Sigduo Long, 10 mg+1000 mg 30 pcs.

Pharmacotherapeutic group: hypoglycemic agent for oral administration (sodium-dependent glucose transporter type 2 inhibitor + biguanide)

ATX code: A10BD15

Pharmacological properties Mechanism of action

The drug Sigduo Long^® combines two hypoglycemic drugs with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus (DM2): dapagliflozin, a selective reversible inhibitor of the type 2 sodium-dependent glucose transporter (SGLT2), and metformin, a member of the biguanide class.

Dapagliflozin

SGLT2 is expressed in the proximal renal tubules and is a major transporter involved in glucose reabsorption. By inhibiting SGLT2, dapagliflozin reduces glucose reabsorption and decreases the renal threshold for glucose, resulting in increased renal excretion.

Metformin

Metformin improves glucose tolerance in patients with DM2 by reducing fasting plasma glucose concentration and postprandial glucose concentration. Metformin reduces glucose production by the liver, reduces intestinal glucose absorption and increases insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not cause hypoglycemia in patients with DM2 or healthy subjects (except for special situations, see section “Special indications”), and hyperinsulinemia. Insulin secretion does not change during metformin therapy, although fasting insulin concentrations and in response to meals during the day may decrease.

Pharmacodynamics

Dapagliflozin

An increase in renal glucose excretion was observed after dapagliflozin administration in healthy volunteers and patients with DM 2. When dapagliflozin was administered at a dose of 5 mg daily or 10 mg daily for 12 weeks in patients with DM2, approximately 70 g of glucose were excreted by the kidneys per day. When dapagliflozin was administered at a dose of 20 mg per day, glucose excretion was almost at its maximum. Renal excretion of glucose when using dapagliflozin also leads to increased urine volume (see section “Side effects”).

Clinical efficacy

Start combination therapy with sustained-release metformin

. The safety and efficacy of starting combination therapy with dapagliflozin and sustained-release metformin were studied in 2 controlled 24-week studies in patients with DM2 and inadequate glycemic control who had not previously received hypoglycemic therapy.

The use of dapagliflozin and sustained-release metformin (daily dose of 2 g) provided significant reductions in glycosylated hemoglobin (HbA1c) and fasting plasma glucose (FPG) concentrations compared with metformin or dapagliflozin monotherapy. Also, combination therapy with dapagliflozin and prolonged-acting metformin provided a significant reduction in body weight compared with prolonged-acting metformin monotherapy.

Adding dapagliflozin to conventional-release metformin therapy The safety and effectiveness of adding dapagliflozin to conventional-release metformin therapy were studied in a 24-week controlled trial in patients with DM2 and inadequate glycemic control. Adding dapagliflozin at a dose of 10 mg to metformin therapy resulted in a significant decrease in HbA1c concentration and HbA1c concentration, as well as in a decrease in body weight compared to placebo at 24 weeks of treatment. There was also a statistically significant (p< 0.05) reduction in mean systolic blood pressure (SBP) by 4.5 mm Hg and 5.3 mm Hg in patients receiving dapagliflozin 5 mg and 10 mg, respectively, compared with the metformin monotherapy group.

Adding dapagliflozin or glipizide to conventional-release metformin therapy

The safety and effectiveness of adding dapagliflozin to conventional-release metformin therapy compared with glipizide were studied in a 52-week controlled trial in patients with DM2 and inadequate glycemic control.

Dapagliflozin was as effective as glipizide in reducing mean HbA1c concentration by 52 weeks of treatment. The dapagliflozin group showed a significant decrease in mean body weight by 52 weeks of treatment, while the glipizide group showed an increase. A statistically significant (p< 0.0001) decrease of 5.0 mmHg in BP was achieved in the dapagliflozin group compared to the glipizide group.

Cardiovascular and renal outcomes

The effect of dapagliflozin compared with placebo on cardiovascular and renal outcomes when added to current baseline therapy was established in the DECLARE clinical trial conducted in 17160 patients with DM2 and two or more additional cardiovascular risk factors (age ≥55 years in men or ≥60 years in women and one or more of the following dyslipidemia, arterial hypertension, or tobacco smoking) or with diagnosed cardiovascular disease.

