Divinus is indicated in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control as:

Monotherapy
When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance.

Add‐on combination therapy
In combination with other glucose‐lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control (see sections 4.4, 4.5 and 5.1 for available data on different combinations).

Posology
Monotherapy and add‐on combination therapy
The recommended dose is 10 mg dapagliflozin once daily for monotherapy and add‐on combination therapy with other glucose‐lowering medicinal products including insulin. When dapagliflozin is used in combination with insulin or an insulin secretagogue, such as a sulphonylurea, a lower dose of insulin or insulin secretagogue may be considered to reduce the risk of hypoglycaemia (see sections 4.5 and 4.8). 

Special populations
Renal impairment
The efficacy of dapagliflozin 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.

Divinus is not recommended for use 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 4.4, 4.8, 5.1 and 5.2).

No dosage adjustment is indicated in patients with mild renal impairment. 

Hepatic impairment
No dosage adjustment is necessary for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, a starting dose of 5 mg is recommended. If well tolerated, the dose may be increased to 10 mg (see sections 4.4 and 5.2).

Elderly (≥ 65 years)
In general, no dosage adjustment is recommended based on age. Renal function and risk of volume depletion should be taken into account (see sections 4.4 and 5.2). Due to the limited therapeutic experience in patients 75 years and older, initiation of dapagliflozin therapy is not recommended.

Paediatric population
The safety and efficacy of dapagliflozin in children aged 0 to < 18 years have not yet been established. No data are available. 

Method of administration
Divinus can be taken orally once daily at any time of day with or without food. Tablets are to be swallowed whole.

Renal impairment
The efficacy of dapagliflozin 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 subjects with moderate renal impairment (patients with CrCl < 60 ml/min or eGFR < 60 ml/min/1.73 m²), a higher proportion of subjects treated with dapagliflozin had adverse
reactions of increase in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension, compared with placebo. Dapagliflozin is not recommended for use in patients with moderate to severe renal impairment (patients with CrCl < 60 ml/min or eGFR < 60 ml/min/1.73 m²).

Dapagliflozin has not been studied in severe renal impairment (CrCl < 30 ml/min or eGFR < 30 ml/min/1.73 m²) or end‐stage renal disease (ESRD).

Monitoring of renal function is recommended as follows:

• Prior to initiation of dapagliflozin 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, dapagliflozin treatment should be discontinued. 

Hepatic impairment
There is limited experience in clinical trials in patients with hepatic impairment. Dapagliflozin exposure is increased in patients with severe hepatic impairment (see sections 4.2 and 5.2).

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 very high blood glucose concentrations.

Dapagliflozin 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 antihypertensive therapy with a history of hypotension or elderly patients.

For patients receiving dapagliflozin, 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 dapagliflozin is recommended for patients who develop volume depletion until the depletion is corrected (see section 4.8). 

Diabetic ketoacidosis
Rare cases of diabetic ketoacidosis (DKA), including life‐threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including dapagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/l (250 mg/dl). It is not known if DKA is more likely to occur with higher doses of dapagliflozin. 

The risk of diabetic ketoacidosis must be considered in the event of non‐specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.

In patients where DKA is suspected or diagnosed, treatment with dapagliflozin should be discontinued immediately.

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. In both cases, treatment with dapagliflozin may be restarted once the patient's condition has stabilised.

Before initiating dapagliflozin, factors in the patient history that may predispose to ketoacidosis should be considered.

Patients who may be at higher risk of DKA include patients with a low beta‐cell function reserve (e.g. type 2 diabetes patients with low C‐peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.

Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.

The safety and efficacy of dapagliflozin in patients with type 1 diabetes have not been established and dapagliflozin should not be used for treatment of patients with type 1 diabetes. Limited data from clinical trials suggest that DKA occurs with common frequency when patients with type 1 diabetes are treated with SGLT2 inhibitors.

Urinary tract infections
Urinary tract infections were more frequently reported for dapagliflozin 10 mg 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 dapagliflozin should be considered when treating pyelonephritis or urosepsis.

Elderly (≥ 65 years)
Elderly patients are more likely to have impaired renal function, and/or to be treated with antihypertensive 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 dapagliflozin 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, dapagliflozin 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.

Lower limb amputations
An increase in cases of lower limb amputation (primarily of the toe) has been observed in ongoing long‐term, clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect. Like for all diabetic patients it is important to counsel patients on routine preventative foot care.

