Xigduo prolong
UkraineTable of Contents
INSTRUCTION for medical use of the medicinal product XIGDUO Prolong (XIGDUO Prolong)
Composition:
Active substances: dapagliflozin propandiol; metformin hydrochloride;
5/1000 mg: 1 prolonged-release film-coated tablet contains 6.15 mg of dapagliflozin propandiol, equivalent to 5 mg of dapagliflozin, and 1005.04 mg of metformin hydrochloride;
10/1000 mg: 1 prolonged-release film-coated tablet contains 12.30 mg of dapagliflozin propandiol, equivalent to 10 mg of dapagliflozin, and 1005.04 mg of metformin hydrochloride;
10/500 mg: 1 prolonged-release film-coated tablet contains 12.30 mg of dapagliflozin propandiol, 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 PH102 (for 10/500 mg), silicon dioxide, magnesium stearate, microcrystalline cellulose PH302, anhydrous lactose, crospovidone, colorant Opadry® II Yellow 85F12372 (for 10/1000 mg), colorant Opadry® II Pink 85F94333 (for 10/500 mg), colorant Opadry® II Pink 85F94592 (for 5/1000 mg).
Pharmaceutical form. Prolonged-release film-coated tablets.
Main physicochemical properties:
5/1000 mg: film-coated tablet, pink to dark pink in color, biconvex, oval, with engraving ″1071″ and ″5/1000″ on one side and flat on the other side.
10/500 mg: film-coated tablet, pink in color, biconvex, capsule-shaped, with engraving ″1072″ and ″10/500″ on one side and flat on the other side.
10/1000 mg: film-coated tablet, yellow to dark yellow in color, biconvex, oval, with engraving ″1073″ and ″10/1000″ on one side and flat on the other side.
Pharmacotherapeutic group. Antidiabetic agents. Metformin in combination with dapagliflozin. ATC code A10BD15.
Pharmacological Properties
Mechanism of Action
XIIGDUO Prolong
XIIGDUO Prolong combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and metformin hydrochloride, a biguanide.
Dapagliflozin
The sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for reabsorbing the majority of filtered glucose from the tubular lumen. Dapagliflozin is an SGLT2 inhibitor. By inhibiting SGLT2, 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 tubules of the kidneys. This may affect several physiological functions, including reduction of both preload and afterload on the heart and decreased sympathetic activity.
Metformin Hydrochloride
Metformin is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes mellitus by lowering both basal and postprandial plasma glucose levels. Metformin reduces hepatic glucose production, decreases intestinal glucose absorption, and increases insulin sensitivity by enhancing peripheral glucose uptake and utilization. Insulin secretion is not increased during metformin therapy; however, fasting insulin levels and daily plasma insulin levels may decrease.
Pharmacodynamics
General Information
Dapagliflozin
In healthy study participants and patients with type 2 diabetes mellitus, administration of dapagliflozin resulted in increased urinary glucose excretion. Approximately 70 g of glucose was excreted in urine per day when dapagliflozin was administered at doses of 5 or 10 mg daily in patients with type 2 diabetes mellitus over 12 weeks. Similar maximal glucose excretion was observed with a daily dose of dapagliflozin 20 mg. This glucose excretion in urine with dapagliflozin also leads to an increase in urine volume (see section "Adverse Reactions"). After discontinuation of dapagliflozin, elevated glucose excretion returns to baseline levels within an average of 3 days when the dapagliflozin dose was 10 mg.
Cardioelectrophysiology
Administration of dapagliflozin was not associated with clinically significant prolongation of the QTc interval when administered at daily doses up to 150 mg (a dose 15 times higher than the maximum recommended dose) in a study involving healthy volunteers. Furthermore, no clinically significant effect on the QTc interval was observed after single doses of dapagliflozin up to 500 mg (a dose 50 times higher than the maximum recommended dose) administered to healthy volunteers.
Pharmacokinetics
Administration of the medicinal product XIIGDUO Prolong to healthy volunteers after a standard meal and in the fasting state provides equivalent exposure to dapagliflozin and extended-release metformin. Compared to administration in the fasting state, administration with a standard meal results in a 35% reduction in the maximum plasma concentration (Cmax) of dapagliflozin and a 1–2 hour delay in its attainment. This food effect is not considered clinically significant. Food intake does not have a significant effect on the pharmacokinetics of metformin when administered as part of the medicinal product XIIGDUO Prolong.
Absorption
Dapagliflozin
After oral administration, maximum plasma concentration (Cmax) of dapagliflozin is generally reached within 2 hours following dosing under fasting conditions. Cmax and AUC values of dapagliflozin increase proportionally with dose within the therapeutic dose range. Absolute bioavailability of dapagliflozin after oral administration of a 10 mg dose is 78%. Administration with a high-fat meal reduces Cmax of dapagliflozin by 50% and prolongs Tmax by approximately 1 hour, but does not alter AUC compared to administration under fasting conditions. These changes are not considered clinically significant, and dapagliflozin can be administered independently of food intake.
Metformin Hydrochloride
After single oral administration of extended-release metformin, the median time to reach Cmax is 7 hours, with a range of 4 to 8 hours. The extent of absorption of metformin (as measured by AUC) from extended-release tablets increases by approximately 50% when administered with food. No food effect on Cmax and Tmax of metformin was observed.
Distribution
Dapagliflozin
Dapagliflozin is approximately 91% bound to plasma proteins. Protein binding of the drug does not change in patients with renal or hepatic impairment.
Metformin Hydrochloride
Distribution studies of extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin after single oral administration of the immediate-release formulation at a dose of 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, unlike sulfonylureas, which are more than 90% protein-bound. Metformin penetrates into erythrocytes.
Metabolism
Dapagliflozin
Metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is minimal in humans. Dapagliflozin is extensively metabolized, primarily forming dapagliflozin 3-O-glucuronide, an inactive metabolite. Dapagliflozin 3-O-glucuronide accounts for 61% of the dose of [14C]-dapagliflozin 50 mg and is the predominant drug-related component in human plasma.
Metformin Hydrochloride
Intravenous single-dose studies in healthy volunteers have shown that metformin is excreted unchanged in urine and is not metabolized in the liver (no metabolites have been identified in humans) or excreted in bile.
Metabolism studies of extended-release metformin administered in tablet form have not been conducted.
Elimination
Dapagliflozin
Dapagliflozin and its related metabolites are primarily eliminated via urinary excretion. After administration of a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% of total radioactivity are excreted in urine and feces, respectively. Less than 2% of the drug dose is excreted unchanged in urine. Approximately 15% of the drug dose is excreted unchanged in feces.
The mean terminal half-life (t1/2) of dapagliflozin in plasma is approximately 12.9 hours after a single 10 mg oral dose.
Metformin Hydrochloride
Renal clearance of metformin exceeds creatinine clearance by approximately 3.5 times, indicating tubular secretion as the main route of metformin elimination. After oral administration, approximately 90% of the absorbed drug is excreted by the kidneys within the first 24 hours. The plasma elimination half-life is about 6.2 hours. The blood elimination half-life is approximately 17.6 hours, suggesting possible involvement of erythrocytes as a distribution reservoir for the drug.
