Xigduo XR FC tablets

XIGDUO XR is indicated in adults with type 2 diabetes mellitus when treatment with both dapagliflozin and metformin is appropriate:

• for the treatment of type 2 diabetes mellitus as an adjunct to diet and exercise.
• to reduce the risk of developing new or worsening existing heart failure or cardiovascular death in Type 2 diabetic mellitus patients with established cardiovascular (CV) disease or multiple CV risk factors.

Posology

The recommended dose of dapagliflozin is 10 mg once daily. The recommended starting dose of metformin is 500 mg once daily, which can be titrated to 2000 mg once daily, with gradual dose escalation to reduce the gastrointestinal side effects due to metformin. In patients treated with metformin, the dose of XIGDUO XR should provide metformin at the dose already being taken, or the nearest therapeutically appropriate dose. If no adequate strength of XIGDUO XR is available, individual mono-components should be used instead of the fixed dose combination. It is recommended to not exceed a dose of dapagliflozin 10 mg daily (two tablets of 5 mg dapagliflozin / 500 mg metformin or two tablets of 5 mg dapagliflozin / 1000 mg metformin).

Special populations

Patients with renal impairment

Assess renal function prior to initiation of XIGDUO XR and periodically thereafter (see section 4.4 and 5.2). Renal impaired patients may have a higher incidence of adverse events.

Table 1 Dosage in patients with renal impairment

Mild renal impairment

No dose adjustment of XIGDUO XR is required for patients with mild renal impairment (eGFR 60-89 mL/min/1,73 m2 by Modified Diet in Renal Disease [MDRD] eGFR equation).

Moderate renal impairment

XIGDUO XR is not recommended for the treatment of diabetes in patients with eGFR persistently below 45 mL/min/1,73 m2 (see section 4.4). No dose adjustment is required for patients with eGFR u2265 45 mL/min/1,73 m2).

Severe renal impairment

Due to the metformin component, XIGDUO XR is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1,73 m2) (see section 4.3).

Patients with hepatic impairment

Since impaired hepatic function has been associated with some cases of lactic acidosis in patients taking metformin, XIGDUO XR should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment (see section 4.4).

Elderly patients

Because metformin is eliminated by the kidneys, and because elderly patients are more likely to have decreased renal function, XIGDUO XR should be used with caution as age increases. The renal function recommendations provided for all patients also apply to elderly patients (see section 4.4).

Paediatric population

The safety and efficacy of XIGDUO XR in paediatric and adolescent patients have not been established. No data are available.

Method of administration

XIGDUO XR should be taken orally, once daily with the evening meal. Patients should be informed that XIGDUO XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of XIGDUO XR will be eliminated in the faeces as a soft, hydrated mass that may resemble the original tablet.

XIGDUO XR is contraindicated in patients with:

• Patients with a history of any serious hypersensitivity reaction to dapagliflozin, metformin hydrochloride or to any of the excipients.
• Severe renal impairment [(metformin component)] (eGFR < 30 mL/min/1,73 m2).
• Acute or chronic metabolic acidosis including diabetic ketoacidosis.
• Diabetes mellitus Type 1.
• Pregnant women or women who are breast-feeding their infants (See section 4.6).

Lactic acidosis

Metformin hydrochloride Lactic acidosis is a very rare, but serious and potentially fatal in the absence of prompt treatment, metabolic complication that can occur due to metformin accumulation (metformin plasma levels generally > 5 mcg/l). Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency, dehydration, any acute conditions associated with hypoxia or impacting renal function (see section 4.4).

Medicines that can acutely impair renal function, such as antihypertensives, diuretics and NSAIDs, should be initiated with caution in metformin-treated patients (see section 4.5).

Patients and/or caregivers should be informed on the risk of lactic acidosis. Lactic acidosis is characterized by symptoms such as acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. If lactic acidosis is suspected, treatment with XIGDUO XR should be discontinued and the patient hospitalized immediately.

Use in patients with renal impairment

XIGDUO XR is not recommended for the treatment of diabetes in patients with eGFR persistently below 45 mL/min/1,73 m2 as the glycaemic efficacy of dapagliflozin is dependent on renal function (see section 4.2.3). The maximum dose of metformin in patients with an eGFR of 30 to less than 45 mL/min/1,73 m2 is 1000 mg once daily. Due to metformin, XIGDUO XR is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1,73 m2) (see section 4.3).

Metformin is excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function (see section 4.4).