Urine laboratory assessments
Due to its mechanism of action, patients taking dapagliflozin will test positive for glucose in their urine.

Lactose
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose‐galactose malabsorption should not take this medicinal product.

Pharmacodynamic interactions
Diuretics
Dapagliflozin 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, dapagliflozin 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 metformin, 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 metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (a P‐gp substrate) or warfarin (Swarfarin, a CYP2C9 substrate), or the anticoagulatory 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. 

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 of alternative methods to monitor glycaemic control is advised.

Paediatric population
Interaction studies have only been performed in adults.

Pregnancy
There are no data from the use of dapagliflozin in pregnant women. Studies in rats 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 dapagliflozin is not recommended during the second and third trimesters of pregnancy.

When pregnancy is detected, treatment with dapagliflozin should be discontinued.

Breast‐feeding
It is unknown whether 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). A risk to the newborns/infants cannot be excluded. Dapagliflozin should not be used while breast-feeding.

Fertility
The effect of dapagliflozin on fertility in humans has not been studied. In male and female rats, dapagliflozin showed no effects on fertility at any dose tested.

Dapagliflozin has no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia when dapagliflozin is used in combination with a sulphonylurea or insulin.

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 hypoglycaemia was similar between treatment groups, including placebo, with the exceptions of studies with add‐on sulphonylurea (SU) and add‐on insulin therapies. Combination therapies with sulphonylurea and add‐on insulin had higher rates of hypoglycaemia (see Hypoglycaemia below).

Tabulated list of adverse reactions
The following adverse reactions have been identified in the placebo‐controlled clinical trials. None were found to be dose‐related. Adverse reactions listed below are classified according to frequency and system organ class (SOC). Frequency categories are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). 

Table 1. Adverse reactions in placebo‐controlled clinical studiesa and postmarketing experience 

^aThe table shows up to 24‐week (short‐term) data regardless of glycaemic rescue.
^bSee corresponding subsection below for additional information.
^cVulvovaginitis, balanitis and related genital infections includes, e.g. the predefined preferred terms: vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis, vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial, vulval abscess.
^dUrinary tract infection includes the following preferred terms, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection and prostatitis.
^eVolume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension.
^fPolyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.
^gMean changes from baseline in haematocrit were 2.30 % for dapagliflozin 10 mg versus‐0.33% for placebo.
Haematocrit values >55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus 0.4% of placebo subjects.
^hMean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total cholesterol 2.5% versus 0.0%; HDL cholesterol 6.0% versus 2.7%; LDL cholesterol 2.9% versus ‐1.0%; triglycerides –2.7% versus ‐0.7%.
ⁱ See section 4.4.
^jAdverse reaction was identified through postmarketing surveillance. Rash includes the following preferred terms, listed in order of frequency in clinical trials: rash, rash generalised, rash pruritic, rash macular, rash maculo‐papular, rash pustular, rash vesicular, and rash erythematous. In active‐ and placebo‐controlled clinical trials (dapagliflozin, N=5936, All control, N=3403), the frequency of rash was similar for dapagliflozin (1.4 %) and all control (1.4 %), respectively.
*Reported in ≥ 2% of subjects and ≥ 1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo.
**Reported by the investigator as possibly related, probably related or related to study treatment and reported in ≥ 0.2% of subjects and ≥ 0.1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo. 

Description of selected adverse reactions
Hypoglycaemia
The frequency of hypoglycaemia depended on the type of background therapy used in each study.

For studies of dapagliflozin in monotherapy, as add‐on to metformin or as add‐on to sitagliptin (with or without metformin), the frequency of minor episodes of hypoglycaemia was similar (< 5%) between treatment groups, including placebo up to 102 weeks of treatment. Across all studies, major events of hypoglycaemia were uncommon and comparable between the groups treated with dapagliflozin or placebo. Studies with add‐on sulphonylurea and add‐on insulin therapies had higher rates of hypoglycaemia (see section 4.5). 

In an add‐on to glimepiride study, at weeks 24 and 48, minor episodes of hypoglycaemia were reported more frequently in the group treated with dapagliflozin 10 mg plus glimepiride (6.0% and 7.9%, respectively) than in the placebo plus glimepiride group (2.1% and 2.1%, respectively).

