Xigduo XR^® (Tablets) Instructions for Use

Marketing Authorization Holder

AstraZeneca AB (Sweden)

Manufactured By

AstraZeneca Pharmaceuticals LP (USA)

Contact Information

AstraZeneca Pharmaceuticals LLC (Russia)

ATC Code

A10BD15 (Metformin and dapagliflozin)

Active Substances

Metformin (Rec.INN registered by WHO)

Dapagliflozin (Rec.INN registered by WHO)

Dosage Forms

	Xigduo XR®	Modified-release film-coated tablets, 5 mg+1000 mg: 60 pcs.
		Modified-release film-coated tablets, 10 mg+1000 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Modified-release film-coated tablets, 5 mg + 1000 mg from pink to dark pink, oval, biconvex, engraved with “1071” and “5/1000” on one side.

Film coating composition: Opadry^® II pink 85F94592⁴ – 40.13 mg⁵.

6 pcs. – aluminum foil blisters (10) – cardboard packs with first opening control.

Modified-release film-coated tablets, 10 mg + 1000 mg from yellow to dark yellow, oval, biconvex, engraved with “1073” and “10/1000” on one side.

Film coating composition Opadry^® II yellow 85F12372⁶ – 40.13 mg⁵.

6 pcs. – aluminum foil blisters (5) – cardboard packs with first opening control.

¹ This mixture consists of 99.5% (w/w) metformin hydrochloride and 0.5% (w/w) magnesium stearate.
² The amount may vary depending on the purity of dapagliflozin and the actual amount of magnesium stearate used.
³ The target total amount of magnesium stearate is 1% (w/w) of the dapagliflozin layer.
⁴ Opadry^® II pink 85F94592 contains (% w/w): partially hydrolyzed polyvinyl alcohol – 40% (E1203), titanium dioxide – 22% (E171), macrogol 3350 – 20.2% (E1521), talc – 14.8% (E553b), iron oxide red dye – 3% (E172).
⁵ The amount of coating material is based on a target tablet weight gain of 2.5% (w/w). The actual amount may vary in the range of 2.0-3.2% (w/w) to achieve an acceptable physical appearance.
⁶ Opadry^® II yellow 85F12372 contains (% w/w): partially hydrolyzed polyvinyl alcohol – 40% (E1203), titanium dioxide – 21.08% (E171), macrogol 3350 – 20.2% (E1521), talc – 14.8% (E553b), iron oxide yellow dye – 3.92% (E172).

Clinical-Pharmacological Group

Hypoglycemic agent for oral administration (sodium-glucose cotransporter 2 inhibitor + biguanide)

Pharmacotherapeutic Group

Oral hypoglycemic agent (sodium-glucose cotransporter 2 inhibitor + biguanide)

Pharmacological Action

Mechanism of action

The drug Xigduo XR^® combines two hypoglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus (T2DM): dapagliflozin, a selective reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2), and metformin, a representative of the biguanide class.

Dapagliflozin

SGLT2 is expressed in the proximal renal tubules and is the main transporter involved in the glucose reabsorption process. By inhibiting SGLT2, dapagliflozin reduces glucose reabsorption and lowers the renal threshold for glucose, leading to increased urinary glucose excretion.

Metformin

Metformin improves glucose tolerance in patients with T2DM by reducing fasting plasma glucose concentration and postprandial glucose concentration. Metformin reduces hepatic glucose production, reduces intestinal glucose absorption, and increases insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not cause hypoglycemia in patients with T2DM or healthy individuals (except in special situations, see section “Special Instructions”), and hyperinsulinemia. During metformin therapy, insulin secretion does not change, although fasting insulin concentrations and insulin response to meals during the day may decrease.

Pharmacodynamics

Dapagliflozin

After administration of dapagliflozin to healthy volunteers and patients with T2DM, an increase in urinary glucose excretion was observed. When dapagliflozin was administered at a dose of 5 mg/day or 10 mg/day for 12 weeks to patients with T2DM, approximately 70 g of glucose was excreted in the urine per day. When dapagliflozin was administered at a dose of 20 mg/day, glucose excretion almost reached its maximum. Urinary glucose excretion with dapagliflozin also leads to an increase in urine volume (see section “Adverse Reactions”).

Clinical efficacy

Initial combination therapy with extended-release metformin

The safety and efficacy of initial combination therapy with dapagliflozin and extended-release metformin were studied in 2 controlled trials of 24 weeks duration in patients with T2DM and inadequate glycemic control who had not previously received hypoglycemic therapy.

The use of dapagliflozin and extended-release metformin (daily dose 2 g) provided a significant reduction in glycated hemoglobin (Hb_A1c) concentration and fasting plasma glucose (FPG) concentration compared with monotherapy with metformin or dapagliflozin. Combination therapy with dapagliflozin and extended-release metformin also provided a significant reduction in body weight compared with extended-release metformin monotherapy.

