Redifarg 5 & 10 5mg, 10mg Tablets

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

• Monotherapy
  As an adjunct diet and exercise to improve glycaemic control in adult patients with type 2 diabetes mellitus.
• Add-on combination therapy
  In combination with glucose-lowering medicines, including metformin, a thiazolidinedione, a sulfonylurea, a DPP4 inhibitor, or insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.

Posology

Monotherapy and add-on combination therapy
The recommended dose is 10 mg REDIFARG once daily for monotherapy and add-on combination therapy with other glucose-lowering medicines, including metformin, a thiazolidinedione, a sulfonylurea, a DPP4 inhibitor, or insulin.

When REDIFARG 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.

Special populations

Renal impairment
No dosage adjustment for REDIFARG is indicated for mild renal impairment. The efficacy of REDIFARG is dependent on renal function. REDIFARG should not be used in patients with moderate to severe renal impairment (defined as eGFR < 60 mL/min/1,73 m2 by Modification of Diet in Renal disease (MDRD) or CrCI < 60 mL/min by Cockcroft-Gault) (See sections 4.3, 4.4, and 4.8).

Monitoring of renal function is recommended as follows:

• Prior to initiation of REDIFARG and at least annually, thereafter.
• Prior to initiation of concomitant medicines 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 CrCI < 60 mL/min or eGFR < 60 mL/min/1,73 m2, REDIFARG treatment should be discontinued.

Hepatic impairment
No dosage adjustment for REDIFARG is necessary for patients with mild or moderate hepatic impairment. REDIFARG is not recommended for patients with severe hepatic impairment as efficacy has not been established (See section 5.2).

Use in patients at risk for volume depletion
For patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics, a 5 mg starting dose of REDIFARG may be appropriate (See sections 4.4 and 4.8).

Elderly (u2265 65 years) patients:
No dosage adjustment for REDIFARG is required based on age (See section 4.4).

Paediatric and adolescent
Safety and effectiveness of REDIFARG in paediatric and adolescent patients have not been established.

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

• Hypersensitivity to the active substance or to any of the excipients of REDIFARG (see section 6.1).
• Moderate and severe renal impairment with GFR < 60 mL/min, end stage renal failure or patients on dialysis.
• Diabetes Mellitus Type 1.
• Pregnant women or women who are breast-feeding their infants (see section 4.6).
• Patients with history of pancreatitis or pancreatic surgery.

Renal impairment
There is limited experience with initiating treatment with REDIFARG in patients with eGFR < 25 mL/min/1.73m2, and no experience with initiating treatment in patients with eGFR < 15 mL/min/1.73m2. Therefore, it is not recommended to initiate treatment with REDIFARG in patients with eGFR < 15 mL/min/1.73m2 (see section 4.2).

The glucose lowering efficacy of REDIFARG is dependent on renal function, and is reduced in patients with eGFR < 45 mL/min/1.73m2 and is likely absent in patients with severe renal impairment (see sections 4.2, 5.1 and 5.2).

In patients with moderate renal impairment (eGFR < 60 mL/min/1.73m2), a higher proportion of patients treated with REDIFARG had adverse reactions of increase in parathyroid hormone (PTH) and hypotension, compared with placebo.

Hepatic impairment
There is limited experience in studies 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 and/or hypotension
Due to its mechanism of action, REDIFARG increases diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see section 5.1). It may be more pronounced in patients with very high blood glucose concentrations. Caution should be exercised in patients for whom a (REDIFARG) dapagliflozin induced drop in blood pressure could pose a risk, such as patients on anti-hypertensive therapy with a history of hypotension or elderly patients.

In case of intercurrent conditions that may lead to volume depletion (e.g., gastrointestinal illness), 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 REDIFARG is recommended for patients who develop volume depletion until the depletion is corrected (see section 4.8).

Diabetic ketoacidosis
Sodium-glucose co-transporter 2 (SGLT2) inhibitors should be used with caution in patients with increased risk of diabetic ketoacidosis (DKA). Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g., type 1 diabetes patients, 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.

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.

Before initiating REDIFARG, factors in the patient history that may predispose to ketoacidosis should be considered. Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with REDIFARG may be restarted when the ketone values are normal and the patient's condition has stabilised.

