Instructions for Xigduo Prolong prolonged-release film-coated tablets 5 mg/1000 mg blister No. 28
Composition
active ingredients: dapagliflozin propanediol; metformin hydrochloride;
5/1000 mg: 1 prolonged-release film-coated tablet contains 6.15 mg of dapagliflozin propanediol, equivalent to 5 mg of dapagliflozin, and 1005.04 mg of metformin hydrochloride;
10/1000 mg: 1 prolonged-release film-coated tablet contains dapagliflozin propanediol 12.30 mg, equivalent to 10 mg dapagliflozin, and metformin hydrochloride 1005.04 mg;
10/500 mg: 1 prolonged-release film-coated tablet contains 12.30 mg of dapagliflozin propanediol, equivalent to 10 mg of dapagliflozin, and 502.61 mg of metformin hydrochloride;
excipients: sodium carboxymethylcellulose, hypromellose 2208, hypromellose 2910 (for 10/500 mg), microcrystalline cellulose РН102 (for 10/500 mg), silicon dioxide, magnesium stearate, microcrystalline cellulose РН302, anhydrous lactose, crospovidone, dye Opadry® II Yellow 85F12372 (for 10/1000 mg), dye Opadry® II Pink 85F94333 (for 10/500 mg), dye Opadry® II Pink 85F94592 (for 5/1000 mg).
Dosage form
Film-coated tablets, prolonged-release.
Main physicochemical properties:
5/1000 mg: film-coated tablet, pink to dark pink, biconvex, oval, engraved with ″1071″ and ″5/1000″ on one side and plain on the other side.
10/500 mg: film-coated tablet, pink, biconvex, capsule-shaped, engraved with ″1072″ and ″10/500″ on one side and plain on the other side.
10/1000 mg: film-coated tablet, yellow to dark yellow, biconvex, oval, engraved with ″1073″ and ″10/1000″ on one side and plain on the other side.
Pharmacotherapeutic group
Drugs for the treatment of diabetes. Metformin in combination with dapagliflozin. ATX code A10B D15.
Pharmacological properties
Mechanism of action
KSIGDUO Prolong
KSIGDUO Prolong combines two hypoglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: dapagliflozin, a sodium-glucose cotransporter type 2 inhibitor (SGTC-2 inhibitor), and metformin hydrochloride, a biguanide.
Dapagliflozin
Sodium-glucose cotransporter type 2 (SGCT-2), which is expressed in the proximal renal tubules, is responsible for the reabsorption of most filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGCT-2. By inhibiting SGCT-2, dapagliflozin reduces the reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion.
Dapagliflozin also reduces sodium reabsorption and increases sodium delivery to the distal renal tubules. This may affect several physiological functions, including a reduction in both pre- and afterload on the heart and a decrease in sympathetic activity.
Metformin hydrochloride
Metformin is a hypoglycemic agent that improves glucose tolerance in patients with type 2 diabetes by reducing basal and postprandial plasma glucose levels. Metformin reduces hepatic glucose production, reduces intestinal glucose absorption, and increases insulin sensitivity by increasing peripheral glucose uptake and utilization. Insulin secretion is not altered during metformin treatment, although fasting insulin levels and daily plasma insulin levels may be reduced.
Pharmacodynamics.
General information
Dapagliflozin
In healthy subjects and patients with type 2 diabetes, an increase in the amount of glucose excreted in the urine was observed after the use of dapagliflozin. Approximately 70 g of glucose was excreted in the urine per day when dapagliflozin was administered at a dose of 5 or 10 mg per day in patients with type 2 diabetes for 12 weeks. A similar maximum glucose excretion was observed when dapagliflozin was administered at a daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also leads to an increase in urine volume (see section "Adverse reactions"). After discontinuation of dapagliflozin, the increased level of glucose excretion returned to baseline levels within a median of 3 days when the dose of dapagliflozin was 10 mg.
Cardioelectrophysiology
Dapagliflozin was not associated with clinically significant prolongation of the QTc interval at daily doses of up to 150 mg (15 times the maximum recommended dose) in a study in healthy volunteers. In addition, no clinically significant effect on the QTc interval was observed after single doses of dapagliflozin up to 500 mg (50 times the maximum recommended dose) were administered to healthy volunteers.
