Avaxiga 5 mg and 10 mg Tablets

Type 2 diabetes mellitus

AVAXIGA is indicated in adults aged 18 years and older with type 2 diabetes mellitus:

• as monotherapy as an adjunct to diet and exercise to improve glycaemic control
• as add-on combination therapy, 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.

Type 2 diabetes mellitus

Monotherapy and add-on combination therapy

The recommended dose is 10 mg AVAXIGA once daily for monotherapy and add-on combination therapy with other glucose-lowering medicines, including metformin a thiazolidinedione. A sulfonylurea, a DPP 4 inhibitor, or insulin.

Use with medicines known to cause hypoglycaemia: When AVAXIGA is used in combination with insulin or an insulin secretagogue, such as a sulfonylurea, a lower dose of insulin or insulin secretagogue may be considered to reduce the risk of hypoglycaemia.

Special Populations

Renal impairment: Treatment of diabetes mellitus No dosage adjustment is required based on renal function. As glycaemic efficacy is dependent on renal function (see sections 4.4 and 4.8), AVAXIGA is not recommended to improve glycaemic control in the treatment of diabetes in patients where eGFR is below 45 mL/min/1,73 m2. Monitoring of renal function is recommended as follows:

• Prior to initiation of AVAXIGA 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 eGFR < 45 mL/min/1, 73 m2. AVAXIGA treatment should be discontinued (See sections 4.3).

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

Elderly population: No dosage adjustment for AVAXIGA is required based on age. (See section 4.4).

Paediatric population: Safety and effectiveness of AVAXIGA in paediatric and adolescent patients have not been established. No data is available.

Method of Administration

For oral use.

• Hypersensitivity to dapagliflozin or to any of the excipients of AVAXIGA. (Listed in section 6.1)
• Moderate and severe renal impairment with GFR < 45 mL/min/1,73 m2, end stage renal failure or patients on dialysis when used for type 2 diabetes mellitus indication.
• Diabetes mellitus Type 1.
• Pregnant women or women who are breast-feeding their infants (See section 4.6).

General

AVAXIGA may cause a decrease in systolic blood pressure and diastolic blood pressure. AVAXIGA should not be used for the treatment of diabetic ketoacidosis.

Use with medicines known to cause hypoglycaemia

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 AVAXIGA (see section 4.8).

Renal impairment

There is limited experience with initiating treatment with dapagliflozin as in AVAXIGA in patients with eGFR < 25 mL/min/1,73 m2. Dapagliflozin as in AVAXIGA is not recommended for the treatment of type 2 diabetes mellitus to improve glycaemic control when eGFR is persistently below 45 mL/min/1,73 m2 as the glycaemic efficacy of dapagliflozin is dependent on renal function (see section 4.2 Posology and method of administration). However, treatment with AVAXIGA should be continued for the management of renal and cardiovascular comorbidities and additional glucose lowering treatment should be considered if further glycaemic control is needed.

Hepatic impairment

There is limited experience in clinical 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, dapagliflozin 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 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 dapagliflozin is recommended for patients who develop volume depletion until the depletion is corrected (see section 4.8).

Diabetic ketoacidosis

Cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with sodium-glucose co-transporter 2 (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). 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, dapagliflozin treatment should be stopped immediately. 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 dapagliflozin as in AVAXIGA may be restarted when the ketone values are normal, and the patient's condition has stabilised. Before initiating AVAXIGA, 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 experiencing a DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.

Necrotising fasciitis of the perineum (Fournier's gangrene)

Postmarketing cases of necrotising fasciitis of the perineum (also known as Fournier's gangrene) have been reported in female and male patients taking SGLT2 inhibitors (see section 4.8). This is a serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment. Patients should be advised to seek medical attention if they 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, AVAXIGA should be discontinued, and prompt treatment (including antibiotics and surgical debridement) should be instituted.

Urinary tract infections

Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of dapagliflozin as in AVAXIGA should be considered when treating pyelonephritis or urosepsis.

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 dapagliflozin in NYHA class IV is limited.

Chronic kidney disease

There is no experience with dapagliflozin for the treatment of chronic kidney disease in patients without diabetes who do not have albuminuria. Dapagliflozin has not been studied for the treatment of chronic kidney disease in patients with polycystic kidney disease, glomerulonephritis with flares (lupus nephritis or ANCA-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, clinical 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 assessments

Due to its mechanism of action, patients taking AVAXIGA will test positive for glucose in their urine. AVAXIGA film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take AVAXIGA.