In an add‐on to insulin study, episodes of major hypoglycaemia were reported in 0.5% and 1.0% of subjects treated with dapagliflozin 10 mg plus insulin at Weeks 24 and 104, respectively, and in 0.5% of subjects treated with placebo plus insulin groups at Weeks 24 and 104. At Weeks 24 and 104, minor episodes of hypoglycaemia were reported, respectively, in 40.3% and 53.1% of subjects who received dapagliflozin 10 mg plus insulin and in 34.0% and 41.6% of the subjects who received placebo plus insulin.

In an add‐on to metformin and a sulphonylurea study, up to 24 weeks, no episodes of major hypoglycaemia were reported. Minor episodes of hypoglycaemia were reported in 12.8% of subjects who received dapagliflozin 10 mg plus metformin and a sulphonylurea and in 3.7% of subjects who received placebo plus metformin and a sulphonylurea. 

Volume depletion
Reactions related to volume depletion (including, reports of dehydration, hypovolaemia or hypotension) were reported in 1.1% and 0.7% of subjects who received dapagliflozin 10 mg and placebo, respectively; serious reactions occurred in < 0.2% of subjects balanced between dapagliflozin 10 mg and placebo (see section 4.4).

Vulvovaginitis, balanitis and related genital infections
Vulvovaginitis, balanitis and related genital infections were reported in 5.5% and 0.6% of subjects who received dapagliflozin 10 mg and placebo, respectively. Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females (8.4% and 1.2% for dapagliflozin and placebo, respectively), and subjects with a prior history were more likely to have a recurrent infection.

Urinary tract infections
Urinary tract infections were more frequently reported for dapagliflozin 10 mg compared to placebo (4.7% versus 3.5%, respectively; see section 4.4). Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females, and subjects with a prior history were more likely to have a recurrent infection. 

Increased creatinine
Adverse reactions related to increased creatinine were grouped (e.g. decreased renal creatinine clearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate).

This grouping of reactions was reported in 3.2% and 1.8% of patients who received dapagliflozin 10 mg and placebo, respectively. In patients with normal renal function or mild renal impairment (baseline eGFR ≥ 60 ml/min/1.73m²) this grouping of reactions were reported in 1.3% and 0.8% of patients who received dapagliflozin 10 mg and placebo, respectively. These reactions were more common in patients with baseline eGFR ≥ 30 and < 60 ml/min/1.73m² (18.5% dapagliflozin 10 mg vs 9.3% placebo).

Further evaluation of patients who had renal‐related adverse events showed that most had serum creatinine changes of ≤ 0.5 mg/dl from baseline. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment. 

Parathyroid hormone (PTH)
Small increases in serum PTH levels were observed with increases being larger in subjects with higher baseline PTH concentrations. Bone mineral density measurements in patients with normal or mildly impaired renal function did not indicate bone loss over a treatment period of two years.

Malignancies
During clinical trials, the overall proportion of subjects with malignant or unspecified tumours was similar between those treated with dapagliflozin (1.50%) and placebo/comparator (1.50%), and there was no carcinogenicity or mutagenicity signal in animal data (see section 5.3). When considering the cases of tumours occurring in the different organ systems, the relative risk associated with dapagliflozin was above 1 for some tumours (bladder, prostate, breast) and below 1 for others (e.g. blood and lymphatic, ovary, renal tract), not resulting in an overall increased tumour risk associated with dapagliflozin. The increased/decreased risk was not statistically significant in any of the organ systems. Considering the lack of tumour findings in non‐clinical studies as well as the short latency between first drug exposure and tumour diagnosis, a causal relationship is considered unlikely. Since the numerical imbalance of breast, bladder and prostate tumours must be considered with caution, it will be further investigated in post- authorisation studies. 

Special populations
Elderly (≥ 65 years)
In subjects ≥ 65 years of age, adverse reactions related to renal impairment or failure were reported in 7.7% of subjects treated with dapagliflozin and 3.8% of subjects treated with placebo (see section 4.4). The most commonly reported adverse reaction related to renal function was increased serum creatinine. The majority of these reactions were transient and reversible. In subjects ≥ 65 years of age, adverse reactions of volume depletion, most commonly reported as hypotension, were reported in 1.7% and 0.8% of dapagliflozin‐treated subjects and placebotreated subjects, respectively (see section 4.4).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: 

• Saudi Arabia

The National Pharmacovigilance and Drug Safety Centrer (NPC)
Fax: + (966‐11) 2057662
Toll free: 800‐249‐0000
Phone No.: + (966‐11) 2038222, Exts: 2317‐2356‐2353‐2354‐2334‐2340.
e‐mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