Special Patient Populations
Patients with Renal Impairment
Dapagliflozin
At steady-state (20 mg dapagliflozin once daily for 7 days), patients with type 2 diabetes mellitus and mild, moderate, or severe renal impairment (defined by estimated glomerular filtration rate [eGFR]) had geometric mean systemic exposures to dapagliflozin that were 45% higher, 2.04 times, and 3.03 times, respectively, compared to patients with type 2 diabetes mellitus and normal renal function. Higher systemic exposure to dapagliflozin in patients with type 2 diabetes mellitus and renal impairment did not result in higher daily glucose excretion. 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, compared to patients with type 2 diabetes mellitus and normal renal function. The effect of hemodialysis on dapagliflozin exposure is unknown (see sections "Dosage and Administration", "Special Warnings", and "Use in Special Populations").
Metformin Hydrochloride
In patients with impaired renal function, the elimination half-life of metformin in plasma and blood is prolonged and renal clearance is reduced (see sections "Contraindications" and "Special Warnings").
Patients with Hepatic Impairment
Dapagliflozin
In patients with mild or moderate hepatic impairment (Child-Pugh class A and B), mean Cmax and AUC values of dapagliflozin were 12% and 36% higher, respectively, compared to matched healthy control subjects after a single 10 mg dose of dapagliflozin. These differences were not considered clinically significant. In patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC values of dapagliflozin were 40% and 67% higher, respectively, compared to matched healthy control subjects.
Metformin Hydrochloride
Pharmacokinetic studies of metformin in patients with hepatic impairment have not been conducted.
Elderly Patients
Dapagliflozin
According to population pharmacokinetic analysis data, age does not have a clinically significant effect on systemic exposure to dapagliflozin; therefore, dose adjustment is not required.
Metformin Hydrochloride
Some data from controlled pharmacokinetic studies of metformin in healthy elderly subjects indicate that total plasma clearance of metformin is reduced, elimination half-life is prolonged, and Cmax is increased compared to younger healthy subjects.
Thus, changes in metformin pharmacokinetics with age are primarily explained by changes in renal function.
Pediatric Population
The pharmacokinetics of the medicinal product XIIGDUO Prolong have not been studied in the pediatric population.
Gender
Dapagliflozin
According to population pharmacokinetic analysis data, patient gender does not have a clinically significant effect on systemic exposure to dapagliflozin; therefore, dose adjustment is not required.
Metformin Hydrochloride
Pharmacokinetic parameters of metformin in healthy subjects and patients with type 2 diabetes mellitus did not differ significantly by gender (males = 19, females = 16) in data analyses. Additionally, in controlled clinical trials in patients with type 2 diabetes mellitus, the hypoglycemic effect of metformin was comparable between males and females.
Race
Dapagliflozin
According to population pharmacokinetic analysis data, patient race (Caucasian, African American, or Asian) does not have a clinically significant effect on systemic exposure to dapagliflozin; therefore, dose adjustment is not required.
Metformin Hydrochloride
Pharmacokinetic studies of metformin according to patient race have not been conducted. In controlled clinical trials of metformin in patients with type 2 diabetes mellitus, the hypoglycemic effect was comparable in Caucasians (n = 249), African Americans (n = 51), and Hispanics (n = 24).
Body Weight
Dapagliflozin
According to population pharmacokinetic analysis data, patient body weight does not have a clinically significant effect on systemic exposure to dapagliflozin; therefore, dose adjustment is not required.
Drug Interactions
Specific pharmacokinetic drug interaction studies with the medicinal product XIIGDUO Prolong have not been conducted, although such studies have been performed with the individual components dapagliflozin and metformin.
In vitro Evaluation of Drug Interactions
Dapagliflozin
In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide did not inhibit the activity of CYP 1A2, 2C9, 2C19, 2D6, or 3A4, and did not induce the activity of CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate of the OAT3 active transporter. Dapagliflozin and dapagliflozin 3-O-glucuronide do not significantly inhibit the activity of active transporters P-gp, OCT2, OAT1, or OAT3. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concomitantly administered drugs that are substrates of P-gp, OCT2, OAT1, or OAT3.
Effect of Other Medicinal Products on Metformin
The table below presents the effects of other concomitantly administered medicinal products on metformin.
Table 1. Effect of Concomitantly Administered Medicinal Products on Plasma Systemic Exposure to Metformin
| Concomitantly administered medicinal product (dosing regimen)* |
Metformin (dosing regimen)* |
Metformin |
|
| Change in parameter† AUC‡ |
Change in parameter† Cmax |
||
| Dose adjustment was not required for the following medicinal products: |
|||
| Glipizide (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 excreted renally via tubular secretion may increase metformin accumulation (see section "Interaction with other medicinal products and other forms of interaction"). |
|||
| Cimetidine (400 mg) |
850 mg |
↑40 % |
↑60 % |
*Metformin and all concomitantly administered medicinal products were administered as single doses.
† Percentage change (with/without concomitant medicinal product administration and no change = 0%); ↑ and ↓ indicate increases and decreases in exposure, respectively.
‡ AUC = AUC(INF) (area under the plasma concentration-time curve from zero to infinity).
§ Ratio of arithmetic means.
Effects of metformin on other medicinal products
The table below presents the effects of metformin on other concomitantly administered medicinal products.
Table 2. Effects of metformin on systemic exposure of concomitantly administered medicinal products
| Concomitantly administered medicinal product (dosing regimen)* |
Metformin (dosing regimen)* |
Concomitantly administered product |
|
| Change in parameter† AUC‡ |
Change in parameter† Cmax |
||
| Dose adjustment was not required for the following medicinal products: |
|||
| Glibenclamide (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 co-administered medicinal products were administered as single doses.
† Percentage change (with/without concomitant medicinal product and no change = 0%); ↑ and ↓ indicate increases and decreases in exposure, respectively.
‡ AUC = AUC(INF) (area under the concentration-time curve from zero to infinity), unless otherwise specified.
§ Ratio of arithmetic means, p-value of difference < 0.05.
¶ AUC (0−24 h) (area under the concentration-time curve from zero to 24 hours) values as reported.
Ratio of arithmetic means.
Effect of other medicinal products on dapagliflozin
The table below presents the effects of co-administered medicinal products on dapagliflozin. Dose adjustment of dapagliflozin is not required.
Table 3. Effect of co-administered medicinal products on systemic exposure of dapagliflozin
| Concomitantly administered medicinal product (dosing regimen)* |
Dapagliflozin (dosing regimen)* |
Dapagliflozin |
|
| Change in parameter† AUC‡ |
Change in parameter† Cmax |
||
| Dose adjustment was not required for the following medicinal products: |
|||
| Oral antihyperglycemic medicinal products |
|||
| 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 daily) |
10 mg |
↑1 % |
↑4 % |
| Other medicinal products |
|||
| 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 medicinal product |
|||
| Rifampicin (600 mg once daily for 6 days) |
10 mg |
↓22 % |
↓7 % |
| Nonsteroidal anti-inflammatory medicinal product |
|||
| Mefenamic acid (loading dose 500 mg followed by 14 doses of 250 mg every 6 hours) |
10 mg |
↑51 % |
↑13 % |
*Single dose, unless otherwise specified.
†Percentage change (with/without concomitant drug administration and no change = 0%); ↑ and ↓ indicate increases and decreases in 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 over the dosing interval with a minimum concentration at the end of the first interval) for drugs administered as multiple doses.
Effect of dapagliflozin on other medicinal products
The table below presents the effects of dapagliflozin on other concomitantly administered medicinal products. Dapagliflozin had no clinically relevant effect on the pharmacokinetics of concomitantly administered drugs.
