DUFORZIG Tablet Ref.[50498] Active ingredients: Dapagliflozin

General

DUFORZIG may cause a decrease in systolic blood pressure and diastolic blood pressure.

DUFORZIG should not be used for the treatment of diabetic ketoacidosis.

Metabolic acidosis including ketoacidosis in patients with diabetes mellitus

There have been reports of ketoacidosis, including diabetic ketoacidosis, in patients with type 2 diabetes mellitus taking DUFORZIG. DUFORZIG is contraindicated for the treatment of patients with type 1 diabetes mellitus (see section 4.3).

Patients treated with DUFORZIG 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 11 mmol/L (196 mg/dL). If ketoacidosis is suspected, DUFORZIG should be discontinued and the patient should be promptly evaluated.

Predisposing factors for ketoacidosis include low beta-cell function reserve resulting from pancreatic disorders, e.g. history of pancreatitis or pancreatic surgery. DUFORZIG is not indicated in these patients.

Impairment of renal function/acute kidney injury

SGLT2 inhibitors such as DUFORZIG may cause a decrease in the glomerular filtration rate (GFR), with an increase in serum creatinine and serum urea. Acute kidney injury (AKI) has been reported with the use of SGLT2 inhibitors.

Based on their mode of action, SGLT2 inhibitors may cause glycosuria, osmotic diuresis, fluid and electrolyte loss with a risk of dehydration/hypovolaemia and hypotension, which may precipitate acute kidney injury. Renal function and hydration status should be assessed before treatment is initiated with a SGLT2 inhibitor such as DUFORZIG and should be frequently monitored during treatment.

Other factors that may predispose patients to AKI during treatment with SGLT2 inhibitors include reduced oral intake of fluids, congestive cardiac failure, gastrointestinal fluid losses, excessive heat exposure, and concomitant use of medicines such as diuretics, NSAIDS, ACE inhibitors and ARBs. Discontinue treatment with SGLT2 inhibitors in patients with AKI and consider other appropriate treatment options for their diabetes mellitus.

SGLT2 inhibitors such as DUFORZIG, are contraindicated in patients with moderate to severe renal impairment and in patients on dialysis (See section 4.3).

There is limited experience with DUFORZIG in patients with severe renal impairment (eGFR <30 mL/min/1,73 m²) or end-stage renal disease (ESRD).

Urinary tract and genital infections

SGLT2 inhibitors such as DUFORZIG have been associated with an increased risk of urinary tract infection and/or genital infection in both males and females caused by bacteria and/or fungi. Genital and fungal infections appear to be more common in females. Balanoposthitis in males may result in phimosis.

Treatment of diabetes mellitus

DUFORZIG is not recommended for use in the treatment of diabetes to improve glycaemic control when eGFR is below 45 mL/min/1,73 m² as the glycaemic efficacy of dapagliflozin is dependent on renal function. Renal function should be evaluated prior to initiation of DUFORZIG and periodically thereafter (See section 4.2).

Use with medicines known to cause hypoglycaemia

Insulin and insulin secretagogues, such as sulfonylureas, 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 DUFORZIG (See section 4.8).

Paediatric use

Safety and efficacy of DUFORZIG in paediatric patients has not been established.

Other populations

Patients with severe renal impairment (eGFR <30 mL/min/1,73 m²) or End Stage Renal Disease or with recent (<2 months) cardiovascular event or who are breastfeeding or are pregnant, have been excluded from clinical studies.

Lactose

DUFORZIG contains lactose anhydrous. Patients with rare hereditary problems of galactose intolerance, e.g. galactosaemia, the Lapp lactase deficiency, or glucosegalactose malabsorption should not use DUFORZIG.

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 CYP 1A2, 2C9, 2C19, 2D6, 3A4, nor induced CYP1A2, 2B6 or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter and dapagliflozin 3-Oglucuronide 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.

The dependence of dapagliflozin elimination on dapagliflozin 3-O-glucuronide formation in humans also suggests the possibility of interactions mediated by UGT1A9. Ketoconazole is an in vitro inhibitor of dapagliflozin 3-O-glucuronide formation by UGT1A9 (IC50 = 32 μM).

Effects of other medicines on DUFORZIG

In interaction studies conducted in healthy subjects, using mainly single dose design, the pharmacokinetics of DUFORZIG were not altered by metformin (a human OCT-1 and hOCT-2 substrate), pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), sitagliptin (a human OAT-3 substrate and P-glycoprotein substrate), glimepiride (a CYP2C9 substrate), voglibose (an alpha-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 alpha-glucosidase inhibitor would not be expected.

A 22% decrease in dapagliflozin systemic exposure following co-administration with rifampicin was considered not to be large enough to warrant a dose adjustment.