Addition of dapagliflozin to immediate-release metformin therapy

The safety and efficacy of adding dapagliflozin to immediate-release metformin therapy were studied in a controlled trial of 24 weeks duration in patients with T2DM and inadequate glycemic control. The addition of dapagliflozin 10 mg to metformin therapy resulted in a significant reduction in Hb_A1c concentration and FPG concentration, as well as a decrease in body weight compared with placebo at 24 weeks of treatment. A statistically significant (p<0.05) mean reduction in systolic BP (SBP) of 4.5 mm Hg and 5.3 mm Hg was also noted compared to the metformin monotherapy group in patients receiving dapagliflozin 5 mg and 10 mg, respectively.

Addition of dapagliflozin or glipizide to immediate-release metformin therapy

The safety and efficacy of adding dapagliflozin to immediate-release metformin therapy compared with glipizide were studied in a controlled trial of 52 weeks duration in patients with T2DM and inadequate glycemic control.

Dapagliflozin was no less effective than glipizide in reducing the mean Hb_A1c concentration by week 52 of treatment. A significant reduction in mean body weight was noted in the dapagliflozin group by week 52 of treatment, while an increase in this parameter was observed in the glipizide group. A statistically significant (p<0.0001) reduction in SBP of 5.0 mm Hg was achieved in the dapagliflozin group compared to the glipizide group.

Pharmacokinetics

The drug Xigduo XR^® is bioequivalent to dapagliflozin (drug Forxiga^®) and extended-release metformin (drug Glucophage^® Long) when taken together in corresponding doses.

The exposure parameters of dapagliflozin and extended-release metformin after administration of Xigduo XR^® to healthy volunteers were comparable after a standard meal and under fasting conditions. When Xigduo XR^® was taken after a standard meal, a 35% decrease in C_max of dapagliflozin and an increase in the time to reach it (T_max) by 1-2 hours were observed compared to taking the drug on an empty stomach. This difference is not clinically significant. Food intake did not have a significant effect on the pharmacokinetic parameters of metformin.

Absorption

Dapagliflozin. After oral administration of dapagliflozin on an empty stomach, C_max is usually reached within 2 hours. C_max and AUC values increase proportionally to the dapagliflozin dose in the therapeutic dose range. The absolute bioavailability of dapagliflozin after oral administration of a 10 mg dose is 78%. Food had a moderate effect on the pharmacokinetics of dapagliflozin in healthy volunteers. A high-fat meal reduced the C_max of dapagliflozin by 50%, prolonged T_max by approximately 1 hour, but did not affect AUC compared to fasting. These changes are not clinically significant, so dapagliflozin can be taken regardless of food intake.

Metformin. After oral administration of extended-release metformin, C_max is reached in 4-8 hours (median 7 hours). The extent of absorption of metformin from extended-release tablets increases by approximately 50% (as assessed by change in AUC) when taken with food. Food intake did not affect T_max and C_max.

Distribution

Dapagliflozin. The protein binding of dapagliflozin is approximately 91%. This indicator did not change in patients with impaired renal or hepatic function.

Metformin. No studies on the distribution of extended-release metformin have been conducted, however, the apparent V_d of metformin after a single oral dose of 850 mg immediate-release metformin tablets averaged 654±358 L. Metformin binds slightly to plasma proteins. Metformin penetrates into erythrocytes.

Metabolism

Dapagliflozin. The metabolism of dapagliflozin occurs mainly under the action of the enzyme uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9); cytochrome CYP isoenzymes are less involved in metabolism in humans. Dapagliflozin is metabolized to form mainly the inactive metabolite dapagliflozin-3-O-glucuronide. After oral administration of 50 mg ¹⁴C-dapagliflozin, 61% of the administered dose was metabolized to dapagliflozin-3-O-glucuronide.

Metformin. Studies with single intravenous administration of the drug to healthy volunteers show that metformin is excreted unchanged by the kidneys, is not metabolized in the liver (no metabolites have been identified in humans), and is not excreted through the intestines. No studies have been conducted on the metabolism of metformin in extended-release tablets.

Excretion

Dapagliflozin. Dapagliflozin and its metabolites are excreted primarily by the kidneys, with less than 2% excreted unchanged. After administration of 50 mg ¹⁴C-dapagliflozin, 96% of the radioactivity was found – 75% in urine and 21% in feces. Approximately 15% of the radioactivity found in feces was attributed to unchanged dapagliflozin. T_1/2 from plasma after a single dose of dapagliflozin 10 mg is approximately 12.9 hours.

Metformin. Renal clearance is approximately 3.5 times higher than GFR, indicating that tubular secretion is the main route of metformin excretion. After oral administration, approximately 90% of the absorbed drug is excreted by the kidneys within the first 24 hours, with a plasma T_1/2 of approximately 6.2 hours. In blood, T_1/2 is approximately 17.6 hours, therefore, the erythrocyte mass may be part of the distribution.

Pharmacokinetics in special patient groups

Renal impairment

Dapagliflozin. At steady state (dapagliflozin 20 mg once daily for 7 days) in patients with T2DM and mild, moderate, or severe renal impairment (defined by estimated GFR (eGFR)), the geometric mean systemic exposure was 45%, 2.04 and 3.03 times higher, respectively, than in patients with T2DM and normal renal function. The increase in systemic exposure to dapagliflozin in patients with T2DM and renal impairment was not accompanied by a corresponding increase in 24-hour urinary glucose excretion.