Administration of the drug KSIGDUO Prolong by healthy volunteers after a standard meal and in the fasting state provides the same exposure of dapagliflozin and metformin extended-release. Compared with administration of the drug in the fasting state, when it is used during a standard meal, a decrease in the maximum concentration of dapagliflozin in the blood plasma by 35% and a delay of 1-2 hours of its achievement are observed. This effect of food intake is not considered clinically significant. Food intake does not have a significant effect on the pharmacokinetics of metformin when used as part of the drug KSIGDUO Prolong.
Absorption
Dapagliflozin
After oral administration, the maximum plasma concentration (Cmax) of dapagliflozin is usually achieved within 2 hours after administration in the fasted state. The Cmax and AUC of dapagliflozin increase in proportion to the dose over the therapeutic dose range. The absolute bioavailability of dapagliflozin after oral administration of 10 mg is 78%. Administration with a high-fat meal reduces the Cmax of dapagliflozin by 50% and prolongs the Tmax by approximately 1 hour, but does not alter the AUC compared to administration in the fasted state. These changes are not considered clinically significant and dapagliflozin can be administered without regard to food intake.
Metformin hydrochloride
After a single oral dose of metformin extended-release, the median time to Cmax is 7 hours with a range of 4 to 8 hours. The extent of metformin absorption (AUC) from metformin extended-release tablets is increased by approximately 50% when taken with food. No effect of food on metformin Cmax or Tmax was observed.
Distribution
Dapagliflozin
Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.
Metformin hydrochloride
Distribution studies of metformin extended-release have not been performed; however, the apparent volume of distribution (V/F) of metformin after a single oral dose of 850 mg immediate-release formulation averaged 654 ± 358 L. Metformin is poorly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin penetrates into erythrocytes.
Metabolism
Dapagliflozin
The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is negligible in humans. Dapagliflozin is extensively metabolized, primarily to form dapagliflozin 3-O-glucuronide, an inactive metabolite. Dapagliflozin 3-O-glucuronide accounts for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.
Metformin hydrochloride
Studies with single intravenous doses in healthy volunteers have shown that metformin is excreted unchanged in the urine and is not metabolized in the liver (no metabolites have been identified in humans) or excreted in the bile.
Metabolism studies of metformin extended-release tablets have not been conducted.
Breeding
Dapagliflozin
Dapagliflozin and its related metabolites are primarily excreted in the urine. Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% of the total radioactivity was excreted in the urine and feces, respectively. Less than 2% of the dose was excreted unchanged in the urine. Approximately 15% of the dose was excreted unchanged in the feces.
The mean terminal plasma elimination half-life (t1/2) of dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg.
Metformin hydrochloride
Renal clearance of metformin is approximately 3.5 times greater than creatinine clearance, indicating tubular secretion as the major route of metformin elimination. After oral administration of metformin, approximately 90% of the absorbed drug is excreted renally within the first 24 hours. The plasma half-life is approximately 6.2 hours. The blood half-life is approximately 17.6 hours, indicating a possible role for erythrocytes as a depot for drug distribution.
Certain patient groups
Patients with renal impairment
At steady-state (20 mg dapagliflozin once daily for 7 days), patients with type 2 diabetes mellitus and mild, moderate, or severe renal impairment (as determined by estimated glomerular filtration rate (eGFR)) had geometric mean systemic exposures to dapagliflozin that were 45% higher, 2.04-fold, and 3.03-fold, respectively, than those in type 2 diabetes mellitus patients with normal renal function. The higher systemic exposure to dapagliflozin in patients with type 2 diabetes mellitus and renal impairment did not result in higher daily glucose excretion. The daily urinary glucose excretion at steady-state in patients with type 2 diabetes mellitus and mild, moderate, or severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 2 diabetes mellitus and normal renal function. The effect of hemodialysis on dapagliflozin exposure is unknown (see sections 4.2, 4.4, and 4.5).
Metformin hydrochloride
In patients with reduced renal function, the half-life of metformin from plasma and blood is prolonged and renal clearance is reduced (see sections "Contraindications" and "Special warnings and precautions for use").
Patients with hepatic impairment
Dapagliflozin
In patients with mild to moderate hepatic impairment (Child-Pugh Class A and B), the mean Cmax and AUC of dapagliflozin were 12% and 36% higher, respectively, compared with matched healthy control subjects after a single dose of dapagliflozin 10 mg. These differences were not considered clinically significant. In patients with severe hepatic impairment (Child-Pugh Class C), the mean Cmax and AUC of dapagliflozin were 40% and 67% higher, respectively, compared with matched healthy control subjects.