Table 4. Effect of dapagliflozin on systemic exposure of concomitantly administered medicinal products
| Concomitantly administered medicinal product (dosing regimen)* |
Dapagliflozin (dosing regimen)* |
Change in concomitant product |
|
| Change in AUC†‡ |
Change in Cmax† |
||
| No dose adjustment required for the following medicinal products: |
|||
| Oral antihyperglycaemic medicinal products |
|||
| 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 medicinal products |
|||
| 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.
† Percentage change (with/without concomitant drug administration and no change = 0%); ↑ and ↓ indicate increases and decreases in 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 over the dosing interval at steady state) for drugs administered as multiple doses.
Clinical characteristics.
Indications.
XIGDUO XR 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 of use
XIGDUO XR is not recommended for use in patients with type 1 diabetes or with diabetic ketoacidosis.
Contraindications.
XIGDUO XR is contraindicated in patients with:
- hypersensitivity to the active substances or to any of the excipients;
- any form of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis);
- diabetic precoma;
- severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end-stage renal disease, or patients on dialysis (see section "Special precautions for use");
- acute conditions that may affect kidney function, such as:
- dehydration,
- severe infection,
- shock;
- acute or chronic conditions that may cause tissue hypoxia, such as:
- cardiac or respiratory failure,
- recent myocardial infarction,
- shock;
- hepatic dysfunction;
- acute alcohol intoxication, alcoholism.
Interaction with other medicinal products and other forms of interaction.
Positive urine glucose test
Dapagliflozin
Monitoring glycemic control using urine glucose tests is not recommended in patients taking SGLT2 inhibitors, as SGLT2 inhibitors increase glucose excretion in urine, which will lead to positive urine glucose test results. Alternative methods of monitoring glycemic status should be used.
Interference with 1,5-anhydroglucitol (1,5-AG)
Dapagliflozin
Monitoring glycemic control using 1,5-AG assays is not recommended, as measurements of 1,5-AG levels are unreliable for assessing glycemic status in patients taking SGLT2 inhibitors. Alternative methods of monitoring glycemic status should be used.
Carbonic anhydrase inhibitors
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide, or dichlorphenamide) frequently cause a reduction in serum bicarbonate levels and lead to hyperchloremic metabolic acidosis without changes in the anion gap. Concomitant use of these medicinal products with XIGDUO XR may increase the risk of lactic acidosis. More frequent monitoring of such patients may be advisable.
Medicinal products that reduce metformin clearance
Concomitant use of medicinal products that affect the renal tubular transport system involved in the elimination of metformin (e.g., organic cation transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase systemic exposure to metformin and increase the risk of lactic acidosis (see section "Pharmacological properties"). The benefits and risks of such concomitant use should be carefully considered.
Alcohol
Alcohol can potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol consumption during treatment with XIGDUO XR.
Insulin or insulin secretagogues
The risk of hypoglycemia may be increased when XIGDUO XR is used concomitantly with insulin or insulin secretagogues (e.g., sulfonylureas) (see section "Special precautions for use"). Lower doses of insulin or insulin secretagogues may be required when used concomitantly to reduce the risk of hypoglycemia.
Medicinal products affecting glycemic control
Metformin hydrochloride
Some medicinal products increase the risk of hyperglycemia and may lead to loss of glycemic control. These include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such medicinal products are prescribed to a patient receiving XIGDUO XR, careful monitoring is required to detect loss of blood glucose control. When such medicinal products are discontinued in a patient receiving XIGDUO XR, careful monitoring for hypoglycemia is required.
Lithium
Concomitant use of an SGLT2 inhibitor with lithium-containing medicinal products may lead to decreased serum lithium concentrations. Serum lithium concentrations should be monitored more frequently at the start of treatment with XIGDUO XR; dose adjustments may be necessary.
Special precautions for use.
Lactic acidosis
Post-marketing cases of lactic acidosis associated with metformin use, including fatal cases, have been reported. In these cases, lactic acidosis began almost imperceptibly and was accompanied by nonspecific symptoms such as malaise, myalgia, abdominal pain, respiratory distress, or increased somnolence; however, in severe acidosis, hypothermia, hypotension, and resistant bradycardia were observed. Lactic acidosis associated with metformin use was characterized by elevated blood lactate concentrations (> 5 mmol/L), acidosis with an increased anion gap (without signs of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; plasma metformin levels were typically > 5 µg/mL. Metformin reduces hepatic lactate uptake, thereby increasing blood lactate levels and increasing the risk of lactic acidosis, particularly in patients at risk.
In case of suspected metformin-associated lactic acidosis, immediate supportive measures in a hospital setting are required, and treatment with KSIHDOO Prolong must be discontinued immediately. If lactic acidosis is diagnosed or strongly suspected in patients receiving KSIHDOO Prolong, hemodialysis should be initiated promptly to correct acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under adequate hemodynamic conditions). Hemodialysis has frequently led to resolution of symptoms and patient recovery.
Patients and their families should be informed about the symptoms of lactic acidosis and instructed to discontinue KSIHDOO Prolong and notify their physician immediately if such symptoms occur.
Recommendations for reducing the risk and managing metformin-associated lactic acidosis in the presence of risk factors are provided below.
Renal impairment. Post-marketing cases of metformin-associated lactic acidosis have predominantly occurred in patients with significant renal impairment. The risk of metformin accumulation and development of metformin-associated lactic acidosis increases with the severity of renal impairment, as metformin is primarily excreted by the kidneys. Clinical recommendations based on the patient's renal function include (see sections "Dosage and administration", "Pharmacological properties"):
- Estimate glomerular filtration rate (eGFR) before initiating therapy with KSIHDOO Prolong.
- KSIHDOO Prolong is contraindicated in patients with eGFR < 30 mL/min/1.73 m² (see section "Contraindications").
- eGFR should be assessed at least annually in all patients receiving KSIHDOO Prolong. Renal function should be monitored more frequently in patients at increased risk of renal impairment (e.g., elderly patients).
Drug interactions. Concomitant use of KSIHDOO Prolong with certain medications increases the risk of metformin-associated lactic acidosis; these include drugs that impair renal function, cause significant hemodynamic changes, affect acid-base balance, or increase metformin accumulation (e.g., cationic drugs) (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, more frequent monitoring of such patients may be advisable.
Age 65 years or older. The risk of metformin-associated lactic acidosis increases with age, as elderly patients are more likely to have impaired liver, kidney, or heart function than younger patients. Renal function should be assessed more frequently in elderly patients (see section "Dosage and administration").
Radiological procedures with contrast agents. Intravascular administration of iodinated contrast agents to patients receiving metformin has led to acute worsening of renal function and development of lactic acidosis. Patients with a history of hepatic impairment, alcoholism, or heart failure, and those undergoing intra-arterial administration of iodinated contrast agents, should discontinue KSIHDOO Prolong before or during the procedure. Renal function (eGFR) should be re-evaluated 48 hours after the procedure, and if renal function remains stable, KSIHDOO Prolong may be resumed.
Surgery and other procedures. Fasting during surgical or other procedures increases the risk of hypovolemia, hypotension, and renal impairment. Treatment with KSIHDOO Prolong should be temporarily discontinued while food and fluid intake are restricted.
Hypoxic conditions. Several post-marketing cases of metformin-associated lactic acidosis have occurred in patients with acute congestive heart failure (particularly when associated with hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other hypoxemic states may precipitate lactic acidosis and may also cause prerenal azotemia. If such conditions occur, KSIHDOO Prolong should be discontinued.
Alcohol abuse. Alcohol potentiates metformin's effect on lactate metabolism, which may increase the risk of metformin-associated lactic acidosis. Patients should be warned against alcohol abuse during treatment with KSIHDOO Prolong.