Steady-state 24-hour urinary glucose excretion in patients with T2DM and mild, moderate, or severe renal impairment was 42%, 80%, and 90% lower, respectively, compared to patients with T2DM and normal renal function. It is not known whether hemodialysis affects the exposure of dapagliflozin (see sections “Dosage Regimen” and “Special Instructions”).

Metformin. In patients with renal impairment (based on GFR measurements), the plasma and blood T_1/2 of metformin is prolonged, and renal clearance is reduced.

Hepatic impairment

Dapagliflozin. In patients with mild or moderate hepatic impairment (Child-Pugh classes A and B), the mean C_max and AUC values of dapagliflozin after a single 10 mg dose were 12% and 36% higher, respectively, compared to healthy volunteers. These differences are not clinically significant. In patients with severe hepatic impairment (Child-Pugh class C), the mean C_max and AUC values of dapagliflozin were 40% and 67% higher, respectively, compared to healthy volunteers.

Metformin. Pharmacokinetic studies of metformin in patients with hepatic impairment have not been conducted.

Elderly age

Dapagliflozin. According to population pharmacokinetic analysis, age does not have a clinically significant effect on the systemic exposure of dapagliflozin. Therefore, dose adjustment based on patient age is not required.

Metformin. Limited data from controlled pharmacokinetic studies of metformin in healthy elderly volunteers suggest that the total plasma clearance of metformin is decreased, T_1/2 is increased, and C_max is increased compared to these parameters in healthy young volunteers. According to these data, the change in metformin pharmacokinetic parameters with increasing age is mainly due to changes in renal function.

Children

No pharmacokinetic studies of Xigduo XR^® have been conducted in children (see section “Contraindications”).

Gender

Dapagliflozin. According to population pharmacokinetic analysis, gender does not have a clinically significant effect on the systemic exposure of dapagliflozin, so dose adjustment based on patient gender is not recommended.

Metformin. The pharmacokinetic parameters of metformin in healthy volunteers and patients with T2DM did not differ significantly by gender. In controlled clinical trials in patients with T2DM, the hypoglycemic effect of metformin was comparable in men and women.

Race and ethnicity

Dapagliflozin. According to population pharmacokinetic analysis, no clinically significant differences in systemic exposure were identified among Caucasian, Black, and Mongoloid races; dose adjustment based on race is not required.

Metformin. No studies have been conducted on the pharmacokinetic parameters of metformin depending on the patient’s race. In clinical trials in patients with T2DM, the hypoglycemic effect of metformin was comparable in Caucasian, Black, and Hispanic patients.

Body weight

Dapagliflozin. According to population pharmacokinetic analysis, body weight does not have a clinically significant effect on the systemic exposure of dapagliflozin, so dose adjustment based on patient body weight is not required.

Indications

• Type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control in adult patients for whom combination therapy with dapagliflozin and metformin is appropriate.

ICD codes

Dosage Regimen

Orally, once a day with breakfast. The tablets should be swallowed whole, without chewing, crushing, or breaking.

The dose should be selected individually, taking into account the effectiveness and tolerability of the therapy. If necessary, the dose should be increased gradually to reduce the risk of gastrointestinal side effects of metformin.

The maximum daily dose of dapagliflozin is 10 mg, and that of extended-release metformin is 2 g.

If Xigduo XR^® was prescribed to a patient taking extended-release metformin in the evening, the last evening dose of extended-release metformin should be skipped on the day before taking the first dose of Xigduo XR^®.

Patients with reduced intravascular volume require correction of this condition before starting therapy with Xigduo XR^®.

The inactive ingredients of Xigduo XR^® may be excreted through the intestines as a soft, moist mass that may retain the shape of the ingested tablet.

Use in special patient groups

Hepatic impairment. In patients with hepatic impairment, the use of metformin may lead to lactic acidosis. Therefore, Xigduo XR^® is contraindicated in patients with hepatic impairment.

Renal impairment. Renal function should be assessed before starting therapy with Xigduo XR^® and periodically during therapy. Xigduo XR^® is contraindicated in patients with moderate to severe renal impairment (eGFR<60 ml/min/1.73 m²), end-stage renal disease and patients receiving hemodialysis (see sections “Contraindications”, “Adverse Reactions” and “Special Precautions”).

In mild renal impairment (eGFR≥60 ml/min/1.73 m²), no dose adjustment of the drug is necessary.

Children. The safety and efficacy of dapagliflozin in patients under 18 years of age have not been studied (see section “Contraindications”).

Elderly. No dose adjustment of the drug is necessary in elderly patients. However, when selecting the dose, it should be taken into account that this category of patients is more likely to have impaired renal function and a risk of reduced intravascular volume. More frequent monitoring of renal function is recommended in elderly patients. Since clinical experience with dapagliflozin in patients 75 years of age and older is limited, initiating dapagliflozin therapy in this age group is contraindicated.

Adverse Reactions

Dapagliflozin and metformin

Safety assessment was based on pooled data from 8 short-term placebo-controlled studies in which dapagliflozin was used in combination with metformin (in this combination and as an add-on to other hypoglycemic therapy). In these studies, 983 patients received dapagliflozin 10 mg once daily and metformin, and 1185 patients received placebo and metformin.