Dapagliflozin 10 mg demonstrated superiority compared with placebo in preventing events of the primary combined end point including hospitalization for heart failure or cardiovascular death (hazard ratio (HR) 0.83 [95% confidence interval (CI) 0.73, 0.95]; p=0.005). The difference in the effect of therapy was due to hospitalization for heart failure (OR 0.73 [95% CI 0.61, 0.88]), with no difference between groups for cardiovascular death (OR 0.98 [95% CI 0.82 to 1.17]).

The benefit of dapagliflozin therapy compared with placebo was observed in patients with or without diagnosed cardiovascular disease, with or without underlying heart failure, and was comparable in key subgroups, including age, sex, renal function (estimated glomerular filtration rate (pGFR)) and region.

Dapagliflozin reduced the incidence of combined point events, which included a confirmed sustained decrease in rCF, end-stage renal failure, death due to renal complications, or cardiovascular death. The difference between groups was due to a reduction in the number of events of the combined renal outcome point components, which included sustained rSKF decline, terminal renal failure, and death due to renal complications.

The hazard ratio of time to nephropathy (sustained decrease in rSKF, end-stage renal failure, or death due to renal complications) was 0.53 (95% CI 0.43, 0.66) for dapagliflozin compared with placebo.

Dapagliflozin also reduced the risk of new cases of persistent albuminuria (OR 0.79 (95% CI 0.72, 0.87)) and resulted in a greater regression

of macroalbuminuria (OR 1.82 (95% CI 1.51, 2.20)) compared with placebo.

Pharmacokinetics

The drug Sigduo Long^® is bioequivalent to dapagliflozin (the drug Forsiga) and sustained-release metformin (the drug Glucofage^® Long) when used together in appropriate doses.

The exposure values of dapagliflozin and sustained-release metformin after administration of Sigduo Long^® by healthy volunteers were comparable after a standard meal and fasting. In case of taking Sigduo Long^® after a standard meal, there was a 35% decrease in maximum concentration (Cmax) of dapagliflozin and increase in time to reach it (Tmax) by 1-2 hours compared to the drug on an empty stomach. This difference is not clinically significant. Food intake had no significant effect on the pharmacokinetic parameters of metformin.

Absorption

Dapagliflozin

After oral dapagliflozin administration on an empty stomach, Cmax is usually reached within 2 hours. The Cmax and AUC values (area under the concentration-time curve) increase in proportion to the dose of dapagliflozin in the range of therapeutic doses. Absolute bioavailability of dapagliflozin at an oral dose of 10 mg is 78%. Food intake had a moderate effect on the pharmacokinetics of dapagliflozin in healthy volunteers. High-fat meals decreased the Cmax of dapagliflozin by 50% and prolonged the Tmax by approximately 1 hour, but had no effect on the AUC compared with fasting meals. These changes are not clinically significant, so dapagliflozin can be taken regardless of food intake.

Metformin

After oral administration of prolonged-acting metformin, Cmax is reached in 4-8 hours (median 7 hours). Absorption of metformin from sustained release tablets is increased by approximately 50% (assessed by change in AUC) when taken with food. Food intake had no effect on Tmax and Cmax.

Distribution

Dapagliflozin

Dapagliflozin is approximately 91% protein-bound. In patients with impaired renal or hepatic function, this figure did not change.

Metformin

There have been no studies of the distribution of sustained-release metformin, but the apparent distribution volume of metformin after a single oral dose of 850 mg conventional-release metformin tablets averaged 654±358 L. Metformin is slightly bound to plasma proteins. Metformin penetrates red blood cells.

Metabolism

Dapagliflozin

The metabolism of dapagliflozin is primarily by the enzyme uridine diphosphate-glucuronyltransferase 1A9 (UGT1A9); CYP cytochrome isoenzymes are less involved in metabolism in humans. Dapagliflozin is metabolized to form mainly the inactive metabolite dapagliflozin-3-O-glucuronide. After ingestion of 50 mg of ¹⁴C-dapagliflozin, 61% of the dose taken is metabolized to dapagliflozin-3-O-glucuronide.

Metformin

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

Elimation

Dapagliflozin

Dapagliflozin and its metabolites are excreted primarily by the kidneys, and only less than 2% are excreted unchanged. After administration of 50 mg of ¹⁴C-dapagliflozin, 96% radioactivity was detected – 75% in urine and 21% in feces. Approximately 15% of the radioactivity detected in the feces was unchanged dapagliflozin. The T1/2 (plasma elimination half-life) after a single dose of dapagliflozin 10 mg is approximately 12.9 h.

