.5 to 4 hours.

The fraction of drug absorbed following administration of a single dose of [14C]-sotagliflozin was estimated to be at least 71%, based on the detected percentage of dose of radioactivity in the urine and for the metabolites of sotagliflozin in the faeces.

When sotagliflozin tablets were administered with a high-caloric breakfast, plasma exposure to sotagliflozin as measured by Cmax and AUC0 inf was about 2.5– and 1.5-fold higher, respectively, compared to fasted condition.

Distribution

Both sotagliflozin and its major human metabolite 3-O-glucuronide (M19), exhibited high binding to human plasma proteins in vitro (fraction unbound approx. 2%) which was not dependent on the concentration of sotagliflozin and M19. In clinical studies the high protein binding was confirmed and was not influenced by reduced renal or hepatic function.

The apparent volume of distribution of sotagliflozin following administration of a single 400 mg oral dose of [14C]-sotagliflozin was found to be very high with a mean value of 9392 L.

Biotransformation

In healthy subjects following the administration of a single dose of 400 mg [14C]-sotagliflozin indicated that sotagliflozin was extensively metabolized predominantly to M19 which represented 94% of the radioactivity in plasma.

The primary route of metabolism of sotagliflozin in humans is glucuronidation by the uridine 5’-diphospho-glucuronosyltran­sferases primarly by UGT1A9, and to a much lesser extent by UGT1A1 and UGT2B7 as well as oxidation, by CYP3A4.

When sotagliflozin is incubated with UGT1A9, M19 was the main conjugate observed. No acyl glucuronides of sotagliflozin were identified.

In in vitro studies, sotagliflozin did not inhibit CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4.

Sotagliflozin and M19 have no significant potential to inhibit OCT1, OCT2, OAT1, OAT3, OATP1B1 and OATP1B3.

M19 is an inducer and inhibitor of CYP3A4 and an inhibitor of CYP2D6.

In vitro sotagliflozin was shown to have inhibitory effects on P-gp and breast cancer resistance protein (BCRP). M19 demonstrated inhibitory effects against OATP1B1/B3 and MRP2 in-vitro.

Elimination/ex­cretion

Following the administration of a single dose of 400 mg [14C]-sotagliflozin, showed 57% and 37% of the radioactivity were excreted in the urine and faeces, respectively. These results indicate that the main route of elimination of drug related material was renal.

The predominant metabolite detected in urine was M19, representing a mean of 33% of the administered radioactive dose. Unchanged [14C]-sotagliflozin was the predominant radioactive peak detected in faecal extracts representing a mean of 23% of the total administered radioactive dose. In healthy volunteers, mean apparent total body clearance (CL/F) of sotagliflozin ranged from 261 to 374 L/hr. The CL/F estimated using a population PK, which mostly evaluated T1DM patients, was 239 L/hr. Mean terminal T1/2 ranged from 21 to 35 hours for sotagliflozin and from 19 to 26 hours for M19.

Linearity/non-linearity

The PK of sotagliflozin appeared to be dose proportional in the therapeutic dose range of 200 mg to 400 mg QD.

Special populations

Renal impairment

Exposure of sotagliflozin was evaluated in a dedicated study of subjects with mild (creatinine clearance [CLcr]: 60 to less than 90 mL/min) and moderate (CLcr: 30 to less than 60 mL/min) renal impairment and with normal renal function. In subjects with renal impairment, exposure to sotagliflozin following a single dose of 400 mg was approximately 1.7 fold higher in subjects with mild and up to 2.7 fold higher in subjects with moderate renal impairment compared to subjects with normal renal function.

The apparent clearance of sotagliflozin decreases with decreasing renal function. A population PK model integrating data from renally impaired patients and healthy subjects estimated for subjects with CKD Stage II (eGFR >60 and <90 mL/min/1.73 m2) and CKD Stage Illa (eGFR >45 and <60 mL/min/1.73 m2) that sotagliflozin exposures were 1.5 fold higher compared to subjects with normal renal function. For subjects with CKD Stage IIIb (eGFR >30 and <45 mL/min/1.73 m2) and CKD Stage IV (eGFR >15 and <30 mL/min/1.73 m2) sotagliflozin exposures were 1.95 and 2.25 fold higher compared to subjects with normal renal function.