Metformin hydrochloride
Pharmacokinetic studies of metformin in patients with hepatic impairment have not been conducted.
Elderly patients
Dapagliflozin
Based on population pharmacokinetic analysis, age has no clinically significant effect on the systemic exposure of dapagliflozin; therefore, no dose adjustment is required.
Metformin hydrochloride
Some data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that the total plasma clearance of metformin is reduced, the half-life of the drug is prolonged, and Cmax is increased compared to healthy younger subjects.
Thus, the change in metformin pharmacokinetics with age is primarily explained by changes in renal function.
Pediatric population
The pharmacokinetics of the drug KSIGDUO Prolong in the pediatric population have not been studied.
Sex
Dapagliflozin
Based on population pharmacokinetic analysis, gender has no clinically significant effect on the systemic exposure of dapagliflozin; therefore, no dose adjustment is required.
Metformin hydrochloride
The pharmacokinetic parameters of metformin in healthy subjects and patients with type 2 diabetes did not differ significantly when analyzed by gender (males = 19, females = 16). In addition, in controlled clinical trials in patients with type 2 diabetes, the hypoglycemic effect of metformin was comparable in men and women.
Racial affiliation
Dapagliflozin
Based on population pharmacokinetic analysis, patient race (Caucasian, Negroid, or Mongoloid) has no clinically significant effect on the systemic exposure of dapagliflozin; therefore, no dose adjustment is required.
Metformin hydrochloride
Studies of the pharmacokinetic parameters of metformin depending on the race of the patient have not been conducted. In controlled clinical studies of the use of metformin in patients with type 2 diabetes mellitus, the hypoglycemic effect was comparable in representatives of the Caucasian (n = 249), Negroid (n = 51) race and Hispanics (n = 24).
Body weight
Dapagliflozin
Based on population pharmacokinetic analysis, patient body weight has no clinically significant effect on the systemic exposure of dapagliflozin; therefore, no dose adjustment is required.
Drug interactions
Separate pharmacokinetic drug interaction studies with the drug KSIGDUO Prolong have not been conducted, although such studies have been conducted with the individual components of the drug, dapagliflozin and metformin.
In vitro drug interaction assessment
In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide did not inhibit CYP 1A2, 2C9, 2C19, 2D6, 3A4 activity and did not induce CYP 1A2, 2B6 or 3A4 activity. Dapagliflozin is a weak substrate for the active transporter P-glycoprotein (P-gp), and dapagliflozin 3-O-glucuronide is a substrate for the active transporter OAT3. Dapagliflozin or dapagliflozin 3-O-glucuronide did not significantly inhibit the active transporters P-gp, OCT2, OAT1 or OAT3. In general, dapagliflozin is unlikely to affect the pharmacokinetics of concomitantly administered medicinal products that are substrates for P-gp, OCT2, OAT1 or OAT3.
Effects of other drugs on metformin
The table below presents the effects of other concomitantly administered medicinal products on metformin.
Table 1. Effect of concomitant medications on plasma systemic exposure of metformin
Simultaneously applied medicine (dosage regimen)* | Metformin (dosage regimen)* | Metformin | |
| Change in AUC† | Change in Cmax† | | |
| No dose adjustment was required for the following drugs: | | | |
| Glyburide (5 mg) | 850 mg | ↓9 %§ | ↓7%§ |
| Furosemide (40 mg) | 850 mg | ↑15%§ | ↑22 %§ |
| Nifedipine (10 mg) | 850 mg | ↑9% | ↑20% |
| Propranolol (40 mg) | 850 mg | ↓10% | ↓6% |
| Ibuprofen (400 mg) | 850 mg | ↑5%§ | ↑7%§ |
| Medicinal products that are excreted by the kidneys via tubular secretion may increase the accumulation of metformin (see section "Interaction with other medicinal products and other types of interactions"). | | | |
| Cimetidine (400 mg) | 850 mg | ↑40% | ↑60% |
*Metformin and all concomitant medications were administered as single doses.
† Percent change (with/without co-administration of medicinal product and no change = 0%); ↑ and ↓ indicate increased and decreased exposure, respectively.
‡ AUC = AUC(INF) (area under the concentration-time curve from zero to infinity).
§ Ratio of arithmetic mean values.
The effect of metformin on other drugs
The table below presents the effects of metformin on other concomitant medications.