The overall incidence of adverse events in the dapagliflozin 10 mg and metformin group was 60.3% compared to 58.2% in the placebo and metformin group. Therapy was discontinued due to adverse reactions in 4% of patients in the dapagliflozin 10 mg and metformin group compared to 3.3% in the placebo and metformin group. The most common adverse events leading to discontinuation of therapy and reported in at least 3 patients in the dapagliflozin 10 mg and metformin group were renal impairment (0.7%), increased serum creatinine concentration (0.2%), decreased glomerular filtration rate (0.2%), and urinary tract infections (0.2%).

Table 1 presents adverse reactions from 8 short-term placebo-controlled studies, regardless of the investigator’s assessment of causality, which were reported in at least 2% of patients taking dapagliflozin and metformin, and at least 1% more frequently compared to patients receiving metformin and placebo.

Table 1. Adverse reactions in placebo-controlled studies¹ (regardless of the investigator’s assessment of causality), reported with a frequency of ≥2% in patients receiving dapagliflozin and metformin, and at least 1% more frequently compared to patients receiving metformin and placebo (except for hypoglycemia)²

¹Volume depletion included the following adverse reactions: dehydration, hypovolemia, orthostatic hypotension, and arterial hypotension.

Renal impairment

During treatment with dapagliflozin, an increase in serum creatinine concentration and a decrease in eGFR were observed. In patients with normal renal function or mild renal impairment at study entry, creatinine concentration and eGFR returned to baseline by week 24.

Adverse reactions related to renal impairment, including renal failure and increased serum creatinine, were more frequently reported in patients taking dapagliflozin (see Table 3). These adverse reactions were more frequently reported in elderly patients and in patients with renal impairment (see Table 3). A persistent decrease in eGFR was observed in patients with moderate renal impairment (60>GFR≥30 ml/min/1.73 m²).

Table 3. Proportion of patients with at least one adverse reaction related to renal impairment

¹Patients from 12 placebo-controlled studies with an extended period.

²Patients from 13 placebo-controlled studies with an extended period.

In a study involving patients with moderate renal impairment (60>eGFR≥30 ml/min/1.73 m²) lasting up to 104 weeks, bone fractures were reported in 13 patients (5 cases in the dapagliflozin 5 mg group; 8 cases in the dapagliflozin 10 mg group; no fractures were recorded in the placebo group). In 11 out of 13 cases, fractures occurred within the first 52 weeks of treatment, and in 8 out of 13 cases, in patients with a baseline eGFR from 30 to 45 ml/min/1.73 m². No pattern regarding the location of fractures was noted.

Hypoglycemia

In 24-week placebo-controlled studies of adding dapagliflozin to metformin therapy, no severe episodes of hypoglycemia were reported; mild episodes of hypoglycemia were reported in 1.5% of patients in the dapagliflozin 5 mg group, 0.7% of patients in the dapagliflozin 10 mg group, and no episodes of hypoglycemia were reported in the placebo group.

In a 52-week study of adding dapagliflozin to metformin therapy compared with glipizide, no severe episodes of hypoglycemia were reported in the dapagliflozin group, while such episodes were reported in 0.7% of patients in the glipizide group: mild episodes of hypoglycemia were reported in 1.7% of patients in the dapagliflozin 10 mg group and in 36% of patients in the glipizide group.

Fungal genital infections

Fungal genital infections were more frequently reported in the dapagliflozin group. Fungal genital infections were reported in 0.9%, 5.7%, and 4.8% of patients taking placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively (pooled data from 12 placebo-controlled studies of dapagliflozin 5 mg and 10 mg). The drug was discontinued due to genital infection in 0.2% of patients in the dapagliflozin 10 mg group (no therapy discontinuations due to a similar adverse reaction were reported in the placebo group). Fungal genital infections were more frequently reported in women, as well as in patients who had episodes of a similar infection before starting the drug (10.0%, 23.1%, and 25.0% compared to 0.8%, 5.9%, and 5.0% in the placebo, dapagliflozin 5 mg, dapagliflozin 10 mg groups, respectively). The most common in women were vulvovaginal fungal infections, and in men, balanitis.

Hypersensitivity reactions

Hypersensitivity reactions (such as angioedema, urticaria, hypersensitivity) have been reported during treatment with dapagliflozin. Within the clinical trial program, serious anaphylactic reactions, severe skin reactions, and angioedema were reported in 0.3% of patients receiving dapagliflozin and 0.2% of patients in the comparator group. If hypersensitivity reactions occur, dapagliflozin should be discontinued, treatment should be administered according to accepted practice, and the patient should be monitored until symptoms completely resolve.
Laboratory test results