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

Effect of DUFORZIG on other medicines

In interaction studies conducted in healthy subjects, using mainly single dose design, DUFORZIG did not alter the pharmacokinetics of metformin (an hOCT 1 and hOCT 2 substrate), pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), sitagliptin (a hOAT 3 substrate and P- glycoprotein substrate), glimepiride (a CYP2C9 substrate), hydrochlorothiazide, bumetanide, valsartan, simvastatin (a CYP3A4 substrate), digoxin (a P-gp substrate) or warfarin (S warfarin, a CYP2C19 substrate, R warfarin or the anticoagulatory effects of warfarin as measured by the prothrombin time [International Normalised Ratio (INR)]).Therefore, dapagliflozin is not a clinically meaningful inhibitor of hOCT-1, hOCT-2, hOAT-3, P-gp transporter pathway, and CYP2C8, CYP2C9, CYP2C19 and CYP3A4 mediated metabolism.

Co-administration 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]).

Other interactions

The effects of smoking, diet, herbal products and alcohol use on the pharmacokinetics of DUFORZIG have not been studied.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay

Monitoring glycaemic control with 1,5-AG assay should not be used, as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors, including DUFORZIG. Alternative methods of monitoring glycaemic control should be used.

Pregnancy

DUFORZIG is contraindicated in pregnancy.

Maternal exposure to DUFORZIG in rat studies was associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny. When pregnancy is detected, DUFORZIG should be discontinued (See section 4.3)

Breastfeeding

Mothers on DUFORZIG should not breast-feed their infants. Alternatively, mothers breastfeeding their infants must not use DUFORZIG. Studies in rats have shown excretion of DUFORZIG in milk. Exposure to DUFORZIG must be avoided during the first 2 years of life (See section 4.3).

Fertility

The effect of dapagliflozin on fertility in humans 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

More than 28000 patients with type 2 diabetes and heart failure were randomised, including 15000 patients treated for type 2 diabetes and more than 2000 subjects treated for heart failure with DUFORZIG, in 22 double-blind, controlled, clinical safety and efficacy studies conducted to evaluate the effects of DUFORZIG. DUFORZIG 10 mg was evaluated in 13 of these studies.

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, 2360 patients were treated once daily with DUFORZIG 10 mg and 2295 were treated with placebo (either as monotherapy or in combination with other antidiabetic therapies).

Additionally, DUFORZIG 5 mg was evaluated in a 12-study, short-term, placebocontrolled pool of type 2 diabetes patients that included 1 145 patients treated with DUFORZIG 5 mg (mean exposure = 22 weeks) and 1393 patients treated with placebo (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 (DECLARE), 8574 patients received DUFORZIG 10 mg and 8569 received placebo for a median exposure time of 48 months. In total, there were 30623 patient-years of exposure to DUFORZIG. In the dapagliflozin cardiovascular outcome study in patients with heart failure with reduced ejection fraction (DAPA-HF), 2368 patients were treated with dapagliflozin 10 mg and 2368 patients with placebo for a median exposure time of 18 months. The patient population included patients with type 2 diabetes mellitus and without diabetes, and patients with eGFR ≥30 mL/min/m².

The safety profile of dapagliflozin was overall consistent across the studied indications. DKA was observed only in patients with diabetes mellitus.

The adverse reactions are listed by system organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1 000, <1/100) and rare (≥1/10 000, <1/1 000).

b) Tabulated list of adverse reactions

Table 1. Adverse reactions (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Studiesa reported in ≥2% of patients treated with DUFORZIG 10 mg and ≥1% more frequently than in patients treated with placebo:

^a The table shows up to 24-week (short-term) data regardless of glycaemic rescue.
^b See corresponding subsection below for additional information.
^c Genital infection includes the preferred terms: Vulvovaginitis, 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, balanoposthitis, genitourinary tract infection, penile abscess, posthitis.
^d Polyuria includes the preferred terms: pollakiuria, polyuria, increased urine output, osmotic diuresis.
^e Urinary tract infection includes the preferred terms: Escherichia urinary tract infection, genitourinary tract infection, trigonitis, urethritis, kidney infection, and prostatitis.
^f Mean 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%.
^g Mean 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.
^h Adverse reaction was identified through post-marketing surveillance. Rash includes the following preferred terms, listed in order of frequency in clinical studies: rash, rash generalised, rash pruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, and rash erythematous. In active- and placebo-controlled clinical studies (dapagliflozin, N = 936, all control, N = 3403), the frequency of rash was similar for dapagliflozin (1,4%) and all control (1,4%), respectively (see “Postmarketing adverse events”).
^* Reported in ≥2% of subjects and ≥1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo/comparator.
^** 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.

c. Description of selected adverse reactions

Genital infections

Events of genital infections were reported in 5,5% and 0,6% of patients who received DUFORZIG 10 mg and placebo, respectively, in the 13-study, short-term, placebocontrolled pool. Infections were more frequently reported in females (8,4% DUFORZIG 10 mg vs. 1,2% placebo) than in males (3,4% DUFORZIG 10 mg vs. 0,2% placebo).

In the DECLARE study, the number of patients with SAEs of genital infections were few and balanced: 2 (<0,1%) patients in each of the DUFORZIG and placebo groups.