Hepatic impairment. Cases of metformin-associated lactic acidosis have occurred 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 using KSIHDOO Prolong.
Arterial hypotension
Dapagliflozin causes a reduction in intravascular volume. Symptomatic arterial hypotension may occur after initiation of dapagliflozin therapy (see section "Adverse reactions"), particularly in patients with impaired renal function (eGFR < 60 mL/min/1.73 m²), elderly patients, or patients receiving loop diuretics. Before initiating KSIHDOO Prolong in such patients, volume depletion should be assessed and corrected. Monitoring for symptoms of hypotension is recommended after starting therapy.
Ketoacidosis
Cases of ketoacidosis, a serious and life-threatening condition requiring immediate hospitalization, have been reported in patients with type 1 and type 2 diabetes receiving SGLT2 inhibitors, including dapagliflozin (see section "Adverse reactions"). Fatal cases of ketoacidosis have occurred in patients treated with dapagliflozin. KSIHDOO Prolong is not indicated for use in patients with type 1 diabetes (see section "Indications").
Patients who develop symptoms of severe metabolic acidosis while receiving KSIHDOO Prolong should be evaluated for ketoacidosis, regardless of blood glucose concentration, as ketoacidosis may be present even when blood glucose levels are below 250 mg/dL. If ketoacidosis is suspected, KSIHDOO Prolong should be discontinued immediately, the patient evaluated, and appropriate treatment initiated without delay. Insulin therapy, fluid replacement, and correction of carbohydrate metabolism may be required to manage ketoacidosis.
According to post-marketing reports, in many cases—particularly in patients with type 1 diabetes—ketoacidosis was not promptly recognized and treatment was delayed because blood glucose concentrations were lower than typically expected in diabetic ketoacidosis (often < 250 mg/dL). Symptoms at presentation included dehydration and severe metabolic acidosis, with nausea, vomiting, abdominal pain, malaise, and dyspnea. In some cases, predisposing factors for ketoacidosis were identified, such as reduced insulin dose, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse.
Before initiating KSIHDOO Prolong, the patient's history should be evaluated for factors that may predispose to ketoacidosis, including pancreatic insulin deficiency due to any cause, restricted caloric intake, and alcohol abuse.
Consideration should be given to temporarily discontinuing KSIHDOO Prolong in patients undergoing surgery (at least 3 days prior to the procedure; see section "Pharmacological properties").
Consideration should also be given to monitoring for ketoacidosis and temporarily discontinuing KSIHDOO Prolong in other clinical situations that may precipitate ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Risk factors for ketoacidosis should be resolved before resuming KSIHDOO Prolong.
Patients should be informed about the signs and symptoms of ketoacidosis and instructed to discontinue KSIHDOO Prolong and seek immediate medical attention if such symptoms occur.
Acute kidney injury
Dapagliflozin causes a reduction in intravascular volume (see section "Special precautions for use") and may lead to acute kidney injury. Post-marketing reports have described cases of acute kidney injury in patients receiving dapagliflozin, some of whom required hospitalization and dialysis.
At the initiation of dapagliflozin therapy, serum creatinine levels may increase and estimated GFR may decrease. Elderly patients and those with impaired renal function may be more susceptible to these changes. Before initiating KSIHDOO Prolong, factors that may predispose to acute kidney injury should be considered, including hypovolemia, chronic kidney disease, heart failure, and concomitant use of medications (diuretics, ACE inhibitors, angiotensin II receptor blockers, NSAIDs). Temporary discontinuation of dapagliflozin may be advisable during reduced oral intake (e.g., due to acute illness or fasting) or fluid loss (e.g., due to gastrointestinal illness or excessive heat exposure); patients should be monitored for signs of acute kidney injury. If acute kidney injury occurs, KSIHDOO Prolong should be discontinued immediately and appropriate treatment initiated.
Renal function should be assessed before initiating KSIHDOO Prolong and periodically thereafter. Use of KSIHDOO Prolong is not recommended if eGFR is < 45 mL/min/1.73 m².
KSIHDOO Prolong is contraindicated in patients with eGFR < 30 mL/min/1.73 m² (see sections "Dosage and administration", "Contraindications", "Special precautions for use").
Urosepsis and pyelonephritis
Post-marketing cases of serious urinary tract infections, including urosepsis and pyelonephritis requiring hospitalization, have been reported in patients receiving SGLT2 inhibitors, including dapagliflozin. SGLT2 inhibitors increase the risk of urinary tract infections. Patients should be evaluated for symptoms of urinary tract infection and appropriate treatment initiated promptly if symptoms are present (see section "Adverse reactions").
Hypoglycemia with concomitant use of insulin and insulin secretagogues
Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia. KSIHDOO Prolong, when used in combination with insulin or an insulin secretagogue, may increase the risk of hypoglycemia (see section "Adverse reactions"). Therefore, to minimize the risk of hypoglycemia, it may be necessary to reduce the dose of insulin or insulin secretagogue when used in combination with KSIHDOO Prolong (see section "Interaction with other medicinal products and other forms of interaction").
Necrotizing fasciitis of the perineum (Fournier’s gangrene)
In the post-marketing period, cases of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been reported in patients with diabetes receiving SGLT2 inhibitors, including dapagliflozin. Cases have occurred in both women and men. Serious outcomes included hospitalization, multiple surgeries, and death.
Patients receiving KSIHDOO Prolong should be evaluated for necrotizing fasciitis if they develop pain or tenderness, erythema, or swelling in the genital or perineal area, or if they have fever or malaise. If suspected, broad-spectrum antibiotics should be initiated immediately and surgical intervention performed if necessary. Treatment with KSIHDOO Prolong should be discontinued, blood glucose levels closely monitored, and alternative therapy initiated for glycemic control.
Vitamin B12 concentrations
In controlled clinical trials lasting 29 weeks, approximately 7% of patients treated with metformin experienced a decrease in serum vitamin B12 levels below the normal range, without clinical manifestations. This decrease is likely due to interference with the vitamin B12–intrinsic factor complex absorption and may be associated with anemia, but it resolves rapidly upon discontinuation of metformin or administration of vitamin B12. Some patients (with inadequate intake or absorption of vitamin B12 or calcium) may be predisposed to subnormal vitamin B12 levels. Hematological parameters should be evaluated annually, and vitamin B12 levels assessed every 2–3 years to monitor for abnormalities in patients receiving KSIHDOO Prolong (see section "Adverse reactions").
Genital fungal infections
Dapagliflozin increases the risk of genital fungal infections. Patients with a history of genital fungal infections are more likely to develop such infections (see section "Adverse reactions").
Recommended monitoring and appropriate treatment should be implemented.
Use during pregnancy or breastfeeding.
Pregnancy
Summary of risk
Based on animal studies indicating adverse renal effects, KSIHDOO Prolong is not recommended during the second and third trimesters of pregnancy.
Limited data on the use of KSIHDOO Prolong or dapagliflozin in pregnant women are insufficient to determine the risk of major congenital malformations or miscarriage. Published studies on metformin use during pregnancy do not report a clear association between metformin use and the risk of major congenital malformations or miscarriage (see "Data from studies"). Risks to the mother and fetus associated with inadequate glycemic control during pregnancy exist (see "Clinical considerations").
In animal studies, adverse effects such as renal pelvis dilation and tubular dilatation, which were not fully reversible, were observed in rats exposed to dapagliflozin during kidney development corresponding to the late second and third trimesters of human pregnancy; the lowest dose corresponded to exposures 15 times higher than at the 10 mg clinical dose (see "Data from studies").