• Increase in hematocrit.
  Dapagliflozin. An increase in hematocrit was observed in patients receiving dapagliflozin from week 1 to week 16 of treatment (pooled data from 13 placebo-controlled studies of dapagliflozin 10 mg). The maximum increase in hematocrit compared to baseline was observed at week 16. At week 24, the mean change in hematocrit from baseline was -0.33% in the placebo group and 2.3% in the dapagliflozin 10 mg group. By week 24, an elevated hematocrit value >55% was recorded in 0.4% of patients in the placebo group and 1.3% of patients in the dapagliflozin 10 mg group.
• Increase in serum inorganic phosphorus concentration.
  Dapagliflozin. An increase in serum inorganic phosphorus concentration compared to baseline was observed at week 24 in patients receiving dapagliflozin 10 mg compared to the placebo group (mean increase was 0.13 mg/dL and -0.04 mg/dL, respectively) (pooled data from 13 placebo-controlled studies of dapagliflozin 10 mg). Hyperphosphatemia (serum inorganic phosphorus concentration ≥5.6 mg/dL for patients 17-65 years and ≥5.1 mg/dL for patients aged ≥66 years) was also more frequently reported in the dapagliflozin 10 mg group compared to the placebo group at week 24 (1.7% and 0.9% of patients, respectively).
• Increase in LDL cholesterol concentration.
  Dapagliflozin. A change in serum lipid concentrations was observed in patients receiving dapagliflozin compared to the placebo group (pooled data from 13 placebo-controlled studies of dapagliflozin 10 mg). The mean percentage increase in serum total cholesterol concentration at week 24 was 2.5% and 0.0% in the dapagliflozin 10 mg and placebo groups, respectively, and LDL cholesterol was 2.9% in the dapagliflozin 10 mg group compared to -1.0% in the placebo group.
• Vitamin B₁₂ concentration.Metformin. Serum vitamin B₁₂ concentration may decrease during metformin treatment. Patients receiving Xigduo XR^® should have hematological parameters assessed annually, and if changes are detected, appropriate examination and treatment should be performed (see section “Special Precautions”).

Post-marketing experience

Dapagliflozin

The following adverse reactions have been reported during post-marketing use: frequency not specified – rash.

It is not possible to reliably assess the causality and frequency of adverse reactions, as the information was obtained from spontaneous reports and the size of the patient population was not precisely determined.

Contraindications

• Hypersensitivity to any component of the drug;
• Type 1 diabetes mellitus;
• Moderate to severe renal impairment (eGFR<60 ml/min/1.73 m²), end-stage renal disease or patients receiving hemodialysis;
• Hepatic impairment;
• Acute conditions with a risk of renal impairment: dehydration (due to vomiting, diarrhea), fever, severe infectious diseases, hypoxic conditions (shock, sepsis, kidney infections, bronchopulmonary diseases);
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma (in case of diabetic ketoacidosis, insulin preparations should be used);
• Clinically significant manifestations of acute and chronic diseases that may lead to tissue hypoxia (respiratory failure, heart failure, acute myocardial infarction);
• Major surgical operations and trauma (when insulin therapy is indicated);
• Chronic alcoholism and acute ethanol intoxication;
• Lactic acidosis (including in history);
• Period at least 48 hours before and 48 hours after radioisotope or X-ray studies with the administration of iodine-containing contrast agents;
• Children under 18 years of age (safety and efficacy have not been studied);
• Patients taking loop diuretics (see section “Drug Interactions”), or with reduced intravascular volume, for example, due to acute illnesses (such as gastrointestinal diseases);
• Elderly patients 75 years of age and older (for initiating dapagliflozin therapy);
• Adherence to a hypocaloric diet (<1000 kcal/day);
• Hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption;
• Pregnancy;
• Breastfeeding period.

With caution urinary tract infections; risk of reduced intravascular volume; elderly patients; elevated hematocrit value; patients over 60 years of age performing heavy physical work.

Use in Pregnancy and Lactation

The use of Xigduo XR^®, as well as its active substances, dapagliflozin and metformin, during pregnancy has not been studied, so the drug is contraindicated during pregnancy. If pregnancy is diagnosed, therapy with Xigduo XR^® should be discontinued.

It is not known whether dapagliflozin, metformin and/or their metabolites pass into human breast milk. A risk to newborns/infants cannot be excluded. Xigduo XR^® is contraindicated during breastfeeding.

Use in Hepatic Impairment

Contraindication: hepatic impairment.

Use in Renal Impairment

Contraindications: moderate to severe renal impairment (eGFR<60 ml/min/1.73 m²), end-stage renal disease or patients receiving hemodialysis.

Pediatric Use

Contraindicated for use under 18 years of age.

Geriatric Use

Since clinical experience with dapagliflozin in patients 75 years of age and older is limited, initiating dapagliflozin therapy in this age group is contraindicated.

Special Precautions

Lactic acidosis

Cases of lactic acidosis, including fatal ones, have been reported during post-marketing use of metformin. In these cases, lactic acidosis had an insidious onset and was accompanied by nonspecific symptoms, such as malaise, myalgia, abdominal pain, respiratory distress, and increased drowsiness. In severe acidosis, hypothermia, arterial hypotension, and resistant bradyarrhythmias were noted. In lactic acidosis associated with metformin use, increased blood lactate concentration (more than 5 mmol/L), acidosis with an anion gap (without ketonuria and ketonemia), and an increased lactate/pyruvate ratio were noted; the plasma concentration of metformin usually exceeded 5 μg/mL. Metformin reduces lactate utilization in the liver, thereby increasing blood lactate concentration, which contributes to the development of lactic acidosis, especially in patients with risk factors.

If lactic acidosis is suspected in a patient taking metformin, general supportive measures should be initiated immediately in a hospital setting and Xigduo XR^® should be discontinued immediately.