Type 2 diabetes mellitus
Cases of DKA, including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including REDIFARG. 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).

In patients where DKA is suspected or diagnosed, REDIFARG treatment should be stopped immediately. Restarting SGLT2 inhibitor treatment in patients experiencing a DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.

Type 1 diabetes mellitus
In type 1 diabetes mellitus studies with dapagliflozin, DKA was reported with common frequency. REDIFARG is contraindicated in treatment of patients with type 1 diabetes (see section 4.3).

Necrotising fasciitis of the perineum (Fournier's gangrene)
If patients experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier's gangrene is suspected, REDIFARG should be discontinued and prompt treatment should be instituted.

Urinary tract and genital infections
SGLT2 inhibitors such as REDIFARG 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.

Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of REDIFARG should be considered when treating pyelonephritis or urosepsis. Discontinuation of dapagliflozin may be considered in cases of recurrent urinary tract infections, see section 4.8 Undesirable effects.

Elderly u2265 65 years
Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics. Elderly patients are more likely to have impaired renal function, and/or to be treated with anti-hypertensive medicines 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).

Cardiac failure
Experience with REDIFARG in NYHA (New York Heart Association) class IV is limited.

Chronic kidney disease
There is no experience with REDIFARG for the treatment of chronic kidney disease in patients without diabetes who do not have albuminuria. REDIFARG has not been studied for the treatment of chronic kidney disease in patients with polycystic kidney disease, glomerulonephritis with flares (lupus nephritis or ANCA (Antineutrophilic cytoplasmic antibody)-associated vasculitis), ongoing or recent requirements of cytotoxic, immunosuppressive or other immunomodulating renal therapy, or in patients who received an organ transplant.

Lower limb amputations
An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term, studies in type 2 diabetes mellitus with SGLT2 inhibitors. It is unknown whether this constitutes a class effect. It is important to counsel patients with diabetes on routine preventative foot care.

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

Pharmacodynamic interactions

Diuretics
REDIFARG 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 sulphonylurea, 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 REDIFARG in patients with type 2 diabetes mellitus (see sections 4.2 and 4.8).

Pharmacokinetic interactions
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-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. 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 UGT 1A9 (IC50 = 32 u03bcM).

Effect of other medicines on REDIFARG
In interaction studies conducted in healthy subjects, using mainly single dose design, the pharmacokinetics of REDIFARG 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.

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

Effect of REDIFARG on other medicines
In interaction studies conducted in healthy subjects, using mainly single dose design, dapagliflozin 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 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]).

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.

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

Paediatric population
Interaction studies have only been performed in adults.

Pregnancy
REDIFARG is contraindicated in pregnancy. Maternal exposure to dapagliflozin as in REDIFARG in rat studies is associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny. When pregnancy is detected, REDIFARG should be discontinued (see section 4.3).

Breast-feeding
Mothers on REDIFARG should not breast-feed their infants. Alternatively, mothers breastfeeding their infants must not use REDIFARG. Studies in rats have shown excretion of REDIFARG in milk. Exposure to REDIFARG 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. In male and female rats, dapagliflozin showed no effects on fertility at any dose tested.

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

Summary of the safety profile
The most frequently reported adverse reactions across the studies were genital infections.

Tabulated list of adverse reactions
Adverse reactions listed below are classified according to frequency and system organ class (SOC). Frequency categories are defined according to the following convention: Frequent (very common and common), Less Frequent (uncommon, rare and vary rare), and Frequency not known (cannot be estimated from the available data).

Table 1: The following undesirable effects have been observed and reported during treatment with Dapagliflozin

Additional adverse reactions in patients treated with REDIFARG are described below by treatment regimen:

• Add-on to metformin studies: headache.
• Add-on to thiazolidinedione study: nasopharyngitis, diarrhoea.

Laboratory findings
Haematocrit: A moderate increase in haematocrit occurs and may be an indication of volume depletion.

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 u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

In overdose, side effects may be elicited or exacerbated. Appropriate symptomatic and supportive treatment should be initiated as dictated by the patientu2019s clinical status. The removal of REDIFARG by haemodialysis has not been studied.