1. Name of the medicinal product
Xigduo 5mg/850 mg film-coated tablets
Xigduo 5mg/1,000 mg film-coated tablets
2. Qualitative and quantitative composition
5 mg/850 mg:
Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 850mg of metformin hydrochloride.
For the full list of excipients, see section 6.1.
5 mg/1,000 mg:
Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin and 1,000 mg of metformin hydrochloride.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet (tablet).
5 mg/850 mg:
Brown, biconvex, 9.5 x 20 mm oval, film-coated tablets engraved with “5/850” on one side and “1067” engraved on the other side.
5 mg/1,000 mg:
Yellow, biconvex, 10.5 x 21.5 mm oval, film-coated tablets engraved with “5/1000” on one side and “1069” engraved on the other side.
4. Clinical particulars
4.1 Therapeutic indications
Xigduo is indicated in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control
• in patients inadequately controlled on their maximally tolerated dose of metformin alone
• in combination with other glucose-lowering medicinal products, including insulin, in patients inadequately controlled with metformin and these medicinal products (see sections 4.4, 4.5 and 5.1 for available data on different combinations)
• in patients already being treated with the combination of dapagliflozin and metformin as separate tablets.
4.2 Posology and method of administration
Posology
For patients inadequately controlled on metformin monotherapy or metformin in combination with other glucose-lowering medicinal products including insulin
The recommended dose is one tablet twice daily. Each tablet contains a fixed dose of dapagliflozin and metformin (see section 2). Patients not adequately controlled on metformin alone or in combination with other glucose-lowering medicinal products, including insulin, should receive a total daily dose of Xigduo equivalent to dapagliflozin 10 mg, plus the total daily dose of metformin, or the nearest therapeutically appropriate dose, already being taken. When Xigduo is used in combination with insulin or an insulin secretagogue such as sulphonylurea, a lower dose of insulin or sulphonylurea may be considered to reduce the risk of hypoglycaemia (see sections 4.5 and 4.8).
For patients switching from separate tablets of dapagliflozin and metformin
Patients switching from separate tablets of dapagliflozin (10 mg total daily dose) and metformin to Xigduo should receive the same daily dose of dapagliflozin and metformin already being taken or the nearest therapeutically appropriate dose of metformin.
Special populations
Renal impairment
No dose adjustment is recommended for patients with mild renal impairment. This medicinal product must not be used in patients with moderate to severe renal impairment (patients with creatinine clearance [CrCl] < 60 ml/min or estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2, see sections 4.3, 4.4, 4.8, 5.1 and 5.2).
Hepatic impairment
This medicinal product must not be used in patients with hepatic impairment (see sections 4.3, 4.4 and 5.2).
Elderly patients (≥ 65 years)
Because metformin is eliminated in part by the kidney, and because elderly patients are more likely to have decreased renal function, this medicinal product should be used with caution as age increases. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in elderly patients (see sections 4.3 and 4.4). Risk of volume depletion with dapagliflozin should also be taken into account (see sections 4.4 and 5.2). Due to the limited therapeutic experience with dapagliflozin in patients 75 years and older, initiation of therapy in this population is not recommended.
Paediatric population
The safety and efficacy of Xigduo in children and adolescents aged 0 to < 18 years have not yet been established. No data are available.
Method of administration
Xigduo should be given twice daily with meals to reduce the gastrointestinal adverse reactions associated with metformin.
4.3 Contraindications
Xigduo is contraindicated in patients with:
- hypersensitivity to the active substances or to any of the excipients listed in section 6.1;
- diabetic ketoacidosis, diabetic pre-coma;
- moderate and severe renal impairment (creatinine clearance < 60 ml/min; eGFR < 60 ml/min/1.73 m2) (see sections 4.2, 4.4 and 5.2);
- acute conditions with the potential to alter renal function such as:
- dehydration,
- severe infection,
- shock;
- acute or chronic disease which may cause tissue hypoxia such as:
- cardiac or respiratory failure,
- recent myocardial infarction,
- shock;
- hepatic impairment (see sections 4.2, 4.4 and 5.2);
- acute alcohol intoxication, alcoholism (see section 4.5).
4.4 Special warnings and precautions for use
General
Xigduo should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Lactic acidosis
Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to accumulation of metformin, a component of this medicinal product. 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 and any conditions associated with hypoxia.
Diagnosis
The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps with digestive disorders, abdominal pain and severe asthenia.
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain 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 metabolic acidosis is suspected, treatment with the medicinal product should be discontinued and the patient hospitalised immediately (see section 4.9).