In case of probable or confirmed lactic acidosis during treatment with Xigduo XR^®, hemodialysis is recommended to be initiated immediately to correct acidosis and remove accumulated metformin (metformin is removed by hemodialysis, with a clearance of up to 170 ml/min under good hemodynamic conditions). Hemodialysis often led to resolution of symptoms and recovery.

Patients and their family members should be informed about the symptoms of lactic acidosis, as well as the need to discontinue therapy with Xigduo XR^® and consult a doctor if these symptoms appear.

Below are recommendations for reducing the risk and correcting lactic acidosis in the presence of known risk factors.

Renal impairment. Lactic acidosis associated with metformin use during post-marketing experience most often occurred in patients with significant renal impairment. Metformin is primarily excreted by the kidneys, so as the severity of renal impairment increases, the risk of metformin accumulation and the development of lactic acidosis increases. Recommendations for assessing renal function (see sections “Pharmacokinetics” and “Dosage and Administration”)

• Before starting therapy with Xigduo XR^®, the eGFR should be determined;
• Xigduo XR^® is contraindicated in patients with eGFR <60 ml/min/1.73 m² (see section “Contraindications”);
• In all patients taking Xigduo XR^®, eGFR should be assessed at least annually. In patients at risk of impaired renal function (e.g., elderly patients), renal function should be monitored more frequently.

Interaction with other medicinal products. Concomitant use of Xigduo XR^® with drugs that may affect renal function may lead to significant hemodynamic changes, cause changes in acid-base balance, or contribute to the accumulation of metformin (e.g., cationic drugs) (see section “Drug Interactions”). Therefore, such patients should be monitored more closely.

Patients aged 65 years and older. The risk of metformin-associated lactic acidosis increases with age, as the risk of impaired hepatic or renal function or heart failure is higher in elderly patients compared to younger patients. In elderly patients, renal function should be monitored more frequently (see section “Dosage and Administration”).

Radiological studies with contrast media administration. Cases of acute renal impairment and lactic acidosis have been reported in patients receiving metformin during radiological studies with intravascular administration of iodinated contrast media. It is necessary to discontinue therapy with Xigduo XR^® 48 hours before such a procedure, determine eGFR 48 hours after the procedure, and resume taking the drug only after confirming stable renal function.

Surgical interventions and other procedures. Restriction of food and fluid intake during surgical or other procedures may increase the risk of reduced blood volume, arterial hypotension, and impaired renal function. Xigduo XR^® should be discontinued during periods of restricted food and fluid intake.

Hypoxia. Several cases of lactic acidosis associated with post-marketing use of metformin occurred against a background of acute heart failure (especially when combined with hypoperfusion and hypoxemia). Vascular collapse (shock), acute myocardial infarction, sepsis, and other conditions characterized by hypoxemia are associated with lactic acidosis and may also cause prerenal azotemia. If such conditions occur, Xigduo XR^® should be discontinued.

Excessive alcohol consumption. Alcohol potentiates the effect of metformin on lactate metabolism and may contribute to the development of lactic acidosis. Patients should be informed about the inadmissibility of consuming large amounts of alcohol during therapy with Xigduo XR^®.

Impaired hepatic function. The use of metformin in patients with impaired hepatic function has in some cases led to lactic acidosis, probably due to impaired lactate utilization in the liver and an increase in its blood concentration. Therefore, Xigduo XR^® is contraindicated in patients with impaired hepatic function.

Arterial Hypotension

Dapagliflozin contributes to a reduction in blood volume. After initiation of dapagliflozin therapy, arterial hypotension with clinical manifestations may occur, especially in patients with impaired renal function (eGFR <60 ml/min/1.73 m²), elderly patients, and patients taking “loop” diuretics. Before prescribing Xigduo XR^® to such patients, blood volume should be assessed and corrected, and after initiation of therapy, monitoring for symptoms of arterial hypotension should be performed.

Ketoacidosis

If a patient receiving Xigduo XR^® develops signs and symptoms of severe metabolic acidosis, ketoacidosis should be ruled out, regardless of blood glucose concentration, as blood glucose concentration during ketoacidosis while taking Xigduo XR^® may be less than 13.9 mmol/L. If ketoacidosis is suspected, Xigduo XR^® should be discontinued, necessary examination should be performed, and appropriate treatment should be prescribed. Treatment of ketoacidosis involves the use of insulin preparations, intravenous administration of solutions, including glucose.

In many post-marketing cases, especially in patients with type 1 diabetes, ketoacidosis was not diagnosed in a timely manner, and treatment was initiated late because blood glucose levels were lower than typical for ketoacidosis (often below 13.9 mmol/L). The initial signs and symptoms of ketoacidosis corresponded to dehydration and severe metabolic acidosis – nausea, vomiting, abdominal pain, general malaise, and shortness of breath. In many, but not all, cases, predisposing factors were identified – reduction of insulin dose, acute illness with fever, reduced caloric intake due to illness or surgery, insufficient insulin secretion due to pancreatic disease (type 1 diabetes, history of pancreatitis, or pancreatic surgery), or alcohol abuse.