• Other GCC States

Please contact the relevant competent authority

Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times the maximum recommended human dose). These subjects had detectable glucose in the urine for a dose‐related period of time (at least 5 days for the 500 mg dose), with no reports of dehydration, hypotension or electrolyte imbalance, and with no clinically meaningful effect on QTc interval. The incidence of hypoglycaemia was similar to placebo. In clinical studies where once‐daily doses of up to 100 mg (10 times the maximum recommended human dose) were administered for 2 weeks in healthy subjects and type 2 diabetes subjects, the incidence of hypoglycaemia was slightly higher than placebo and was not dose‐related. Rates of adverse events including dehydration or hypotension were similar to placebo, and there were no clinically meaningful dose‐related changes in laboratory parameters, including serum electrolytes and biomarkers of renal function.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status. The removal of dapagliflozin by haemodialysis has not been studied.

Pharmacotherapeutic group: Drugs used in diabetes, Sodium‐glucose co‐transporter 2 (SGLT2) inhibitors, ATC code: A10BK01. 

Mechanism of action 

Dapagliflozin is a highly potent (Ki: 0.55 nM), selective and reversible inhibitor of sodium‐glucose co‐transporter 2 (SGLT2). The SGLT2 is selectively expressed in the kidney with no expression detected in more than 70 other tissues including liver, skeletal muscle, adipose tissue, breast, bladder and brain. SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Despite the presence of hyperglycaemia in type 2 diabetes, reabsorption of filtered glucose continues. Dapagliflozin improves both fasting and post‐prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. This glucose excretion (glucuretic effect) is observed after the first dose, is continuous over the 24‐ hour dosing interval and is sustained for the duration of treatment. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and GFR. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycaemia. Dapagliflozin acts independently of insulin secretion and insulin action. Improvement in homeostasis model assessment for beta cell function (HOMA beta‐cell) has been observed in clinical studies with dapagliflozin.

Urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric loss and reduction in weight. Inhibition of glucose and sodium co‐transport by dapagliflozin is also associated with mild diuresis and transient natriuresis.

Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is > 1,400 times more selective for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption. 

Pharmacodynamic effects
Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in subjects with type 2 diabetes mellitus following the administration of dapagliflozin.

Approximately 70 g of glucose was excreted in the urine per day (corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in subjects with type 2 diabetes mellitus for 12 weeks.

Evidence of sustained glucose excretion was seen in subjects with type 2 diabetes mellitus given dapagliflozin 10 mg/day for up to 2 years.

This urinary glucose excretion with dapagliflozin also results in osmotic diuresis and increases in urinary volume in subjects with type 2 diabetes mellitus. Urinary volume increases in subjects with type 2 diabetes mellitus treated with dapagliflozin 10 mg were sustained at 12 weeks and amounted to approximately 375 ml/day. The increase in urinary volume was associated with a small and transient increase in urinary sodium excretion that was not associated with changes in serum sodium concentrations. 

Urinary uric acid excretion was also increased transiently (for 3‐7 days) and accompanied by a sustained reduction in serum uric acid concentration. At 24 weeks, reductions in serum uric acid concentrations ranged from ‐48.3 to ‐18.3 micromoles/l (‐0.87 to ‐0.33 mg/dl).

Clinical efficacy and safety
Fourteen double‐blind, randomised, controlled clinical trials were conducted with 7,056 subjects with type 2 diabetes to evaluate the efficacy and safety of dapagliflozin; 4,737 subjects in these studies were treated with dapagliflozin. Twelve studies had a treatment period of 24 weeks duration, 8 with long‐term extensions ranging from 24 to 80 weeks (up to a total study duration of 104 weeks), one study had a 28‐week treatment period, and one study was 52 weeks in duration with long‐term extensions of 52 and 104 weeks (total study duration of 208 weeks).

Mean duration of diabetes ranged from 1.4 to 16.9 years. Fifty percent (50%) had mild renal impairment and 11% had moderate renal impairment. Fifty‐one percent (51%) of the subjects were men, 84% were White, 8% were Asian, 4% were Black and 4% were of other racial groups.

Eighty‐one percent (81%) of the subjects had a body mass index (BMI) ≥ 27. Furthermore, two 12‐ week, placebo‐controlled studies were conducted in patients with inadequately controlled type 2 diabetes and hypertension. 