Table 2. Effect of metformin on the systemic exposure of concomitantly administered medicinal products
Concomitant medication (dosage regimen)* | Metformin (dosage regimen)* | Concomitant drug | |
| Change in AUC† | Change in Cmax† | | |
| No dose adjustment was required for the following drugs: | | | |
| Glyburide (5 mg) | 850 mg | ↓22 %§ | ↓37 %§ |
| Furosemide (40 mg) | 850 mg | ↓12 %§ | ↓31 %§ |
| Nifedipine (10 mg) | 850 mg | ↑10%¶ | ↑8% |
| Propranolol (40 mg) | 850 mg | ↑1 %¶ | ↑2% |
| Ibuprofen (400 mg) | 850 mg | ↓3 %# | ↑1 %# |
| Cimetidine (400 mg) | 850 mg | ↓5%¶ | ↑1% |
*Metformin and all concomitant medications were administered as single doses.
† Percent change (with/without co-administration of medicinal product and no change = 0%); ↑ and ↓ indicate increased and decreased exposure, respectively.
‡ AUC = AUC(INF) (area under the concentration-time curve from zero to infinity), unless otherwise stated.
§ Ratio of arithmetic mean values, p-value of difference < 0.05.
¶ AUC (0-24h) values (area under the concentration-time curve from zero to 24h) reported.
# Ratio of arithmetic mean values.
Effects of other medicinal products on dapagliflozin
The table below shows the effects of concomitant medications on dapagliflozin. No dose adjustment of dapagliflozin is required.
Table 3. Effect of co-administered medicinal products on the systemic exposure of dapagliflozin
Concomitant medication (dosage regimen)* | Dapagliflozin (dosage regimen)* | Dapagliflozin | |
| Change in AUC† | Change in Cmax† | | |
| No dose adjustment was required for the following drugs: | | | |
| Oral hypoglycemic drugs | | | |
| Metformin (1000 mg) | 20 mg | ↓1% | ↓7% |
| Pioglitazone (45 mg) | 50 mg | 0 % | ↑9% |
| Sitagliptin (100 mg) | 20 mg | ↑8% | ↓4% |
| Glimepiride (4 mg) | 20 mg | ↓1% | ↑1% |
| Voglibose (0.2 mg three times a day) | 10 mg | ↑1% | ↑4% |
| Other medicines | | | |
| Hydrochlorothiazide (25 mg) | 50 mg | ↑7% | ↓1% |
| Bumetanide (1 mg) | 10 mg once daily for 7 days | ↑5% | ↑8% |
| Valsartan (320 mg) | 20 mg | ↑2% | ↓12% |
| Simvastatin (40 mg) | 20 mg | ↓1% | ↓2% |
| Antibacterial drug | | | |
Rifampin (600 mg once daily for 6 days) | 10 mg | ↓22% | ↓7% | | Nonsteroidal anti-inflammatory drug | | | |
| Mefenamic acid (loading dose of 500 mg followed by 14 doses of 250 mg every 6 hours) | 10 mg | ↑51% | ↑13% |
*Single dose unless otherwise stated.
†Percent change (with/without co-administration of medicinal product and no change = 0%); ↑ and ↓ indicate increased and decreased exposure, respectively.
‡ AUC = AUC(INF) (area under the concentration-time curve from zero to infinity) for drugs administered as single doses, and AUC = AUC(TAU) (area under the concentration-time curve with the minimum concentration at the end of the first dosing interval) for drugs administered as multiple doses.
Effects of dapagliflozin on other medicinal products
The table below presents the effects of dapagliflozin on other concomitantly administered medicinal products. Dapagliflozin did not significantly affect the pharmacokinetics of concomitantly administered medicinal products.
Table 4. Effect of dapagliflozin on the systemic exposure of concomitantly administered medicinal products
Concomitant medication (dosage regimen)* | Dapagliflozin (dosage regimen)* | Concomitant drug | |
| Change in AUC† | Change in Cmax† | | |
| No dose adjustment was required for the following drugs: | | | |
| Oral hypoglycemic drugs | | | |
| Metformin (1000 mg) | 20 mg | 0 % | ↓5% |
| Pioglitazone (45 mg) | 50 mg | 0 % | ↓7% |
| Sitagliptin (100 mg) | 20 mg | ↑1% | ↓11% |
| Glimepiride (4 mg) | 20 mg | ↑13% | ↑4% |
| Other medicines | | | |
| Hydrochlorothiazide (25 mg) | 50 mg | ↓1% | ↓5% |
| Bumetanide (1 mg) | 10 mg once daily for 7 days | ↑13% | ↑13% |
| Valsartan (320 mg) | 20 mg | ↑5% | ↓6% |
| Simvastatin (40 mg) | 20 mg | ↑19% | ↓6% |
| Digoxin (0.25 mg) | 20 mg loading dose, then 10 mg once daily for 7 days | 0 % | ↓1% |
Warfarin (25 mg) S-warfarin R-warfarin | 20 mg loading dose, then 10 mg once daily for 7 days | ↑3% ↑6% | ↑7% ↑8% |
*Single dose unless otherwise stated.