Assess renal function prior to initiation of XIGDUO XR and then periodically thereafter:

• at least annually
• at least two to four times a year in patients with renal function where eGFR levels are approaching 45 mL/min/1,73 m2 and in elderly patients.

Acute conditions associated with hypoxia or impacting renal function

Metformin hydrochloride Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. Acute conditions such as dehydration, severe infections, and hypoperfusion, have potential to alter renal function. In these situations, metformin must be discontinued.

Radiologic studies with intravascular iodinated contrast materials

Metformin hydrochloride Intravascular administration of iodinated contrast agents in radiological studies can lead to an acute decrease in renal function and has been associated with lactic acidosis in patients receiving metformin. XIGDUO XR should temporarily be discontinued prior to, or at the time of the procedure and not reinstituted until 48 hours afterwards and only after renal function has been re-evaluated and found to be stable.

Surgical procedures

Metformin hydrochloride Use of XIGDUO XR should be temporarily suspended before any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patientu2019s oral intake has resumed and renal function has been evaluated as stable.

The patient should receive regular monitoring of their blood glucose with the administration of soluble insulin perioperatively as indicated.

Use in patients with hepatic impairment

Metformin hydrochloride Since impaired hepatic function has been associated with some cases of metformin-associated lactic acidosis, XIGDUO XR should be avoided in patients with clinical or laboratory evidence of hepatic disease.

Excessive alcohol intake

Metformin hydrochloride Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving XIGDUO XR.

Ketoacidosis

Dapagliflozin There have been reports of ketoacidosis, including diabetic ketoacidosis, in patients with type 1 and type 2 diabetes mellitus taking dapagliflozin and other SGLT2 inhibitors. XIGDUO XR is not indicated for the treatment of patients with type 1 diabetes mellitus. Patients treated with XIGDUO XR who present with signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L (250 mg/dL). If ketoacidosis is suspected, discontinuation or temporary interruption of XIGDUO XR should be considered and the patient should be promptly evaluated.

Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from pancreatic disorders (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), insulin dose reduction, reduced caloric intake or increased insulin requirements due to infections, illness, surgery or alcohol abuse. XIGDUO XR should be used with caution in these patients.

Change in clinical status of patients with previously controlled type 2 diabetes A patient with type 2 diabetes previously well controlled on XIGDUO XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes, urine and serum ketones, blood glucose, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, XIGDUO XR must be stopped immediately, and other appropriate corrective measures initiated.

Use in patients at risk for volume depletion

Dapagliflozin Due to its mechanism of action, dapagliflozin induces osmotic diuresis which may lead to modest decrease in blood pressure (see section 5.1). Temporary interruption of XIGDUO XR should be considered for patients who develop volume depletion.

Use with medications known to cause hypoglycaemia

Dapagliflozin Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycaemia. Therefore, a lower dose of insulin or the insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with dapagliflozin (see section 5.1). Metformin hydrochloride Hypoglycaemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycaemic effects. Hypoglycaemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking medicines.

Lactose

XIGDUO XR contains lactose. Patients with rare hereditary problems of galactose intolerance, e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take XIGDUO XR.

Vitamin B12 decrease/deficiency

Metformin hydrochloride Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contraindicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines.

Interaction with dapagliflozin and metformin

Coadministration of multiple doses of dapagliflozin and metformin did not meaningfully alter the pharmacokinetics of either dapagliflozin or metformin in healthy subjects. There have been no formal interaction studies for XIGDUO XR. The following statements reflect the information available on the individual active substances.

Drug interactions with dapagliflozin

The metabolism of dapagliflozin is primarily mediated by UGT1A9-dependent glucuronide conjugation. The major metabolite, dapagliflozin 3-O-glucuronide, is not an SGLT2 inhibitor. In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP1A2, 2C9, 2C19, 2D6, 3A4, nor induced CYP1A2, 2B6 or 3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of co-administered medicines that are metabolized by these enzymes, and medicines that inhibit or induce these enzymes are not expected to alter the metabolic clearance of dapagliflozin.

Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.

Effect of other medicines on dapagliflozin

In interaction studies conducted in healthy subjects, using mainly single dose design, the pharmacokinetics properties of dapagliflozin were not altered by metformin (an hOCT-1 and hOCT-2 substrate), pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), sitagliptin (an hOAT-3 substrate and P-glycoprotein substrate), glimepiride (a CYP2C9 substrate), voglibose (an u03b1-glucosidase inhibitor), hydrochlorothiazide, bumetanide, valsartan, or simvastatin (a CYP3A4 substrate). Therefore, meaningful interaction of dapagliflozin with other substrates of hOCT-1, hOCT-2, hOAT-3, P-gp, CYP2C8, CYP2C9, CYP3A4, and other u03b1-glucosidase inhibitors would not be expected.