In the DAPA-HF study, no patient reported a SAE of genital infections in the DUFORZIG group and one in the placebo group. There were 7 (0,3%) patients with adverse events leading to discontinuations (DAE) due to genital infections in the DUFORZIG group and none in the placebo group.

Urinary tract infections

Events of urinary tract infections were reported in 4,7% and 3,5% of patients who received DUFORZIG 10 mg and placebo, respectively, in the short term, placebocontrolled pool. Infections were more frequently reported in females (8,5% DUFORZIG 10 mg vs. 6,7% placebo) than in males (1,8% DUFORZIG 10 mg vs. 1,3% placebo).

In the DECLARE study there were fewer patients with SAEs of urinary tract infections in the DUFORZIG group compared with the placebo group: 79 (0,9%) and 109 (1,3%), respectively.

In the DAPA-HF study, the number of patients with SAEs of UTI were low and balanced: 14 (0,6%) patients in the DUFORZIG group and 17 (0,7%) patients in the placebo group. There were 5 (0,2%) patients with DAEs due to urinary tract infections in each of the DUFORZIG and placebo groups.

Diabetic ketoacidosis (DKA)

In the DECLARE CV outcomes study with a median exposure time of 48 months, events of DKA were reported in 27 patients in the DUFORZIG 10 mg group and 12 patients in the placebo group. The events occurred evenly distributed over the study period. Of the 27 patients with DKA events in the DUFORZIG group, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKA were as expected in a type 2 diabetes mellitus population (see section 4.4).

In the DAPA-HF study, events of DKA were reported in 3 patients with type 2 diabetes mellitus in the DUFORZIG group and none in the placebo group.

Hypoglycaemia

The frequency of hypoglycaemia depended on the type of background therapy used in each study. Studies with add-on sulfonylurea and add-on insulin therapies had higher rates of hypoglycaemia. (See section 4.4). In an add-on to glimepiride study up to 24 weeks, episodes of hypoglycaemia were reported in 10 (6,6%) patients in the DUFORZIG 10 mg plus glimepiride group and 3 (2,1%) patients in the placebo plus glimepiride group.

In an add-on to insulin study up to 24 weeks, episodes of hypoglycaemia were reported in 79 (40,3%) patients in the DUFORZIG 10 mg plus insulin group and in 67 (34%) patients in placebo plus insulin group. Patients in this study could also be treated with a maximum of 2 oral anti-diabetes medications (OADs) including metformin.

In the DECLARE study, no increased risk of major hypoglycaemia was observed with dapagliflozin therapy compared with placebo. Major events of hypoglycaemia were reported in 58 (0.7%) patients treated with dapagliflozin and 83 (1.0%) patients treated with placebo.

In the DAPA-HF study, major events of hypoglycaemia were reported in 4 (0.2%) patients in both the dapagliflozin therapy and placebo treatment groups and observed only in patients with type 2 diabetes mellitus.

Laboratory findings:

Haematocrit

A moderate increase in haematocrit occurs and may be an indication of volume depletion.

Serum inorganic phosphorous

In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in DUFORZIG 10 mg treated patients compared with placebo (mean increases of 0,0419 mmol/L vs. 0,0129 mmol/L, respectively). Similar results were seen at Week 102. Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥1,81 mmol/L if age 17-65 or ≥ 1,65 mmol/L if ≥ age 66) were reported in DUFORZIG 10 mg group vs. placebo at Week 24 (1,7% vs. 0,9%, respectively) and during the short-term plus long-term phase (3,0% vs. 1,6%, respectively). The clinical relevance of these findings is unknown.

Lipids

In the pool of 13 placebo-controlled studies, small changes from baseline in mean lipid values were reported at Week 24 in DUFORZIG 10 mg treated patients compared with placebo. Mean percent change from baseline at Week 24 for DUFORZIG 10 mg vs. placebo, respectively was as follows: total cholesterol 2,5% vs. 0,0%; HDL cholesterol 6,0% vs. 2,7%; LDL cholesterol 2,9% vs. -1,0%; triglycerides -2,7% vs. -0,7%. Mean percent change from baseline at Week 102 for DUFORZIG 10 mg vs. placebo, respectively was as HDL cholesterol 6,6% vs. 2,1%; LDL cholesterol 2,9% vs. -2,2%; follows: total cholesterol 2,1% vs. -1,5%; triglycerides -1,8% vs. -1,8%. The ratio between LDL cholesterol and HDL cholesterol decreased for all treatment groups at Week 24.

In the CV outcomes study, no clinical important differences in total cholesterol, HDL cholesterol, LDL cholesterol or triglycerides were seen.

Post-marketing adverse events

Spontaneous reports

Skin and sub-cutaneous tissue disorders: Rash, rash generalised, rash pruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, rash erythematous.

Acute kidney injury (AKI) and phimosis have been reported with the use of SGLT2 inhibitors such as DUFORZIG.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

Not applicable.