Metformin

The renal clearance is approximately 3.5 times that of creatinine clearance (CK), indicating that tubular secretion is the major route of metformin excretion. After oral administration, approximately 90% of the absorbed drug is excreted by the kidneys during the first 24 h, with a plasma elimination half-life of approximately 6.2 h. In blood, the elimination half-life is approximately 17.6 h, hence erythrocyte mass may be part of the distribution.

Pharmacokinetics in special patient groups Renal dysfunction

Dapagliflozin

At equilibrium (administration of dapagliflozin once daily at a dose of 20 mg for 7 days), patients with DM2 and mild, moderate, or severe renal impairment (determined by pSCF) had geometric mean systemic exposure 45%, 2.04 and 3.03 times higher than patients with DM2 and normal renal function, respectively. Increased systemic exposure to dapagliflozin in patients with DM 2 and impaired renal function was not accompanied by a corresponding increase in the amount of glucose excreted by the kidneys during the day.

Daily renal glucose excretion at equilibrium in patients with DM 2 and mild, moderate, or severe renal impairment was 42%, 80%, and 90% lower, respectively, compared with patients with DM 2 and normal renal function. It is unknown whether hemodialysis has an effect on dapagliflozin exposure (see sections “Dosage and administration” and “Cautions”).

Metformin

In patients with impaired renal function, the elimination half-life of metformin from plasma and blood is prolonged in proportion to decreased renal function.

Hepatic dysfunction

Dapagliflozin

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

Metformin

Pharmacokinetic studies of metformin in patients with impaired liver function have not been performed.

Elderly age

Dapagliflozin

. Based on population pharmacokinetic analysis, age has no clinically significant effect on systemic exposure to dapagliflozin, so no dose adjustment based on patient age is required.

Metformin

. Limited data from controlled studies of metformin pharmacokinetics in healthy elderly volunteers suggest that total plasma clearance of metformin is decreased, elimination half-life is increased, and Cmax is increased compared to values of 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

There have been no studies of the pharmacokinetics of Sigduo Long^® in children (see section “Contraindications”).

Gender

Dapagliflozin

According to the results of population pharmacokinetic analysis, gender has no clinically significant effect on the systemic exposure of dapagliflozin, so no dose adjustment according to patient gender is recommended.

Metformin

The pharmacokinetic parameters of metformin in healthy volunteers and patients with DM2 did not differ significantly depending on gender. In controlled clinical trials in patients with DM 2 the hypoglycemic effect of metformin in men and women was comparable.

Race and ethnicity

Dapagliflozin

. Based on population pharmacokinetic analysis, there were no clinically significant differences in systemic exposure among Caucasoid, Negroid, and Mongoloid races; race-specific dose adjustments were not necessary.

Metformin

There have been no studies of metformin pharmacokinetic parameters depending on patient race. In clinical studies in patients with DM2, the hypoglycemic effect of metformin in Caucasian, non-Hispanic, and Hispanic patients was comparable.

Body weight

Dapagliflozin

. Based on population pharmacokinetic analysis, body weight has no clinically significant effect on the systemic exposure of dapagliflozin, so no dose adjustment based on patient body weight is required.

Indications

Type 2 diabetes mellitus in adults, in addition to diet and exercise to improve glycemic control.
Dapagliflozin is recommended in adult patients with type 2 diabetes mellitus with established cardiovascular disease or two or more cardiovascular risk factors* to reduce the risk of hospitalization for heart failure.

* age ≥ 55 years in men or ≥ 60 years in women and the presence of at least one risk factor: dyslipidemia, hypertension or smoking.