Before starting Xigduo XR^®, risk factors for ketoacidosis should be assessed, including insufficient insulin production by the pancreas due to various reasons, reduced caloric intake, and alcohol abuse. When monitoring patients taking Xigduo XR^®, the possibility of developing ketoacidosis and the need for temporary discontinuation of therapy in clinical situations predisposing to the development of ketoacidosis (such as prolonged fasting due to acute illness or surgery) should be kept in mind.

Renal impairment and acute renal failure

Dapagliflozin contributes to a reduction in blood volume and may cause impaired renal function (see section “Adverse Reactions”). Cases of acute renal failure (including in patients under 65 years of age) have been observed during post-marketing use of dapagliflozin, some of which required hospitalization and dialysis.

Before prescribing Xigduo XR^®, possible risk factors for acute renal failure should be assessed, such as hypovolemia, chronic renal failure, chronic heart failure, and concomitant medications (diuretics, ACE inhibitors, angiotensin II receptor blockers, NSAIDs). During periods of restricted food and fluid intake (e.g., during acute illness or fasting), or fluid loss (e.g., due to gastrointestinal illness or exposure to high temperatures), temporary discontinuation of therapy with Xigduo XR^® and monitoring of the patient for possible symptoms of acute renal failure should be considered. If acute renal failure develops, Xigduo XR^® should be discontinued immediately and appropriate treatment initiated.

Cases of increased serum creatinine concentration and decreased eGFR have been observed during treatment with dapagliflozin, especially in elderly patients and patients with impaired renal function. After initiation of therapy with Xigduo XR^®, adverse reactions related to impaired renal function may occur (see section “Adverse Reactions”). Renal function should be assessed before starting Xigduo XR^® and periodically during therapy. Xigduo XR^® is contraindicated in patients with eGFR <60 ml/min/1.73 m² (see sections “Contraindications” and “Dosage and Administration”).

Urosepsis and pyelonephritis

Cases of severe urinary tract infections, including pyelonephritis and urosepsis, requiring hospitalization, have been reported during post-marketing use of SGLT2 inhibitors, including dapagliflozin. Therapy with SGLT2 inhibitors increases the risk of urinary tract infections. Patients should be monitored for possible symptoms of urinary tract infection and, if necessary, treatment should be initiated promptly (see section “Adverse Reactions”).

Vitamin B₁₂ concentration

In controlled clinical trials of metformin lasting 29 weeks, approximately 7% of patients had a decrease in serum vitamin B₁₂ concentration from previously normal to subnormal levels without clinical manifestations. However, such a decrease is very rarely accompanied by the development of anemia, and the concentration quickly recovers after discontinuation of metformin or additional intake of vitamin B₁₂. Patients receiving Xigduo XR^® should have hematological parameters assessed annually, and if changes are detected, appropriate examination and treatment should be performed (see section “Adverse Reactions”).

Some patients (e.g., those with insufficient dietary intake or impaired absorption of vitamin B₁₂ and calcium) are predisposed to a decrease in vitamin B₁₂ concentration to subnormal values. In such patients, it may be advisable to determine serum vitamin B₁₂ concentration every 2-3 years of therapy.

Fungal genital infections

Patients receiving dapagliflozin may have an increased risk of fungal genital infections. The risk of genital infections is higher in patients who had episodes of similar infection before starting the drug (see section “Adverse Reactions”). Patients should be monitored for possible symptoms and appropriate treatment should be administered in case of such an infection.

Increase in LDL cholesterol concentration

Patients receiving dapagliflozin may have an increased serum LDL-C concentration. During therapy with Xigduo XR^®, LDL-C concentration should be monitored and, if necessary, treatment should be prescribed according to accepted practice.

Bladder cancer

In 22 clinical trials, bladder cancer was diagnosed in 10 out of 6045 patients (0.17%) in the dapagliflozin group and in 1 out of 3512 patients (0.03%) in the placebo/comparator group. After excluding patients who had taken the drug for less than 1 year at the time of bladder cancer diagnosis from the analysis, there were 4 cases of bladder cancer in the dapagliflozin group and no cases in the placebo/comparator group. At the start of the study, the groups were balanced regarding risk factors for bladder cancer and hematuria (a potential indicator of an undiagnosed tumor). The small number of cases does not allow a conclusion about a causal relationship with dapagliflozin intake.

Nevertheless, Xigduo XR^® should not be prescribed to patients with bladder cancer. There are no data to assess the possible effect of dapagliflozin on a pre-existing bladder tumor. In patients with a history of bladder cancer, the benefit of glycemic control and the possible unspecified risk of bladder cancer recurrence should be assessed before prescribing Xigduo XR^®.

Macrovascular complications

No studies have been conducted that convincingly demonstrate a reduction in the risk of macrovascular complications with the use of Xigduo XR^®.

Effect on ability to drive vehicles and machinery

No studies have been conducted on the effect of Xigduo XR^® on the ability to drive vehicles and machinery.

Overdose

Dapagliflozin

No cases of overdose with dapagliflozin have been reported in the clinical trial program. In case of overdose, supportive therapy should be provided, taking into account the patient’s condition. The removal of dapagliflozin by hemodialysis has not been studied.