Use in patients with renal impairment
The efficacy of dapagliflozin, a component of this medicinal product, is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see section 4.2). In addition, metformin is excreted by the kidney, and moderate to severe renal insufficiency increases the risk of lactic acidosis (see section 4.4). Therefore, this medicinal product must not be used in patients with moderate to severe renal impairment (patients with CrCl < 60 ml/min or estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2; see section 4.3).
Monitoring of renal function is recommended as follows:
• Prior to initiation of treatment and at least yearly thereafter (see sections 4.2, 4.8, 5.1 and 5.2)
• Prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter
• For renal function approaching moderate renal impairment, at least 2 to 4 times per year. If renal function falls below CrCl < 60 ml/min or eGFR < 60 ml/min/1.73 m2, treatment must be discontinued.
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating anti-hypertensive or diuretic therapy or when starting treatment with a nonsteroidal anti-inflammatory drug (NSAID).
Use in patients at risk for volume depletion, hypotension and/or electrolyte imbalances
Due to its mechanism of action, dapagliflozin increases diuresis associated with a modest decrease in blood pressure (see section 5.1), which may be more pronounced in patients with high blood glucose concentrations.
This medicinal product is not recommended for use in patients receiving loop diuretics (see section 4.5) or who are volume depleted, e.g. due to acute illness (such as gastrointestinal illness).
Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or elderly patients.
For patients receiving this medicinal product, in case of intercurrent conditions that may lead to volume depletion, careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended. Temporary interruption of treatment with this medicinal product is recommended for patients who develop volume depletion until the depletion is corrected (see section 4.8).
Urinary tract infections
Urinary tract infections were more frequently reported for dapagliflozin compared to placebo in a pooled analysis up to 24 weeks (see section 4.8). Pyelonephritis was uncommon and occurred at a similar frequency to control. Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of treatment should be considered when treating pyelonephritis or urosepsis.
Elderly patients (≥ 65 years)
Elderly patients are more likely to have impaired renal function, and/or to be treated with anti-hypertensive medicinal products that may cause changes in renal function such as angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB). The same recommendations for renal function apply to elderly patients as to all patients (see sections 4.2, 4.4, 4.8 and 5.1).
In subjects ≥ 65 years of age, a higher proportion of subjects treated with dapagliflozin had adverse reactions related to renal impairment or failure compared with placebo. The most commonly reported adverse reaction related to renal function was serum creatinine increases, the majority of which were transient and reversible (see section 4.8).
Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics. In subjects ≥ 65 years of age, a higher proportion of subjects treated with dapagliflozin had adverse reactions related to volume depletion (see section 4.8).
Therapeutic experience in patients 75 years and older is limited. Initiation of therapy in this population is not recommended (see sections 4.2 and 5.2).
Cardiac failure
Experience in NYHA class I-II is limited, and there is no experience in clinical studies with dapagliflozin in NYHA class III-IV.
Use in patients treated with pioglitazone
While a causal relationship between dapagliflozin and bladder cancer is unlikely (see sections 4.8 and 5.3), as a precautionary measure, this medicinal product is not recommended for use in patients concomitantly treated with pioglitazone. Available epidemiological data for pioglitazone suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone.
Elevated haematocrit
Haematocrit increase was observed with dapagliflozin treatment (see section 4.8); therefore, caution in patients with already elevated haematocrit is warranted.
Combinations not studied
Dapagliflozin has not been studied in combination with glucagon-like peptide 1 (GLP-1) analogues.
Urine laboratory assessments
Due to its mechanism of action, patients taking this medicinal product will test positive for glucose in their urine.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast agents in radiological studies can lead to renal failure. This may induce metformin accumulation which may increase the risk for lactic acidosis. Therefore, this medicinal product must be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-eva luated and found to be normal (see section 4.5).
Surgery
As this medicinal product contains metformin, the treatment must be discontinued 48 hours before elective surgery with general, spinal or epidural anaesthesia. The treatment may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and only if normal renal function has been established.
Change in clinical status of patients with previously controlled type 2 diabetes
As this medicinal product contains metformin, a patient with type 2 diabetes previously well-controlled on it who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be eva luated promptly for evidence of ketoacidosis or lactic acidosis. eva luation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, treatment must be stopped immediately and other appropriate corrective measures initiated.
4.5 Interaction with other medicinal products and other forms of interaction
Coadministration of multiple doses of dapagliflozin and metformin does not meaningfully alter the pharmacokinetics of either dapagliflozin or metformin in healthy subjects.
No interaction studies have been performed for Xigduo. The following statements reflect the information available on the individual active substances.