Glycaemic control
Monotherapy
A double‐blind, placebo‐controlled study of 24‐week duration (with an additional extension period) was conducted to evaluate the safety and efficacy of monotherapy with dapagliflozin in subjects with inadequately controlled type 2 diabetes mellitus. Once‐daily treatment with dapagliflozin resulted in statistically significant (p < 0.0001) reductions in HbA1c compared to placebo (Table 2).

In the extension period, HbA1c reductions were sustained through Week 102 (‐0.61%, and ‐0.17% adjusted mean change from baseline for dapagliflozin 10 mg and placebo, respectively). 

Table 2. Results at Week 24 (LOCF^a) of a placebo‐controlled study of dapagliflozin as monotherapy 

Combination therapy
In a 52‐week, active‐controlled non‐inferiority study (with 52‐ and 104‐week extension periods), dapagliflozin was evaluated as add‐on therapy to metformin compared with a sulphonylurea (glipizide) as add‐on therapy to metformin in subjects with inadequate glycaemic control (HbA1c > 6.5% and ≤ 10%). The results showed a similar mean reduction in HbA1c from baseline to Week 52, compared to glipizide, thus demonstrating non‐inferiority (Table 3). At Week 104, adjusted mean change from baseline in HbA1c was ‐0.32% for dapagliflozin and ‐0.14% for glipizide. At Week 208, adjusted mean change from baseline in HbA1c was ‐0.10% for dapagliflozin and 0.20% for glipizide. At 52, 104 and 208 weeks, a significantly lower proportion of subjects in the group treated with dapagliflozin (3.5%, 4.3% and 5.0%, respectively) experienced at least one event of hypoglycaemia compared to the group treated with glipizide (40.8%, 47.0% and 50%, respectively). The proportion of subjects remaining in the study at Week 104 and Week 208 was 56.2% and 39.7% for the group treated with dapagliflozin and 50.0% and 34.6% for the group treated with glipizide. 

Table 3. Results at Week 52 (LOCF^a) in an active‐controlled study comparing dapagliflozin to glipizide as add‐on to metformin 

Dapagliflozin as an add‐on with either metformin, glimepiride, metformin and a sulphonylurea, sitagliptin (with or without metformin) or insulin resulted in statistically significant reductions in HbA1c at 24 weeks compared with subjects receiving placebo (p < 0.0001; Tables 4, 5 and 6).

The reductions in HbA1c observed at Week 24 were sustained in add‐on combination studies (glimepiride and insulin) with 48‐week data (glimepiride) and up to 104‐week data (insulin). At Week 48 when added to sitagliptin (with or without metformin), the adjusted mean change from baseline for dapagliflozin 10 mg and placebo was ‐0.30% and 0.38%, respectively. For the add‐on to metformin study, HbA1c reductions were sustained through Week 102 (‐0.78% and 0.02% adjusted mean change from baseline for 10 mg and placebo, respectively). At Week 104 for insulin (with or without additional oral glucose‐lowering medicinal products), the HbA1c reductions were ‐0.71% and ‐0.06% adjusted mean change from baseline for dapagliflozin 10 mg and placebo, respectively. At Weeks 48 and 104, the insulin dose remained stable compared to baseline in subjects treated with dapagliflozin 10 mg at an average dose of 76 IU/day. In the placebo group there was a mean increase of 10.5 IU/day and 18.3 IU/day from baseline (mean average dose of 84 and 92 IU/day) at Weeks 48 and 104, respectively. The proportion of subjects remaining in the study at Week 104 was 72.4% for the group treated with dapagliflozin 10 mg and 54.8% for the placebo group. 

Table 4. Results of 24‐week (LOCF^a) placebo‐controlled studies of dapagliflozin in add‐on combination with metformin or sitagliptin (with or without metformin)  

Table 5. Results of 24‐week placebo‐controlled studies of dapagliflozin in add‐on combination with sulphonylurea (glimepiride) or metformin and a sulphonylurea 

 Table 6. Results at Week 24 (LOCF^a) in a placebo‐controlled study of dapagliflozin in combination with insulin (alone or with oral glucose‐lowering medicinal products) 

 Combination therapy with prolonged‐release exenatide
In a 28‐week, double‐blind, active comparator‐controlled study, the combination of dapagliflozin and prolonged‐release exenatide (a GLP‐1 receptor agonist) was compared to dapagliflozin alone and prolonged‐release exenatide alone in subjects with inadequate glycaemic control on metformin alone (HbA1c ≥ 8% and ≤ 12%). All treatment groups had a reduction in HbA1c compared to baseline.