† Percent change (with/without co-administration of medicinal product and no change = 0%); ↑ and ↓ indicate increased and decreased exposure, respectively.
‡ AUC = AUC(INF) (area under the concentration-time curve from zero to infinity) for drugs administered as single doses, and AUC = AUC(TAU) (area under the concentration-time curve with the minimum concentration at the end of the first dosing interval) for drugs administered as multiple doses.
Indication
XYGDUO Prolong is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Dapagliflozin is indicated to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.
Limitations in use
The use of the drug KSIGDUO Prolong is not recommended for patients with type 1 diabetes mellitus or diabetic ketoacidosis.
Contraindication
KSIGDUO Prolong is contraindicated in patients with:
hypersensitivity to the active substances or to any of the excipients;
any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis);
diabetic precoma;
severe renal insufficiency (eGFR less than 30 ml/min/1.73 m2), end-stage renal disease or patients on dialysis (see section "Special warnings and precautions for use");
acute conditions that can affect kidney function, such as:
dehydration,
severe infection,
shock;
acute or chronic disease that can cause tissue hypoxia, such as:
heart or respiratory failure,
recent myocardial infarction,
shock;
liver dysfunction;
acute alcohol intoxication, alcoholism.
Interaction with other medicinal products and other types of interactions
Positive test for glucose in urine
Dapagliflozin
Monitoring of glycemic control with urine glucose testing is not recommended for patients taking ACE inhibitors because ACE inhibitors increase urinary glucose excretion and will result in positive urine glucose results. Alternative methods of testing should be used for glycemic monitoring.
Interference with 1,5-anhydroglucitol (1,5-AG)
Monitoring glycemic control with 1,5-AG is not recommended because 1,5-AG levels are unreliable in assessing glycemic status in patients taking ACE inhibitors. Alternative methods should be used for glycemic monitoring.
Carbonic anhydrase inhibitors
Topiramate or other carbonic anhydrase inhibitors (e.g. zonisamide, acetazolamide or dichlorphenamide) often cause a decrease in serum bicarbonate levels and lead to hyperchloremic metabolic acidosis without changes in the anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with the drug KSIGDUO Prolong may increase the risk of lactic acidosis. More frequent monitoring of the condition of such patients may be advisable.
Drugs that reduce metformin clearance
Concomitant use of medicinal products that affect the common renal tubular transport system involved in the renal elimination of metformin (e.g. organic cation transporter-2 [OCT2]/drug and toxin extrusion [DTE] inhibitors such as ranolazine, vandetanib, dolutegravir and cimetidine) may increase systemic exposure to metformin and increase the risk of lactic acidosis (see section 5.1). The benefits and risks of such concomitant use should be considered.
Alcohol
Alcohol may potentiate the effect of metformin on lactate metabolism. Patients should be cautioned against excessive alcohol consumption while taking KSIGDUO Prolong.
Insulin or insulin secretagogues
The risk of hypoglycaemia may be increased when Xigduo Prolong is used concomitantly with insulin or insulin secretagogues (e.g. sulphonylureas) (see section 4.4). In the event of concomitant use, lower doses of insulin or insulin secretagogues may be required to reduce the risk of hypoglycaemia.
Drugs affecting glycemic control
Metformin hydrochloride
Some drugs increase the risk of hyperglycemia and may lead to loss of glycemic control. Such drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving XYGDUO Prolong, the patient should be closely monitored for loss of blood glucose control. When such drugs are withdrawn from a patient receiving XYGDUO Prolong, the patient should be closely monitored for hypoglycemia.
Lithium
Concomitant use of an ACE inhibitor with lithium may result in decreased serum lithium concentrations. Serum lithium concentrations should be monitored more frequently at the start of treatment with Xigduo Prolong; dose adjustment may be necessary.