Metformin

Cases of metformin overdose have been reported, including intake of more than 50 g. Hypoglycemia developed in approximately 10% of cases, but a causal relationship with metformin intake has not been established. Lactic acidosis was observed in approximately 32% of metformin overdose cases. Metformin is eliminated by dialysis, with a clearance of up to 170 ml/min. Therefore, hemodialysis is advisable in case of suspected overdose of a drug containing metformin.

Drug Interactions

Pharmacokinetic interaction studies with Xigduo XR^® have not been conducted; however, such studies have been conducted for dapagliflozin and metformin, which are components of Xigduo XR^®.

Dapagliflozin

In in vitro studies, dapagliflozin and dapagliflozin-3-O-glucuronide did not inhibit the cytochrome P450 system isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and did not induce isoenzymes CYP1A2, CYP2B6, or CYP3A4. Dapagliflozin is a weak substrate of P-glycoprotein (Pgp), and dapagliflozin-3-O-glucuronide is a substrate of the active transporter OAT3. Dapagliflozin and dapagliflozin-3-O-glucuronide do not significantly inhibit the active transporters Pgp, OCT2, OAT1, and OAT3. Overall, no effect of dapagliflozin on the pharmacokinetics of drugs that are substrates of Pgp, OCT2, OAT1, and OAT3 is expected when used concomitantly.

Effect of other medicinal products on dapagliflozin

Interaction studies, mainly with single-dose administration, have shown that metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin do not affect the pharmacokinetics of dapagliflozin.

After concomitant use of dapagliflozin and rifampicin, an inducer of various active transporters and enzymes involved in drug metabolism, a 22% decrease in the systemic exposure (AUC) of dapagliflozin was observed without a clinically significant effect on the amount of glucose excreted in the urine over 24 hours. Dose adjustment is not recommended.

After concomitant use of dapagliflozin and mefenamic acid (an inhibitor of UGT1A9), a 51% increase in the systemic exposure of dapagliflozin was observed without a clinically significant effect on the amount of glucose excreted in the urine over 24 hours. Dose adjustment is not recommended.

Effect of dapagliflozin on other medicinal products

In interaction studies involving healthy volunteers, mainly with single-dose administration, dapagliflozin did not affect the pharmacokinetic parameters of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, simvastatin, digoxin, or warfarin. Administration of a single 20 mg dose of dapagliflozin and simvastatin resulted in a 19% increase in the AUC of simvastatin. The increase in exposure to simvastatin and simvastatin acid is not considered clinically significant.

Metformin

Effect of other medicinal products on metformin

Interaction studies with single-dose administration have shown that glibenclamide, furosemide, nifedipine, propranolol, and ibuprofen do not affect the pharmacokinetics of metformin.

Carbonic anhydrase inhibitors topiramate and other carbonic anhydrase inhibitors (such as zonisamide, acetazolamide, or diclofenamide) often cause a decrease in serum bicarbonate concentration and non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Xigduo XR^® may increase the risk of lactic acidosis. Such patients require more frequent monitoring.

Drugs that slow the elimination of metformin: concomitant use of drugs that affect the renal tubular transport systems involved in the renal elimination of metformin (OCT2 and MATE inhibitors, such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the systemic exposure to metformin and the risk of lactic acidosis. The expected benefit and possible risk of concomitant use of these drugs should be assessed.

Effect of metformin on other medicinal products

Interaction studies with single-dose administration have shown that metformin does not affect the pharmacokinetics of glibenclamide, furosemide, nifedipine, propranolol, ibuprofen, and cimetidine.

Medicinal products that can cause hyperglycemia

Use of certain medicinal products, such as diuretics (including thiazides), corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid, may predispose to the development of hyperglycemia and worsening of glycemic control. When these drugs are used concomitantly with Xigduo XR^®, careful monitoring of blood glucose is necessary, and upon their discontinuation, the patient should be monitored for the possibility of hypoglycemia.

In interaction studies involving healthy volunteers with single-dose administration, no interaction was observed between metformin and propranolol, or between metformin and ibuprofen.

Use of drugs that may cause hypoglycemia

Metformin. Hypoglycemia does not develop in patients taking metformin alone in the usual regimen, but may develop with a hypocaloric diet, or if intense physical activity is not compensated by caloric intake, or when used concomitantly with other hypoglycemic drugs (such as sulfonylurea derivatives and insulin) or alcohol. Elderly, debilitated, or malnourished patients and patients with adrenal or pituitary insufficiency or alcohol intoxication are most sensitive to the hypoglycemic effects. In elderly people and patients taking beta-blockers, diagnosis of hypoglycemia may be difficult.

Evaluation of the 1,5-anhydroglucitol test

Dapagliflozin. In patients receiving SGLT2 inhibitors, the use of the 1,5-anhydroglucitol test for glycemic monitoring is not recommended. Alternative monitoring methods should be used.

Evaluation of urinalysis results

Dapagliflozin. SGLT2 inhibitors increase renal glucose excretion. Therefore, results of urine glucose testing in patients taking Xigduo XR^® will be positive. Alternative monitoring methods should be used.

Alcohol

Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be informed about the inadmissibility of consuming large amounts of alcohol during therapy with Xigduo XR^®.

Storage Conditions

The drug should be stored at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life is 2 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.