The combination treatment with dapagliflozin 10 mg and prolongedrelease exenatide group showed superior reductions in HbA1c from baseline compared to dapagliflozin alone and prolonged‐release exenatide alone (Table 7). 

Table 7. Results of one 28‐week trial of dapagliflozin and prolonged‐release exenatide versus dapagliflozin alone and prolonged‐release exenatide alone, in combination with metformin (intent to treat patients) 

 QD=once daily, QW=once weekly, N=number of patients, CI=confidence interval.
^aAdjusted least squares means (LS Means) and treatment group difference(s) in the change from baseline values at Week 28 are modelled using a mixed model with repeated measures (MMRM) including treatment, region, baseline HbA1c stratum (< 9.0% or ≥ 9.0%), week, and treatment by week interaction as fixed factors, and baseline value as a covariate.
*p < 0.001, **p < 0.01.
P‐values are all adjusted p‐values for multiplicity. 

Analyses exclude measurements post rescue therapy and post premature discontinuation of study medicinal product. 

Fasting plasma glucose
Treatment with dapagliflozin 10 mg as a monotherapy or as an add‐on to either metformin, glimepiride, metformin and a sulphonylurea, sitagliptin (with or without metformin) or insulin resulted in statistically significant reductions in fasting plasma glucose (‐1.90 to ‐1.20 mmol/l [‐ 34.2 to ‐21.7 mg/dl]) compared to placebo (‐0.33 to 0.21 mmol/l [‐6.0 to 3.8 mg/dl]). This effect
was observed at Week 1 of treatment and maintained in studies extended through Week 104.

Combination therapy of dapagliflozin 10 mg and prolonged‐release exenatide resulted in significantly greater reductions in fasting plasma glucose at Week 28: ‐3.66 mmol/l (‐65.8 mg/dl), compared to ‐2.73 mmol/l (‐49.2 mg/dl) for dapagliflozin alone (p < 0.001) and ‐2.54 mmol/l (‐ 45.8 mg/dl) for exenatide alone (p < 0.001).

Post‐prandial glucose
Treatment with dapagliflozin 10 mg as an add‐on to glimepiride resulted in statistically significant reductions in 2‐hour post‐prandial glucose at 24 weeks that were maintained up to Week 48.

Treatment with dapagliflozin 10 mg as an add‐on to sitagliptin (with or without metformin) resulted in reductions in 2‐hour post‐prandial glucose at 24 weeks that were maintained up to Week 48.

Combination therapy of dapagliflozin 10 mg and prolonged‐release exenatide resulted in significantly greater reductions in 2‐hour post‐prandial glucose at Week 28 compared to either agent alone.

Body weight
Dapagliflozin 10 mg as an add‐on to metformin, glimepiride, metformin and a sulphonylurea, sitagliptin (with or without metformin) or insulin resulted in statistically significant body weight reduction at 24 weeks (p < 0.0001, Tables 4 and 5). These effects were sustained in longer‐term trials. At 48 weeks, the difference for dapagliflozin as add‐on to sitagliptin (with or without metformin) compared with placebo was ‐2.22 kg. At 102 weeks, the difference for dapagliflozin as add‐on to metformin compared with placebo, or as add‐on to insulin compared with placebo was ‐2.14 and ‐2.88 kg, respectively. 

As an add‐on therapy to metformin in an active‐controlled non‐inferiority study, dapagliflozin resulted in a statistically significant body weight reduction compared with glipizide of ‐4.65 kg at 52 weeks (p < 0.0001, Table 3) that was sustained at 104 and 208 weeks (‐5.06 kg and ‐4.38 kg, respectively).

The combination of dapagliflozin 10 mg and prolonged‐release exenatide demonstrated significantly greater weight reductions compared to either agent alone (Table 7). 

A 24‐week study in 182 diabetic subjects using dual energy X‐ray absorptiometry (DXA) to evaluate body composition demonstrated reductions with dapagliflozin 10 mg plus metformin compared with placebo plus metformin, respectively, in body weight and body fat mass as measured by DXA rather than lean tissue or fluid loss. Treatment with dapagliflozin plus metformin showed a numerical decrease in visceral adipose tissue compared with placebo plus metformin treatment in a magnetic resonance imaging substudy.