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 in patients with type 2 diabetes mellitus (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 medicines that are metabolised by these enzymes.

Effect of other medicines 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 medicines

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 (S-warfarin, 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.

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.

Pregnancy

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

Breastfeeding

Mothers on AVAXIGA should not breast-feed their infants. Alternatively, mothers breastfeeding their infants must not use AVAXIGA. Studies in rats have shown excretion of AVAXIGA in milk. Exposure to AVAXIGA 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.

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

Type 2 diabetes mellitus

In the clinical studies in type 2 diabetes, more than 15,000 patients have been treated with dapagliflozin. The primary assessment of safety and tolerability was conducted in a pre-specified pooled analysis of 13 short-term (up to 24 weeks) placebo-controlled studies with 2,360 subjects treated with dapagliflozin 10 mg and 2,295 treated with placebo. In the dapagliflozin cardiovascular outcomes study in type 2 diabetes mellitus (DECLARE study, see section 5.1), 8,574 patients received dapagliflozin 10 mg and 8,569 received placebo for a median exposure time of 48 months. In total, there were 30,623 patient-years of exposure to dapagliflozin. The most frequently reported adverse reactions across the clinical studies were genital infections.

Chronic kidney disease

In the dapagliflozin renal outcome study in patients with chronic kidney disease (DAPA-CKD), 2,149 patients were treated with dapagliflozin 10 mg and 2,149 patients with placebo for a median exposure time of 27 months. The patient population included patients with type 2 diabetes mellitus and without diabetes, with eGFR u2265 25 to u2264 75 mL/min/1.73 m2. Treatment was continued if eGFR fell to levels below 25 mL/min/1.73 m2. The overall safety profile of dapagliflozin in patients with chronic kidney disease was consistent with the known safety profile of dapagliflozin.

Tabulated list of adverse reactions

The following adverse reactions have been identified in the placebo-controlled clinical studies and postmarketing surveillance. None were found to be dose related. Adverse reactions listed below are classified according to frequency and system organ class (SOC).

Table 1. Adverse reactions in placebo-controlled clinical studies and postmarketing experience

System organ class

Frequent

Less Frequent

Frequency Unknown

Infections and infestations

Vulvovaginitis, balanitis and related genital infections *, b,c , Urinary tract infection *, b,d including pyelo-nephritis, cystitis. Fungal infection**, Necrotising fasciitis of the perineum (Fournier's gangrene) b,i

Metabolism and nutrition disorders

Hypoglycaemia (when used with SU or insulin) b Volume depletion b,e , Thirst ** , Diabetic ketoacidosis (when used in type 2 diabetes mellitus) b,i,k

Nervous system disorders

Dizziness

Gastrointestinal disorders

Constipation**, Dry mouth**

Skin and subcutaneous tissue disorders

Rash j Angioedema, Hyperhidrosis

Musculoskeletal and connective tissue disorders

Back pain*

Renal and urinary disorders

Dysuria

Polyuria * , f Glucosuria

Nocturia **

Reproductive system and breast disorders

Vulvovaginal pruritus ** , Pruritus genital **

Investigations

Haematocrit increased g , Creatinine renal clearance decreased during initial treatment b , Dyslipidaemia h Blood creatinine increased during initial treatment* *,b , Blood urea increased ** Weight decreased **

a The table shows up to 24-week (short-term) data regardless of glycaemic rescue. b See corresponding subsection below for additional information. c 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.

d Urinary 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.

e Volume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension.

f Polyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.

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 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 u20132.7% versus - 0.7%.

I See section 4.4.

j Adverse reaction was identified through postmarketing 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=5936, All control, N=3403), the frequency of rash was similar for dapagliflozin (1.4 %) and all control (1.4%), respectively.

k Reported in the cardiovascular outcomes study in patients with type 2 diabetes (DECLARE). Frequency is based on annual rate.

* Reported in u2265 2% of subjects and u2265 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 u2265 0.2% of subjects and u2265 0.1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo.

Reporting side effects

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of 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: hppts://www.sahpra.or.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 patient's clinical status. The removal of AVAXIGA by haemodialysis has not been studied.