Application features
Lactic acidosis
In the post-marketing period, cases of lactic acidosis associated with metformin have been reported, including fatalities. In these cases, the onset of lactic acidosis was almost insidious and was accompanied by nonspecific symptoms such as malaise, myalgia, abdominal pain, respiratory distress or increased drowsiness; however, severe acidosis has been associated with hypothermia, hypotension and resistant bradyarrhythmia. Lactic acidosis associated with metformin has been characterised by elevated blood lactate concentrations (> 5 mmol/L), anion gap acidosis (without signs of ketonuria or ketonemia) and an increased lactate:pyruvate ratio; plasma metformin levels were usually > 5 μg/mL. Metformin reduces the uptake of lactate by the liver, increasing blood lactate levels, which increases the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, immediate supportive measures should be instituted in a hospital setting and the use of XYGDUO Prolong should be discontinued immediately. If lactic acidosis is diagnosed or strongly suspected in patients treated with XYGDUO Prolong, immediate hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 ml/min under adequate hemodynamic conditions). Hemodialysis has often resulted in resolution of symptoms and recovery.
Patients and their families should be informed about the symptoms of lactic acidosis and instructed to discontinue use of XYGDUO Prolong and report these symptoms to their physician if they develop these symptoms.
Renal impairment. Post-marketing reports of lactic acidosis associated with metformin have occurred predominantly in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with increasing severity of renal impairment, as metformin is largely eliminated by the kidneys. Clinical recommendations based on the patient's renal function include (see sections 4.2 and 5.1):
Before starting therapy with the drug KSIGDUO Prolong, it is necessary to calculate the glomerular filtration rate (GFR).
KSIGDUO Prolong is contraindicated in patients with eGFR less than 30 ml/min/1.73 m2 (see section “Contraindications”).
eGFR should be determined at least annually in all patients receiving KSIGDUO Prolong. In patients at increased risk of renal impairment (e.g. elderly patients), renal function should be assessed more frequently.
Drug interactions. Concomitant use of KSIGDUO Prolong with certain drugs increases the risk of metformin-associated lactic acidosis; these include drugs that impair renal function, cause significant hemodynamic changes, affect acid-base status, or increase metformin accumulation (including cationic drugs) (see section "Interaction with other drugs and other types of interactions"). Therefore, more frequent monitoring of the condition of such patients may be appropriate.
Age 65 years or older. The risk of lactic acidosis associated with metformin use increases with age, as elderly patients are more likely to have impaired hepatic, renal, or cardiac function than younger patients. Elderly patients should have their renal function assessed more frequently (see Dosage and Administration).
Radiological studies using contrast agents. Intravascular administration of iodinated contrast agents in patients receiving metformin has resulted in acute deterioration of renal function and the development of lactic acidosis. Patients with a history of liver dysfunction, alcoholism or heart failure, and patients who will be administered iodinated contrast agents intraarterially, should discontinue the use of the drug KSIGDUO Prolong for the duration of the examination procedure involving the administration of iodinated contrast agents or before it. 48 hours after the procedure, eGFR should be re-evaluated, and if renal function is stable, the use of the drug KSIGDUO Prolong can be resumed.
Surgery and other procedures. Withholding food and fluids during surgery or other procedures increases the risk of hypovolemia, hypotension, and renal impairment. Use of KSIGDUO Prolong should be temporarily discontinued while patients are on restricted food and fluid intake.
Hypoxic conditions. Several cases of lactic acidosis associated with metformin have been reported in postmarketing experience in patients with acute congestive heart failure (particularly those with hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions with hypoxemia have been associated with lactic acidosis and may also lead to prerenal azotemia. If such events occur, KSIGDUO Prolong should be discontinued.
Alcohol abuse. Alcohol potentiates the effect of metformin on lactate metabolism, which may increase the risk of metformin-associated lactic acidosis. Patients should be cautioned against alcohol abuse while taking KSIGDUO Prolong.
Hepatic impairment. Lactic acidosis has been reported with metformin in patients with hepatic impairment. This may be due to impaired lactate clearance, leading to higher blood lactate levels. Therefore, patients with clinical or laboratory evidence of liver disease should avoid the use of KSIGDUO Prolong.
Arterial hypotension
Dapagliflozin causes intravascular volume depletion. Symptomatic hypotension may occur after initiation of treatment with dapagliflozin (see section 4.8), particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m2), the elderly, or patients receiving loop diuretics. Before initiating treatment with dapagliflozin,