Blood pressure
In a pre‐specified pooled analysis of 13 placebo‐controlled studies, treatment with dapagliflozin 10 mg resulted in a systolic blood pressure change from baseline of ‐3.7 mmHg and diastolic blood pressure of ‐1.8 mmHg versus ‐0.5 mmHg systolic and ‐0.5 mmHg diastolic blood pressure for placebo group at Week 24. Similar reductions were observed up to 104 weeks.

Combination therapy of dapagliflozin 10 mg and prolonged‐release exenatide resulted in a significantly greater reduction in systolic blood pressure at Week 28 (‐4.3 mmHg) compared to dapagliflozin alone (‐1.8 mmHg, p < 0.05) and prolonged‐release exenatide alone (‐1.2 mmHg, p < 0.01).

In two 12‐week, placebo‐controlled studies a total of 1,062 patients with inadequately controlled type 2 diabetes and hypertension (despite pre‐existing stable treatment with an ACE‐I or ARB in one study and an ACE‐I or ARB plus one additional antihypertensive treatment in another study) were treated with dapagliflozin 10 mg or placebo. At Week 12 for both studies, dapagliflozin 10 mg plus usual antidiabetic treatment provided improvement in HbA1c and decreased the placebocorrected systolic blood pressure on average by 3.1 and 4.3 mmHg, respectively. 

Cardiovascular safety
A meta‐analysis of cardiovascular events in the clinical program was performed. In the clinical program, 34.4% of subjects had a history of cardiovascular disease (excluding hypertension) at baseline and 67.9% had hypertension. Cardiovascular episodes were adjudicated by an independent adjudication committee. The primary end point was the time‐to‐first event of one of the following outcomes: cardiovascular death, stroke, myocardial infarction (MI) or hospitalisation for unstable angina. Primary episodes occurred at a rate of 1.62% per patient‐year in subjects treated with dapagliflozin and 2.06% in comparator‐treatment subjects, per patientyear.

The hazard ratio comparing dapagliflozin to comparator was 0.79 (95% Confidence interval [CI]: 0.58, 1.07), indicating that in this analysis dapagliflozin is not associated with an increase in cardiovascular risk in patients with type 2 diabetes mellitus. Cardiovascular death, MI and stroke were observed with a hazard ratio of 0.77 (95% CI: 0.54, 1.10). 

Renal impairment
Moderate renal impairment (eGFR ≥ 30 to < 60 ml/min/1.73 m²)
The efficacy of dapagliflozin was also assessed separately in a dedicated study of diabetic subjects with moderate renal impairment (252 subjects with mean eGFR 45 ml/min/1.73 m²). The mean change from baseline in HbA1c at 24 weeks was ‐0.44% and ‐0.33%, for dapagliflozin 10 mg and placebo, respectively. 

Patients with baseline HbA1c ≥ 9%
In a pre‐specified analysis of subjects with baseline HbA1c ≥ 9.0%, treatment with dapagliflozin 10 mg resulted in statistically significant reductions in HbA1c at Week 24 as a monotherapy (adjusted mean change from baseline: ‐2.04% and 0.19% for dapagliflozin 10 mg and placebo, respectively) and as an add‐on to metformin (adjusted mean change from baseline: ‐1.32% and ‐
0.53% for dapagliflozin and placebo, respectively).

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with dapagliflozin in one or more subsets of the paediatric population in the treatment of type 2 diabetes (see section 4.2 for information on paediatric use).

Absorption
Dapagliflozin was rapidly and well absorbed after oral administration. Maximum dapagliflozin plasma concentrations (C_max) were usually attained within 2 hours after administration in the fasted state. Geometric mean steady‐state dapagliflozin C_max and AUC values following once daily 10 mg doses of dapagliflozin were 158 ng/ml and 628 ng h/ml, respectively. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration with a high‐fat meal decreased dapagliflozin C_max by up to 50% and prolonged T_max by approximately 1 hour, but did not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful. Hence, dapagliflozin can be administered with or without food.

Distribution
Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various disease states (e.g. renal or hepatic impairment). The mean steady‐state volume of distribution of dapagliflozin was 118 litres.

Biotransformation
Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3‐O‐glucuronide, which is an inactive metabolite. Dapagliflozin 3‐O‐glucuronide or other metabolites do not contribute to the glucose‐lowering effects. The formation of dapagliflozin 3‐O‐glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP‐mediated metabolism was a minor clearance pathway in humans. 