Following coadministration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolizing enzymes) or mefenamic acid (an inhibitor of UGT1A9), a 22 % decrease and a 51 % increase, respectively, in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion in either case.

Coadministration of dapagliflozin and bumetanide did not meaningfully change the pharmacodynamic effect of dapagliflozin to increase urinary glucose excretion in healthy subjects.

Effect of dapagliflozin on other medicines

Concomitant use of dapagliflozin and lithium may lead to a reduction in serum lithium concentrations due to a possible increased urinary clearance of lithium. The dose of lithium may need to be adjusted. In interaction studies conducted in healthy subjects, using mainly a single dose design, dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, simvastatin, digoxin (a P-gp substrate), or warfarin (S-warfarin is a CYP2C substrate). Therefore, dapagliflozin is not a clinical meaningful inhibitor of hOCT-1, hOCT-2, hOAT-3, P-gp transporter pathway, and CYP2C8, CYP2C9, CYP2C19 and CYP3A4 mediated metabolism. Coadministration of dapagliflozin and bumetanide did not meaningfully alter the steady-state pharmacodynamic responses (urinary sodium excretion, urine volume) to bumetanide in healthy subjects. Dapagliflozin did not affect the anticoagulant activity of warfarin as measured by the prothrombin time (International Normalized Ratio [INR]).

Interactions between metformin hydrochloride and other medicines

Cationic medicines Cationic medicines (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug-interaction studies, with a 60 % increase in peak metformin plasma and whole blood concentrations and a 40 % increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin and/or the interfering medicine is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Glyburide In a single-dose interaction study in type 2 diabetic patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and maximum concentration (C max) were observed but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects make the clinical significance of this interaction uncertain.

Furosemide A single-dose, metformin-furosemide drug-interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood C max by 22 % and blood AUC by 15 %, without any significant change in metformin renal clearance. When administered with metformin, the C max and AUC of furosemide were 31 % and 12 % smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32 %, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.

Nifedipine A single-dose, metformin-nifedipine drug-interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C max and AUC by 20 % and 9 %, respectively, and increased the amount excreted in the urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Use with other medicines Certain medicines tend to produce hyperglycaemia and may lead to loss of glycaemic control. These medicines include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, oestrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking medicines, and isoniazid. When such medicines are administered to a patient receiving metformin, the patient should be closely observed for loss of blood glucose control. When such medicines are withdrawn from a patient receiving metformin, the patient should be observed closely for hypoglycaemia.

In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen was not affected when coadministered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and, therefore, is less likely to interact with highly protein-bound medicines such as salicylates, sulphonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

Other interactions The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of dapagliflozin have not been specifically studied. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycaemic control.

Pregnancy

XIGDUO XR is contraindicated in pregnancy. When pregnancy is detected XIGDUO XR should be discontinued. In the time period corresponding to second and third trimester of pregnancy with respect to human renal maturation, maternal exposure to dapagliflozin in rat studies was associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny (see section 5.3). There are no adequate and well-controlled studies of XIGDUO XR in pregnant women.

Breastfeeding

XIGDUO XR must not be used by a nursing woman. No studies in lactating animals have been conducted with the combined components of XIGDUO XR. In studies performed with the individual components, both dapagliflozin and metformin are excreted in the milk of lactating rats. Direct and indirect exposure of dapagliflozin to weanling juvenile rats and during late pregnancy are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny, although the long-term functional consequences of these effects are unknown. These periods of exposure coincide with a critical window of renal maturation in rats. As functional maturation of the kidneys in humans continues in the first 2 years of life, dapagliflozin-associated dilated renal pelvis and tubules noted in juvenile rats could constitute potential risk for human renal maturation during the first 2 years of life. Additionally, the negative effects on body-weight gain associated with lactational exposure in weanling juvenile rats suggest that dapagliflozin must be avoided during the first 2 years of life (see section 5.3).

Fertility

The effect of XIGDUO XR on human fertility has not been studied.