Hepatic impairment

In a study with subjects with reduced hepatic function, AUC of sotagliflozin was not increased in mild (Child Pugh A) hepatic impaired subjects, but was increased by ~3 fold in moderate (Child Pugh B) and ~ 6 fold in severe (Child Pugh C) hepatic impaired subjects.

No dose adjustment is needed in patients with mild hepatic impairment.

Elderly

Based on a population PK analysis, age had no clinically meaningful effect on the pharmacokinetics of sotagliflozin.

Body weight

Based on a population PK analysis, sotagliflozin exposure was found to decrease with increased body weight. Consequently, low-weight patients may have somewhat increased exposure and patients with high weight somewhat decreased exposure. However, the differences in exposure were not considered clinically meaningful and therefore no dose adjustment is required based on weight.

Gender and race

Based on a population PK analysis gender and race had no clinically meaningful effect on the PK of sotagliflozin.

Paediatric patients

No data are available.

5.3 Preclinical safety data

In a rat carcinogenicity study, a statistically significant increase in thyroid follicular cell carcinoma was observed in males at 75 mg/kg/day, approx. 14 times the MRHD, the highest dose evaluated. In a repeat-dose study evaluating potential mechanisms responsible for the increase incidence of thyroid carcinoma observed in the rat carcinogenicity study, it was concluded that the increase was associated with a sotagliflozin-related increase in thyroid stimulating hormone (TSH). In the rat, TSH was considered the primary carcinogen with sotagliflozin functioning as a secondary carcinogen. These changes were not considered relevant for humans as TSH is not carcinogenic in humans.

Sotagliflozin was not mutagenic or clastogenic.

In a fertility study in rats, sotagliflozin had no effect on reproductive performance, fertility, and embryo/fetal viability.

In a juvenile toxicology study in rats, renal changes were observed when sotagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Exposure was approximately 5 times (males) and 11 times (females) the clinical exposure at the Maximum Recommended Human Dose (MRHD) and caused reversible renal tubular dilation.

In embryo-fetal development studies in rats and rabbits, sotagliflozin was orally administered at doses up to 350 mg/kg in rats and 200 mg/kg in rabbits. In the rat study, embryo-lethality, effects on fetal growth along with cardiovascular and skeletal abnormalities were observed at an exposure multiple of 158-times the human exposure at 400 mg/day. The adverse effects on embryo-fetal development at 350 mg/kg/day were associated with maternal toxicity (body weight loss/decreased body weight gain and decreased food consumption during gestation day (GD) 6 to 8). Exposure at the rat no-observedeffect level was 40-times the exposure at the MRHD. No developmental toxicity was observed at doses up to 200 mg/kg/day in the rabbit, which was up to 9-times the human exposure at the MRHD.

In a pre-/post-natal development study, no sotagliflozin-related adverse effects in pregnant and lactating females and offspring development were observed in rats

In a study evaluating the potential effects of sotagliflozin on the development of juvenile rats, no sotagliflozin-related toxicity was observed following the administration of oral doses up to approximately 18 and 31 fold that of the MRHD (400 mg/day) for males and females, respectively.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core

Microcrystalline cellulose (E460i)

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Talc

Film-coating

Poly(vinyl alcohol)

Macrogol

Titanium dioxide (E171)

Talc

Indigo carmine aluminium lake (E132).

Printing ink

Shellac

Iron oxide black (E172)

Propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PCTFE/Aluminium opaque blisters.

Pack sizes of 10, 20, 30, 60, 90, 100, 180 film-coated tablets, and a multipack of 200 film-coated tablets (2 packs of 100 film-coated tablets).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Guidehouse Germany GmbH

Albrechtstr. 10c

10117 Berlin

Germany

8. MARKETING AUTHORISATION NUMBER(S)

Zynquista 200 mg film coated tablets:

EU/1/19/1363/001 10 film coated tablets

EU/1/19/1363/002 20 film coated tablets

EU/1/19/1363/003 30 film coated tablets

EU/1/19/1363/004 60 film coated tablets

EU/1/19/1363/005 90 film coated tablets

EU/1/19/1363/­006 100 film coated tablets

EU/1/19/1363/­007 180 film coated tablets

EU/1/19/1363/­008 200 (2×100) film coated tablets (multipack)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 April 2019