Pharmacological effect

Pharmacotherapeutic group: hypoglycemic agent for oral administration (inhibitor of sodium-dependent glucose transporter type 2 + biguanide)

ATX code: A10BD15

Pharmacological properties

Special instructions

Lactic acidosis

Active ingredient

Dapagliflozin, Metformin

Composition

One modified-release film-coated tablet, 5 mg + 1000 mg, contains:

Long-acting metformin layer

Active ingredient: metformin hydrochloride mixed with 0.5% magnesium stearate1 1005.04 mg (1000.00 mg metformin hydrochloride + 5.04 mg magnesium stearate) Excipients: carmellose sodium 49.99 mg, hypromellose 2208 234.98 mg, silicon dioxide 13.00 mg, magnesium stearate 1.99 mg

Pregnancy

The use of the drug Sigduo Long®, as well as its active ingredients, dapagliflozin and metformin, has not been studied during pregnancy, therefore the drug is contraindicated during pregnancy. If pregnancy is diagnosed, therapy with Sigduo Long® should be discontinued.
It is unknown whether dapagliflozin, metformin and/or their metabolites are excreted in human breast milk. A risk to newborns/infants cannot be excluded. The drug Sigduo Long® is contraindicated during breastfeeding.

Contraindications

• Increased individual sensitivity to any component of the drug.
• Diabetes mellitus type 1.
• Severe renal impairment (eGFR less than 30 ml/min/1.73 m2), end-stage renal disease and patients receiving hemodialysis.
• Hereditary lactose intolerance, lactase deficiency and glucose-galactose intolerance.
• Pregnancy and breastfeeding.
• Children under 18 years of age (safety and effectiveness have not been studied).
• Liver dysfunction.
• Acute diseases in which there is a risk of developing renal dysfunction: dehydration (with vomiting, diarrhea), fever, severe infectious diseases, hypoxia 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 pronounced manifestations of acute and chronic diseases that can lead to the development of tissue hypoxia (respiratory failure, acute uncompensated heart failure, acute myocardial infarction).
• Serious surgery and trauma (when insulin therapy is indicated).
• Chronic alcoholism and acute ethanol poisoning.
• Lactic acidosis (including history).
• A period of less than 48 hours before and within 48 hours after radioisotope or x-ray studies with the introduction of iodinated contrast agents.
• Following a hypocaloric diet (< 1000 kcal/day).With caution: urinary tract infections; risk of decreased circulating blood volume (CBV); elderly patients; increased hematocrit value; patients over 60 years of age performing heavy physical work.

Side Effects

Dapagliflozin and metformin

The safety assessment was based on pooled data from 8 short-term placebo-controlled studies in which dapagliflozin was used in combination with metformin (in combination and in addition 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 with 58.2% in the placebo and metformin group. 4% of patients in the dapagliflozin 10 mg and metformin group had therapy discontinued due to adverse reactions compared with 3.3% in the placebo and metformin group. The most common adverse events leading to discontinuation of therapy and observed in at least 3 patients in the dapagliflozin 10 mg and metformin group were impaired renal function (0.7%), increased serum creatinine concentration (0.2%), decreased creatinine clearance (0.2%), and urinary tract infections (0.2%).

Table 1 shows adverse reactions from 8 short-term, placebo-controlled studies, regardless of investigator assessment of causality, that were reported in at least 2% of patients treated with dapagliflozin and metformin and at least 1% more likely than patients treated with metformin and placebo.

Table 1. Adverse reactions in placebo-controlled studies1 (regardless of investigator’s assessment of causality) reported at an incidence of ≥ 2% in patients treated with dapagliflozin and metformin and at least 1% more often than in patients treated with metformin and placebo (excluding hypoglycemia) (2)

Interaction

Pharmacokinetic studies of interactions of the drug Sigduo Long® have not been conducted, however, such studies have been conducted for dapagliflozin and metformin, which are part of the drug Sigduo Long®.

Dapagliflozin

Overdose

Dapagliflozin
There were no cases of overdose observed during the clinical trial program for dapagliflozin. In case of overdose, maintenance therapy should be carried out, taking into account the patient’s condition. Elimination of dapagliflozin by hemodialysis has not been studied.

Metformin
Cases of metformin overdose have been reported, including when taking more than 50 g. In approximately 10% of cases, hypoglycemia developed, but its causal relationship with metformin use has not been established. In approximately 32% of cases of metformin overdose, patients experienced lactic acidosis. Metformin is eliminated by dialysis, with clearance reaching 170 ml/min. Therefore, if there is a suspected overdose of a drug containing metformin, hemodialysis is advisable.

Storage conditions

At a temperature not exceeding 30 C.
Keep out of the reach of children.

Shelf life

2 years.
Do not use after the expiration date indicated on the package.

Manufacturer

AstraZeneca Pharmaceuticals LP, USA