Patients must bear in mind the possibility of hypoglycaemia and its effects on their motor skills.

a. Summary of the safety profile

Dapagliflozin + metformin Data from a pre-specified pool of patients from 8 short-term, placebo-controlled studies of dapagliflozin co-administered with metformin immediate- or extended-release was used to evaluate safety data. This pool included several add-on studies (metformin alone and in combination with a DPP4 inhibitor and metformin, or insulin and metformin, 2 initial combination with metformin studies, and 2 studies of patients with cardiovascular disease (CVD) and type 2 diabetes who received their usual treatment (with metformin as background therapy)). For studies that included background therapy with and without metformin, only patients who received metformin were included in the 8-study placebo-controlled pool. Across these 8 studies 983 patients were treated once daily with dapagliflozin 10 mg and metformin and 1 185 were treated with placebo and metformin.

The safety profile of dapagliflozin in type 2 diabetes mellitus has been evaluated in clinical studies including more than 15 000 subjects treated with dapagliflozin. For further information about the clinical studies, see section 5.1.

The incidence of adverse reactions was determined using a pre-specified pool of patients from 13 short-term (mean duration 22 weeks), placebo-controlled studies in type 2 diabetes. Across these 13 studies, 2 360 patients were treated once daily with dapagliflozin 10 mg and 2 295 were treated with placebo (either as monotherapy or in combination with other antidiabetic therapies).

Additionally, dapagliflozin 5 mg was evaluated in a 12-study, short-term, placebo-controlled pool of patients that included 1 145 patients treated with dapagliflozin 5 mg (mean exposure = 22 weeks) and 1 393 patients treated with (mean exposure = 21 weeks), either as monotherapy or in combination with other antidiabetic therapies.

In the dedicated cardiovascular (CV) outcomes study in patients with type 2 diabetes mellitus, 8 574 patients received dapagliflozin 10 mg and 8 569 received placebo for a median exposure time of 48 months. In total, there were 30 623 patient-years of exposure to dapagliflozin.

The adverse reactions in patients treated with dapagliflozin 10 mg with and without metformin in clinical trials in type 2 diabetes mellitus and post marketing are shown in Table 2 and Table 3 respectively. Frequencies of occurrence of adverse reactions are defined as: very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data).

Table 2 Adverse Drug Reactions by Frequency and System Organ Class (SOC) in clinical trials.

a Identified from 8 placebo-controlled studies, including 2 initial combination with metformin, 2 add-on to metformin, 1 add-on to insulin, 1 add-on to sitagliptin, and 2 studies with combination add-on therapy.

b Multiple adverse events terms, including vulvovaginal infections and candidiasis, balanoposthitis, balanitis candida, penile abscess, penile infection, vulval abscess and vaginitis bacterial.

c Multiple adverse events terms, including genitourinary tract infection, cystitis, pyelonephritis, trigonitis, urethritis and prostatitis.

d Additional events identified from 13 placebo-controlled studies with dapagliflozin 10 mg in type 2 diabetes mellitus including 3 monotherapy, 1 initial combination with metformin, 2 add-on to metformin, 2 add-on to insulin, 1 add-on to pioglitazone, 1 add-on to sitagliptin, 1 add-on to glimepiride, and 2 studies with combination add-on therapy.

e Represents multiple adverse events terms, including polyuria, urine output increased.

f Identified from the cardiovascular outcomes study in patients with type 2 diabetes. Frequency is based on annual rate.

Table 3 Post-marketing experience

a Identified during post marketed use of dapagliflozin. Because these reactions are reported voluntarily from a population of an uncertain size, it is not always possible to reliably estimate their frequency.

b Rash includes the following preferred terms, listed in order of frequency in clinical trials: Rash, generalized rash, pruritic rash, macular rash, maculo-papular rash, pustular rash, vesicular rash, erythematous rash. In active- and placebo-controlled clinical trials (dapagliflozin, n=5 936, All control, n=3 403), the frequency of Rash was similar for dapagliflozin (1,4 %) and All control (1,4 %), respectively, corresponding to the frequency u2018Commonu2019.

Clinical trial and post-market data u2013 metformin hydrochloride

Table 4 presents adverse reactions by system organ class and by frequency category. Frequency categories are based on information available from the metformin Summary of Product Characteristics available in the EU.

a Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain, and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.

Dapagliflozin Orally administered dapagliflozin has been shown to be safe and well-tolerated in healthy subjects at single doses up to 500 mg (50 times the MRHD). In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patientu2019s clinical status. The removal of dapagliflozin by haemodialysis has not been studied.

Metformin hydrochloride High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in a hospital. The most effective method to remove lactate and metformin is haemodialysis. Events of hypoglycaemia have been reported with overdoses of metformin.