The predicted risk of major congenital malformations is 6–10% in women with pre-gestational diabetes and HbA1c > 7%, and up to 20–25% in women with HbA1c > 10%. The predicted risk of miscarriage in this patient group is unknown. In the general U.S. population, the predicted risks of major congenital malformations and miscarriage in clinically confirmed pregnancies are 2–4% and 15–20%, respectively.
Clinical considerations
Risk to the mother and/or embryo/fetus due to the disease
Poorly controlled diabetes during pregnancy increases the risk of diabetic ketoacidosis in the pregnant woman, preeclampsia, spontaneous miscarriage, preterm delivery, and delivery complications. Poorly controlled diabetes during pregnancy also increases the risk of major congenital malformations, stillbirth, and morbidity associated with macrosomia.
Data from studies
Human data
Published post-marketing studies do not report a clear association between metformin and major congenital malformations, miscarriage, or adverse maternal or fetal outcomes. However, due to methodological limitations, including small sample size and lack of appropriate comparator groups, these studies cannot definitively rule out any risk associated with metformin use.
Animal data
Dapagliflozin
In a study where dapagliflozin was administered directly to juvenile rats from postnatal day 21 to 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weight and higher incidence of renal pelvis dilation and tubular dilatation were reported at all dose levels. Exposure at the lowest dose tested was 15 times higher than at the 10 mg clinical dose (based on AUC). Renal pelvis dilation and tubular dilatation observed in juvenile animals were not fully reversible after approximately one month.
In a prenatal and postnatal development study, dapagliflozin was administered to pregnant rats from day 6 of gestation through day 21 of lactation at doses of 1, 15, or 75 mg/kg/day, and offspring were indirectly exposed during in utero development and lactation. Increased incidence and severity of renal pelvis dilation were observed in 21-day-old offspring exposed to 75 mg/kg/day (maternal and offspring exposures were 1415 and 137 times higher than in humans at the 10 mg clinical dose, based on AUC). Dose-dependent reductions in offspring body weight were observed at doses 29 times or higher than the 10 mg clinical dose (based on AUC). No adverse developmental effects were observed at 1 mg/kg/day (19 times the 10 mg clinical dose based on AUC). These effects occurred during drug exposure during kidney development in rats, corresponding to the late second and third trimesters of human fetal development.
In embryo-fetal development studies in rats and rabbits, dapagliflozin was administered during organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin showed no embryolethal or teratogenic effects at doses up to 75 mg/kg/day (1441 times the 10 mg clinical dose based on AUC). Dose-dependent effects in rat fetuses (structural anomalies and reduced body weight) occurred only at high doses equal to or exceeding 150 mg/kg (2344 times the 10 mg clinical dose based on AUC), associated with maternal toxicity. No toxic effects on rabbit fetal development were observed at doses up to 180 mg/kg/day (1191 times the 10 mg clinical dose based on AUC).
Metformin hydrochloride
Metformin hydrochloride showed no adverse effects on fetal development in pregnant Sprague-Dawley rats and rabbits at doses up to 600 mg/kg/day during organogenesis. This corresponds to exposures 2–6 times higher than at the 2000 mg clinical dose based on body surface area (mg/m²) for rats and rabbits, respectively. Measurement of intrauterine concentrations demonstrated a partial placental barrier to metformin.
Breastfeeding
Summary of risk
There is currently no information on the presence of KSIHDOO Prolong or dapagliflozin in human breast milk, their effects on breastfed infants, or their impact on milk production.
Limited published data suggest the presence of metformin in human breast milk (see "Data from studies"). However, there is insufficient information on the effects of metformin on breastfed infants, and no data are available on its effect on milk production. Dapagliflozin was detected in rat milk (see "Data from studies"). However, due to species-specific differences in lactation physiology, the clinical relevance of these findings is uncertain. As human kidney maturation occurs in utero and during the first two years of life—the period during which breastfeeding may occur—there may be a risk to the developing kidneys of the infant.
Due to the potential for serious adverse reactions in breastfed infants, women are advised not to breastfeed while taking KSIHDOO Prolong.
Data from studies
Dapagliflozin
Dapagliflozin was present in rat milk at a milk-to-plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are excreted into breast milk at concentrations approximately 50% of maternal plasma concentrations. Juvenile rats directly exposed to dapagliflozin are at risk of impaired kidney development (renal pelvis dilation and tubular dilatation) during maturation.
Metformin hydrochloride
Published clinical lactation studies indicate the presence of metformin in human breast milk, resulting in infant exposure of approximately 0.11–1% of the maternal dose adjusted for body weight; milk-to-plasma metformin concentration ratios ranged from 0.13 to 1. However, these studies were not designed to precisely determine the risk of metformin use during breastfeeding due to small sample sizes and limited data on adverse events in infants.
Use in women and men of reproductive potential
Women of premenopausal age should be counseled about the possibility of unintended pregnancy, as metformin therapy may induce ovulation in some anovulatory women.
Ability to drive and use machines
Dapagliflozin and metformin have no or negligible effects on the ability to drive or operate machinery. However, if dapagliflozin is used in combination with sulfonylurea or insulin, patients should be warned about the risk of hypoglycemia.
Dosage and Administration
Before initiating treatment with KSIGDUO Prolong
- Renal function should be assessed before initiating therapy with KSIGDUO Prolong and periodically thereafter (see section "Special Warnings and Precautions for Use").
- In patients with reduced extracellular fluid volume, this condition should be corrected prior to initiating KSIGDUO Prolong (see sections "Special Warnings and Precautions for Use" and "Use in Specific Patient Populations").
Recommended dosage
- KSIGDUO Prolong should be taken once daily in the morning with food.
- KSIGDUO Prolong tablets should be swallowed whole and must not be divided, crushed, or chewed. Occasionally, inactive components of KSIGDUO Prolong may be eliminated in the feces as a soft, hydrated mass resembling the original tablet.
- The initial dose of KSIGDUO Prolong should be individualized based on the patient's current therapy.
- For improved glycemic control in patients not previously treated with dapagliflozin, the recommended initial dose of dapagliflozin is 5 mg once daily.
- The recommended dose of dapagliflozin to reduce the risk of hospitalization for heart failure is 10 mg once daily.
- The dose of the medicinal product may be adjusted according to efficacy and tolerability, without exceeding the maximum recommended daily dose of 10 mg for dapagliflozin and 2000 mg for metformin hydrochloride.
- Patients currently taking an evening dose of extended-release metformin should skip the evening dose before initiating KSIGDUO Prolong.
Patients with renal impairment
KSIGDUO Prolong is contraindicated in patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² (see sections "Contraindications", "Special Warnings and Precautions for Use", "Use in Specific Patient Populations").
No dose adjustment of KSIGDUO Prolong is required in patients with eGFR ≥45 mL/min/1.73 m².
KSIGDUO Prolong is not recommended in patients with eGFR <45 mL/min/1.73 m².
Discontinuation of KSIGDUO Prolong for procedures involving iodinated contrast agents
Patients with a history of liver disease, alcoholism, or heart failure, and those undergoing intra-arterial administration of iodinated contrast agents, should discontinue KSIGDUO Prolong prior to or during the procedure. Renal function (eGFR) should be re-evaluated 48 hours after the procedure; if renal function is stable, KSIGDUO Prolong may be restarted (see section "Special Warnings and Precautions for Use").
Use in specific patient populations
Elderly patients
No dosage adjustment of KSIGDUO Prolong is required based on age. However, more frequent monitoring of renal function is recommended in elderly patients.