Dapagliflozin
Pharmacodynamic interactions
Diuretics
This medicinal product may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension (see section 4.4).
Insulin and insulin secretagogues
Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with dapagliflozin (see sections 4.2 and 4.8).
Pharmacokinetic interactions
The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP-glucuronosyltransferase 1A9 (UGT1A9).
In in vitro studies, dapagliflozin neither inhibited cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induced CYP1A2, CYP2B6 or CYP3A4. Therefore, this medicinal product is not expected to alter the metabolic clearance of coadministered medicinal products that are metabolised by these enzymes.
Effect of other medicinal products on dapagliflozin
Interaction studies conducted in healthy subjects, using mainly a single-dose design, suggest that the pharmacokinetics of dapagliflozin are not altered by pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin.
Following coadministration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) was observed, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended. A clinically relevant effect with other inducers (e.g. carbamazepine, phenytoin, phenobarbital) is not expected.
Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55% increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended.
Effect of dapagliflozin on other medicinal products
In interaction studies conducted in healthy subjects, using mainly a single-dose design, dapagliflozin did not alter the pharmacokinetics of pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a CYP2C9 substrate), or the anti-coagulatory effects of warfarin as measured by INR. Combination of a single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and 31% increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposures are not considered clinically relevant.
Other interactions
The effects of smoking, diet, herbal products and alcohol use on the pharmacokinetics of dapagliflozin have not been studied.
Paediatric population
Interaction studies have only been performed in adults.
Metformin
Combinations not recommended
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic impairment) due to the metformin active substance of this medicinal product (see section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.
Cationic substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased metformin systemic exposure (AUC) by 50% and Cmax by 81%. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal products that are eliminated by renal tubular secretion are coadministered.
The intravascular administration of iodinated contrast agents in radiological studies may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis. Therefore, this medicinal product must be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-eva luated and found to be normal (see section 4.4).
Combination requiring precautions for use
Glucocorticoids (given by systemic and local routes), beta-2 agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring perfomed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of the glucose-lowering medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.
Diuretics, especially loop diuretics, may increase the risk of lactic acidosis due to their potential to decrease renal function.
Insulin and insulin secretagogues
Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Therefore a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with metformin (see sections 4.2 and 4.8).
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no data from the use of Xigduo or dapagliflozin in pregnant women. Studies in rats treated with dapagliflozin have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy (see section 5.3). Therefore, the use of this medicinal product is not recommended during the second and third trimesters of pregnancy. A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development (see section 5.3).
When the patient plans to become pregnant, and during pregnancy, it is recommended that diabetes is not treated with this medicinal product, but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus associated with abnormal blood glucose levels.
Breast-feeding
It is unknown whether this medicinal product or dapagliflozin (and/or its metabolites) are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk, as well as pharmacologically-mediated effects in nursing offspring (see section 5.3). Metformin is excreted in human milk in small amounts. A risk to the newborns/infants cannot be excluded.
This medicinal product should not be used while breast-feeding.
Fertility
The effect of this medicinal product or dapagliflozin on fertility in humans has not been studied. In male and female rats, dapagliflozin showed no effects on fertility at any dose tested. For metformin, studies in animals have not shown reproductive toxicity (see section 5.3).
4.7 Effects on ability to drive and use machines
Dapagliflozin or metformin have no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia when this medicinal product is used in combination with other glucose-lowering medicinal products known to cause hypoglycaemia.
4.8 Undesirable effects
Xigduo has been demonstrated to be bioequivalent with coadministered dapagliflozin and metformin (see section 5.2). There have been no therapeutic clinical trials conducted with Xigduo tablets.
Dapagliflozin plus metformin
Summary of the safety profile
In an analysis of 5 placebo-controlled dapagliflozin add-on to metformin studies, the safety results were similar to that of the pre-specified pooled analysis of 12 placebo-controlled dapagliflozin studies (see Dapagliflozin, Summary of the safety profile below). No additional adverse reactions were identified for the dapagliflozin plus metformin group compared with those reported for the individual components. In the separate dapagliflozin add-on to metformin pooled analysis, 623 subjects were treated with dapagliflozin 10 mg as add-on to metformin and 523 were treated with placebo plus metformin.
Dapagliflozin
Summary of the safety profile
In a pre-specified pooled analysis of 13 placebo-controlled studies, 2,360 subjects were treated with dapagliflozin 10 mg and 2,295 were treated with placebo.
The most frequently reported adverse reaction was hypoglycaemia, which depended on the type of background therapy used in each study. The frequency of minor episodes of