Elimination
The mean plasma terminal half‐life (t_1/2) for dapagliflozin was 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects. The mean total systemic clearance of dapagliflozin administered intravenously was 207 ml/min. Dapagliflozin and related metabolites are primarily eliminated via urinary excretion with less than 2% as unchanged dapagliflozin. After administration of a 50 mg [14C]‐dapagliflozin dose, 96% was recovered, 75% in urine and 21% in faeces. In faeces, approximately 15% of the dose was excreted as parent drug.

Linearity
Dapagliflozin exposure increased proportional to the increment in dapagliflozin dose over the range of 0.1 to 500 mg and its pharmacokinetics did not change with time upon repeated daily dosing for up to 24 weeks. 

Special populations
Renal impairment
At steady‐state (20 mg once‐daily dapagliflozin for 7 days), subjects with type 2 diabetes mellitus and mild, moderate or severe renal impairment (as determined by iohexol plasma clearance) had mean systemic exposures of dapagliflozin of 32%, 60% and 87% higher, respectively, than those of subjects with type 2 diabetes mellitus and normal renal function. The steady‐state 24‐hour urinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excreted by subjects with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. The impact of hemodialysis on dapagliflozin exposure is not known. 

Hepatic impairment
In subjects with mild or moderate hepatic impairment (Child‐Pugh classes A and B), mean C_max and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful. In subjects with severe hepatic impairment (Child‐Pugh class C) mean C_max and AUC of dapagliflozin were 40%
and 67% higher than matched healthy controls, respectively.

Elderly (≥ 65 years)
There is no clinically meaningful increase in exposure based on age alone in subjects up to 70 years old. However, an increased exposure due to age‐related decrease in renal function can be expected. There are insufficient data to draw conclusions regarding exposure in patients > 70 years old.

Paediatric population
Pharmacokinetics in the paediatric population have not been studied. 

Gender
The mean dapagliflozin AUCss in females was estimated to be about 22% higher than in males.

Race
There were no clinically relevant differences in systemic exposures between White, Black or Asian races.

Body weight
Dapagliflozin exposure was found to decrease with increased weight. Consequently, low‐weight patients may have somewhat increased exposure and patients with high weight somewhat decreased exposure. However, the differences in exposure were not considered clinically meaningful.

Non‐clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and fertility.

Dapagliflozin did not induce tumours in either mice or rats at any of the doses evaluated in twoyear carcinogenicity studies.

Reproductive and developmental toxicity
Direct administration of dapagliflozin to weanling juvenile rats and indirect exposure during late pregnancy (time periods corresponding to the second and third trimesters of pregnancy with respect to human renal maturation) and lactation are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny.

In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day 21 until postnatal day 90, renal pelvic and tubular dilatations were reported at all dose levels; pup exposures at the lowest dose tested were ≥ 15 times the maximum recommended human dose. These findings were associated with dose‐related increases in kidney weight and macroscopic kidney enlargement observed at all doses. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1‐month recovery period.

In a separate study of pre‐ and postnatal development, maternal rats were dosed from gestation day 6 through postnatal day 21, and pups were indirectly exposed in utero and throughout lactation. (A satellite study was conducted to assess dapagliflozin exposures in milk and pups.) Increased incidence or severity of renal pelvic dilatation was observed in adult offspring of treated dams, although only at the highest dose tested (associated maternal and pup dapagliflozin exposures were 1,415 times and 137 times, respectively, the human values at the maximum recommended human dose). Additional developmental toxicity was limited to dose‐related
reductions in pup body weights, and observed only at doses ≥ 15 mg/kg/day (associated with pup exposures that are ≥ 29 times the human values at the maximum recommended human dose). 

Maternal toxicity was evident only at the highest dose tested, and limited to transient reductions in body weight and food consumption at dose. The no observed adverse effect level (NOAEL) for developmental toxicity, the lowest dose tested, is associated with a maternal systemic exposure multiple that is approximately 19 times the human value at the maximum recommended human
dose.

In additional studies of embryo‐foetal development in rats and rabbits, dapagliflozin was administered for intervals coinciding with the major periods of organogenesis in each species. Neither maternal nor developmental toxicities were observed in rabbits at any dose tested; the highest dose tested is associated with a systemic exposure multiple of approximately 1,191 times the maximum recommended human dose. In rats, dapagliflozin was neither embryolethal nor teratogenic at exposures up to 1,441 times the maximum recommended human dose. 

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