Dapagliflozin
In a pooled population of 5,936 patients from 21 double-blind, controlled clinical trials evaluating the efficacy of dapagliflozin for improving glycemic control, 1,424 (24%) patients receiving dapagliflozin were aged 65 years or older, and 207 (3.5%) were aged 75 years or older. After monitoring renal function (eGFR), it was concluded that efficacy in patients under 65 years of age was similar to that in patients over 65 years of age. However, in patients aged ≥65 years, adverse reactions such as hypotension occurred more frequently in those treated with dapagliflozin (see sections "Special Warnings and Precautions for Use" and "Undesirable Effects").
Metformin hydrochloride
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for elderly patients should be cautious, starting at the lower end of the dosing range, considering the higher prevalence of impaired hepatic, renal, or cardiac function, concomitant diseases, other drug therapies, and the increased risk of lactic acidosis. More frequent monitoring of renal function is recommended in elderly patients (see section "Special Warnings and Precautions for Use").
Renal impairment
Dapagliflozin
Dapagliflozin is not recommended if eGFR is <45 mL/min/1.73 m² (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use") and is contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease (see section "Contraindications").
The use of dapagliflozin was studied in two glycemic control trials that included patients with moderate renal impairment (eGFR 45–60 mL/min/1.73 m² and eGFR 30–60 mL/min/1.73 m²). The safety profile of dapagliflozin in patients with eGFR 45–60 mL/min/1.73 m² was similar to that in the overall population of patients with type 2 diabetes. Although a reduction in eGFR was observed in the dapagliflozin group compared to placebo, eGFR typically returned to baseline after discontinuation of treatment. In patients with renal impairment receiving dapagliflozin for glycemic control, the risk of arterial hypotension and acute kidney injury is increased. In a study of patients with eGFR 30–60 mL/min/1.73 m², 13 patients in the dapagliflozin group experienced bone fractures compared to no fractures in the placebo group.
Metformin hydrochloride
Metformin is primarily excreted by the kidneys, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. KSIGDUO Prolong is contraindicated in severe renal impairment and in patients with eGFR <30 mL/min/1.73 m² (see sections "Dosage and Administration", "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacological Properties").
Hepatic impairment
The use of metformin in patients with hepatic impairment has been associated with cases of lactic acidosis. KSIGDUO Prolong is not recommended in patients with hepatic impairment (see section "Special Warnings and Precautions for Use").
Pediatric population
The safety and efficacy of KSIGDUO Prolong in pediatric patients (under 18 years of age) have not been established.
Overdose
Dapagliflozin
There have been no reports of dapagliflozin overdose during clinical trials. In the event of overdose, contact a poison control center. Supportive measures appropriate to the patient's clinical condition should be initiated. Elimination of dapagliflozin by hemodialysis has not been studied.
Metformin hydrochloride
Cases of metformin hydrochloride overdose have been reported, including doses exceeding 50 g. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see section "Special Warnings and Precautions for Use"). Metformin is dialyzable with a clearance of up to 170 mL/min under adequate hemodynamic conditions. Therefore, hemodialysis may be useful in removing accumulated drug in patients suspected of metformin overdose.
Adverse Reactions
Important adverse reactions described below and in other sections of the prescribing information: lactic acidosis; hypotension; ketoacidosis; acute kidney injury; urosepsis and pyelonephritis; use with medications that can cause hypoglycemia; necrotizing fasciitis of the perineum (Fournier’s gangrene); decreased vitamin B12 concentration; genital fungal infections.
Clinical Trial Data
Because clinical trials are conducted under varying conditions, the adverse reaction rates observed in the clinical trials of a particular drug product cannot be directly compared to those in the clinical trials of other drugs, and may not reflect the rates observed in clinical practice.
Dapagliflozin and Metformin Hydrochloride
Data from 8 short-term, placebo-controlled studies evaluating the combination of dapagliflozin and immediate- or extended-release metformin were used to assess safety. Additionally, several other studies were conducted: metformin monotherapy studies, combination studies of a dipeptidyl peptidase-4 (DPP-4) inhibitor with metformin or insulin with metformin, two studies of early combination therapy with metformin, and two studies involving patients with cardiovascular disease (CVD) and type 2 diabetes receiving their standard of care (metformin as background therapy). For inclusion in the combined group of 8 placebo-controlled studies, only patients receiving metformin therapy were included as participants in studies where background therapy with or without metformin was provided. In these 8 studies, 983 patients received once-daily treatment with dapagliflozin 10 mg and metformin, and 1185 patients received placebo and metformin. The mean duration of exposure in these 8 studies was 23 weeks. The mean age of the population was 57 years, with 2% of participants over 75 years of age. Men comprised 54% of the population; 88% were of Caucasian race, 6% were of Asian descent, and 3% were of Black or African American descent. At baseline, study participants had type 2 diabetes with a mean duration of 8 years; mean hemoglobin A1c (HbA1c) level was 8.4%; renal function was normal or mildly impaired in 90% of patients, and moderately impaired in 10%.
The overall incidence of adverse reactions in the combined patient group (from 8 short-term, placebo-controlled studies) receiving dapagliflozin 10 mg and metformin was 60.3%, compared to 58.2% in the placebo plus metformin group. The incidence of discontinuation due to adverse reactions was 4% in patients receiving dapagliflozin 10 mg and metformin, compared to 3.3% in the placebo plus metformin group. The most common reactions leading to discontinuation, reported in at least 3 patients receiving dapagliflozin 10 mg and metformin, were renal function abnormalities (0.7%), increased blood creatinine levels (0.2%), decreased creatinine clearance (0.2%), and urinary tract infections (0.2%).
The table below lists the most common adverse reactions associated with the use of dapagliflozin and metformin. These adverse reactions were absent at baseline, occurred more frequently in the dapagliflozin and metformin treatment group than in the placebo group, and were observed in at least 2% of patients receiving either dapagliflozin 5 mg or dapagliflozin 10 mg in combination with metformin.
Table 5. Adverse Reactions Reported in Placebo-Controlled Studies in ≥ 2% of Patients Receiving Dapagliflozin and Metformin
| Adverse reaction |
% of patients |
||
| Analysis of data from 8 pooled placebo-controlled studies |
|||
| Placebo and metformin N = 1185 |
Dapagliflozin 5 mg and metformin N = 410 |
Dapagliflozin 10 mg and metformin N = 983 |
|
| Fungal genital infections in women* |
1.5 |
9.4 |
9.3 |
| Nasopharyngitis |
5.9 |
6.3 |
5.2 |
| Urinary tract infections† |
3.6 |
6.1 |
5.5 |
| Diarrhea |
5.6 |
5.9 |
4.2 |
| Headache |
2.8 |
5.4 |
3.3 |
| Fungal genital infections in men‡ |
0 |
4.3 |
3.6 |
| Influenza |
2.4 |
4.1 |
2.6 |
| Nausea |
2.0 |
3.9 |
2.6 |
| Back pain |
3.2 |
3.4 |
2.5 |
| Dizziness |
2.2 |
3.2 |
1.8 |
| Cough |
1.9 |
3.2 |
1.4 |
| Constipation |
1.6 |
2.9 |
1.9 |
| Dyslipidemia |
1.4 |
2.7 |
1.5 |
| Pharyngitis |
1.1 |
2.7 |
1.5 |
| Increased frequency of urination§ |
1.4 |
2.4 |
2.6 |
| Discomfort during urination |
1.1 |
2.2 |
1.6 |
* Genital fungal infections include the following adverse reactions (listed in decreasing order of frequency; observed in women): vulvovaginal candidiasis, vaginal infection, genital infection, vulvovaginitis, fungal genital infection, candidal vulvovaginitis, vulvar abscess, genital candidiasis, and bacterial vaginosis. (Number (N) of women: placebo and metformin = 534, dapagliflozin 5 mg and metformin = 223, dapagliflozin 10 mg and metformin = 430).
† Urinary tract infections include the following adverse reactions (listed in decreasing order of frequency): urinary tract infection, cystitis, pyelonephritis, urethritis, and prostatitis.
‡ Genital fungal infections include the following adverse reactions (listed in decreasing order of frequency; observed in men): balanitis, fungal genital infection, candidal balanitis, genital candidiasis, genital infection, inflammation of the foreskin, balanoposthitis.
(Number (N) of men: placebo and metformin = 651, dapagliflozin 5 mg and metformin = 187, dapagliflozin 10 mg and metformin = 553).
§ Increased urination includes the following adverse reactions (listed in decreasing order of frequency): pollakiuria, polyuria, and increased diuresis.
Metformin hydrochloride
In placebo-controlled monotherapy studies with extended-release metformin, diarrhea and nausea/vomiting were reported in > 5% of patients receiving metformin treatment and more frequently than in placebo-treated patients (diarrhea: 9.6% vs. 2.6%; nausea/vomiting: 6.5% vs. 1.5%). Diarrhea led to discontinuation of the investigational drug in 0.6% of patients receiving extended-release metformin.
Analysis of pooled data from 12 placebo-controlled studies of dapagliflozin treatment at doses of 5 and 10 mg
Dapagliflozin
The data presented in the table below were obtained from 12 placebo-controlled studies lasting 12 to 24 weeks. In 4 studies, dapagliflozin was used as monotherapy; in 8 studies, dapagliflozin was used as add-on therapy to standard antidiabetic medications or in combination with metformin.
These data reflect the effects of dapagliflozin in 2338 patients with a mean exposure duration of 21 weeks. Patients received placebo (N = 1393), dapagliflozin 5 mg (N = 1145), or dapagliflozin 10 mg (N = 1193) once daily.
The mean age of the population was 55 years, and 2% of subjects were over 75 years of age. Men comprised 50% of the population; 81% were of Caucasian race, 14% were of Asian origin, and 3% were of Black or African American race. At baseline, study participants had diabetes with a mean duration of 6 years; mean HbA1c level was 8.3%; 21% of study participants had confirmed microvascular complications of diabetes. Renal function at baseline was normal or mildly impaired in 92% of patients and moderately impaired in 8% (mean eGFR was 86 mL/min/1.73 m²).
The table below lists the most common adverse reactions associated with dapagliflozin use. These adverse reactions were absent at baseline, occurred more frequently in the dapagliflozin treatment group than in the placebo group, and were observed in at least 2% of patients receiving dapagliflozin 5 mg or 10 mg.
Table 6. Adverse reactions reported in placebo-controlled studies in ≥ 2% of patients treated with dapagliflozin
| Adverse reaction |
% of patients |
||
| Pooled data analysis from 12 placebo-controlled studies |
|||
| Placebo N = 1393 |
Dapagliflozin 5 mg N = 1145 |
Dapagliflozin 10 mg N = 1193 |
|
| Genital fungal infections in women* |
1.5 |
8.4 |
6.9 |
| Nasopharyngitis |
6.2 |
6.6 |
6.3 |
| Urinary tract infections† |
3.7 |
5.7 |
4.3 |
| Back pain |
3.2 |
3.1 |
4.2 |
| Increased frequency of urination‡ |
1.7 |
2.9 |
3.8 |
| Genital fungal infections in men§ |
0.3 |
2.8 |
2.7 |
| Nausea |
2.4 |
2.8 |
2.5 |
| Influenza |
2.3 |
2.7 |
2.3 |
| Dyslipidemia |
1.5 |
2.1 |
2.5 |
| Constipation |
1.5 |
2.2 |
1.9 |
| Discomfort during urination |
0.7 |
1.6 |
2.1 |
| Limb pain |
1.4 |
2.0 |
1.7 |
*Genital fungal infections include the following adverse reactions (listed in descending order of frequency; observed in women): vulvovaginal fungal infection, vaginal infection, candidal vulvovaginitis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, urogenital tract infection, vulvar abscess, and bacterial vaginosis. (Number (N) of women: placebo = 677, dapagliflozin 5 mg = 581, dapagliflozin 10 mg = 598).
† Urinary tract infections include the following adverse reactions (listed in descending order of frequency): urinary tract infection, cystitis, Escherichia-induced urinary tract infection, urogenital tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis.
‡ Increased urination frequency includes the following adverse reactions (listed in descending order of frequency): pollakiuria, polyuria, and increased diuresis.
§ Genital fungal infections include the following adverse reactions (listed in descending order of frequency; reported in men): balanitis, fungal genital infection, candidal balanitis, genital candidiasis, genital infection in men, penile infection, balanoposthitis, infectious balanoposthitis, genital infection, and phimosis. (Number (N) of men: placebo = 716, dapagliflozin 5 mg = 564, dapagliflozin 10 mg = 595).
Pooled analysis of 13 placebo-controlled studies of dapagliflozin 10 mg for glycemic control
The safety and tolerability of dapagliflozin 10 mg were also evaluated based on data from placebo-controlled trials. The data included results from 13 placebo-controlled studies, including 3 monotherapy trials, 9 trials of dapagliflozin added to background antidiabetic therapy, and a study of early combination therapy with metformin. During these 13 trials, 2360 patients received dapagliflozin 10 mg once daily, with a mean exposure duration of 22 weeks. The mean age of the study population was 59 years, with 4% of subjects aged 75 years or older. Men comprised 58% of the population; 84% were Caucasian, 9% were of Asian origin, and 3% were Black or African American. At baseline, study participants had diabetes with a mean duration of 9 years; mean HbA1c level was 8.2%; 30% of participants had confirmed microvascular disease. Renal function at baseline was normal or mildly impaired in 88% of patients, and moderately impaired in 11% (mean eGFR 82 mL/min/1.73 m²).
Reduction in intravascular volume
Dapagliflozin causes osmotic diuresis, which may lead to a reduction in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) for pooled study groups from 12 and 13 short-term placebo-controlled trials, as well as for the DECLARE study, are presented in the table below (see also section "Special Warnings and Precautions. Arterial Hypotension").
Table 7. Adverse reactions related to reduction in intravascular volume*, in clinical studies of dapagliflozin use
| Parameter |
Analysis of data from 12 pooled placebo-controlled studies |
Analysis of data from 13 pooled placebo-controlled studies |
DECLARE Study |
||||
| Placebo |
Dapagliflo |
Dapagliflo |
Placebo |
Dapagliflo |
Placebo |
Dapagliflo |
|
| Total number of study participants |
N = 1393 5 (0.4 %) |
N = 1145 7 (0.6 %) |
N = 1193 9 (0.8 %) |
N = 2295 17 (0.7 %) |
N = 2360 27 (1.1 %) |
N = 8569 207 (2.4 %) |
N = 8574 213 (2.5 %) |
| Subgroup of patients, n (%) |
|||||||
| Patients receiving loop diuretics |
n = 55 1 (1.8 %) |
n = 40 0 |
n = 31 3 (9.7 %) |
n = 267 4 (1.5 %) |
n = 236 6 (2.5 %) |
n = 934 57 (6.1 %) |
n = 866 57 (6.6 %) |
| Patients with moderate renal impairment |
n = 107 2 (1.9 %) |
n = 107 1 (0.9 %) |
n = 89 1 (1.1 %) |
n = 268 4 (1.5 %) |
n = 265 5 (1.9 %) |
n = 658 30 (4.6 %) |
n = 604 35 (5.8 %) |
| Patients aged ≥65 years |
n = 276 1 (0.4 %) |
n = 216 1 (0.5 %) |
n = 204 3 (1.5 %) |
n = 711 6 (0.8 %) |
n = 665 11 (1.7 %) |
n = 3950 121 (3.1 %) |
n = 3948 117 (3.0 %) |
* Reduction in intravascular volume includes reports of dehydration, hypovolemia, orthostatic hypotension, or arterial hypotension.
Hypoglycemia
The frequency of hypoglycemic episodes recorded during the study is presented in the table below. Hypoglycemic episodes occurred more frequently when dapagliflozin was added to sulfonylurea or insulin (see section "Special precautions").
Table 8. Frequency of severe hypoglycemia* and hypoglycemia with glucose levels < 54 mg/dL† in controlled clinical trials
| Parameter |
Placebo |
Dapagliflozin |
Dapagliflozin |
| Add-on to metformin (24 weeks) |
N = 137 |
N = 137 |
N = 135 |
| Severe episodes [n (%)] |
0 |
0 |
0 |
| Glucose level < 54 mg/dL [n (%)] |
0 |
0 |
0 |
| Add-on to DPP-4 inhibitor (with or without metformin) (24 weeks) |
N = 226 |
‒ |
N = 225 |
| Severe episodes [n (%)] |
0 |
‒ |
1 (0.4) |
| Glucose level < 54 mg/dL [n (%)] |
1 (0.4) |
‒ |
1 (0.4) |
| Add-on to insulin with other OADs‡ (24 weeks) |
N = 197 |
N = 212 |
N = 196 |
| Severe episodes [n (%)] |
1 (0.5) |
2 (0.9) |
2 (1.0) |
| Glucose level < 54 mg/dL [n (%)] |
43 (21.8) |
55 (25.9) |
45 (23.0) |
* Severe hypoglycemic episodes were defined as serious disturbances in consciousness or behavior requiring external (third-party) assistance and characterized by rapid recovery regardless of glucose level.
† Hypoglycemic episodes with glucose levels < 54 mg/dL (3 mmol/L) were defined as hypoglycemic episodes meeting the glucose level criteria and not classified as severe episodes.
‡ OAD – treatment with oral antidiabetic medicinal products.
In the DECLARE study, severe hypoglycemic episodes were observed in 58 (0.7%) of 8,574 patients receiving dapagliflozin 10 mg and in 83 (1.0%) of 8,569 patients receiving placebo.
Genital fungal infections
Genital fungal infections occurred more frequently with dapagliflozin treatment. Genital fungal infections in 12 placebo-controlled studies were reported in 0.9% of patients receiving placebo, 5.7% of patients receiving dapagliflozin 5 mg, and 4.8% of patients receiving dapagliflozin 10 mg. Treatment was discontinued due to genital infection in 0% of patients receiving placebo and 0.2% of patients receiving dapagliflozin 10 mg. Infections occurred more frequently in women than in men (see Table 6). The most commonly reported genital fungal infections were vulvovaginal candidiasis in women and balanitis in men.
Patients with a history of genital fungal infections had higher rates of such infections during the study compared to patients without such history (10.0%, 23.1%, and 25.0% vs. 0.8%, 5.9%, and 5.0% in the placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg groups, respectively). In the DECLARE study, serious genital fungal infections were reported in < 0.1% of patients receiving dapagliflozin 10 mg and in < 0.1% of patients receiving placebo. Genital fungal infections leading to discontinuation of the investigational drug occurred in 0.9% of patients receiving dapagliflozin 10 mg and in < 0.1% of patients receiving placebo.
Hypersensitivity reactions
Hypersensitivity reactions (e.g., angioedema, urticaria, drug hypersensitivity) have been reported during treatment with dapagliflozin. In clinical trials, serious anaphylactic reactions, severe skin reactions, and cases of angioedema occurred in 0.2% of patients receiving the comparator drug and in 0.3% of patients receiving dapagliflozin. If hypersensitivity reactions occur, dapagliflozin should be discontinued; treatment should be administered according to standard medical practice until symptoms resolve.
Ketoacidosis
In the DECLARE study, cases of diabetic ketoacidosis were reported in 27 of 8,574 patients in the dapagliflozin treatment group and in 12 of 8,569 patients in the placebo group. The observed episodes were evenly distributed throughout the study period.
Laboratory tests and monitoring
Increased serum creatinine levels and decreased eGFR
Dapagliflozin
Initiation of dapagliflozin treatment causes an increase in serum creatinine levels and a decrease in eGFR. In patients with normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline values by week 24. Sustained reductions in eGFR were observed in patients with moderate renal impairment (eGFR 30 to 60 mL/min/1.73 m²) (see sections "Special warnings and precautions for use" and "Pharmacological properties").
Increased hematocrit
Dapagliflozin
In the pooled group of patients from 13 placebo-controlled studies, an increase from baseline in mean hematocrit values was observed in patients receiving dapagliflozin, starting at week 1 and continuing until week 16, when the difference between mean hematocrit values and baseline mean values reached its maximum. At week 24, mean changes in hematocrit from baseline were -0.33% in the placebo group and 2.30% in the dapagliflozin 10 mg treatment group. At week 24, hematocrit levels > 55% were recorded in 0.4% of patients receiving placebo and in 1.3% of patients receiving dapagliflozin 10 mg.
Increased levels of low-density lipoprotein cholesterol with dapagliflozin use
Dapagliflozin
In the pooled group of patients from 13 placebo-controlled studies, changes from baseline in mean lipid metabolism parameters were observed in the group receiving dapagliflozin compared to the placebo group. At week 24, mean percent change from baseline was 0.0% vs. 2.5% for total cholesterol and -1.0% vs. 2.9% for LDL cholesterol in the placebo and dapagliflozin 10 mg groups, respectively. In the DECLARE study, mean changes from baseline after 4 years were 0.4 mg/dL vs. -4.1 mg/dL for total cholesterol and -2.5 mg/dL vs. -4.4 mg/dL for LDL cholesterol in the dapagliflozin 10 mg and placebo groups, respectively.
Vitamin B12 concentrations
Metformin hydrochloride
During clinical trials of metformin lasting 29 weeks, approximately 7% of patients experienced a decrease in serum vitamin B12 levels below the normal range.
Post-marketing experience
Dapagliflozin
Additional adverse reactions have been identified during post-marketing use of dapagliflozin: ketoacidosis; acute kidney injury, urosepsis, and pyelonephritis; necrotizing fasciitis of the perineum (Fournier’s gangrene); rash. Because these reports are from voluntary reporting from a population of unknown size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Metformin hydrochloride
- Cholestatic, hepatocellular, and mixed hepatocellular liver injury
Reporting suspected adverse reactions
It is important to report suspected adverse reactions during the post-marketing phase of drug use. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.
Shelf life.
3 years.
Storage conditions.
Store below 25°C. Store in the original packaging. Keep out of reach of children.
Packaging.
7 tablets in a blister; 4 blisters in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
AstraZeneca Pharmaceuticals LP.
Manufacturer's address and location of operations.
4601 Highway 62 East, Mount Vernon, IN, 47620, USA.