Dapagliflozin 5 mg/10 mg Tablets

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

• Monotherapy
  As an adjunct to 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 sulphonylurea, a dipeptidyl peptidase 4 (DPP 4) 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 DAPAGLIFLOZIN ZYDUS once daily for monotherapy and add-on combination therapy with other glucose-lowering medicines, including metformin, a thiazolidinedione, a sulphonylurea, a DPP 4 inhibitor, or insulin. When DAPAGLIFLOZIN ZYDUS 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 DAPAGLIFLOZIN ZYDUS is indicated for mild renal impairment. The efficacy of DAPAGLIFLOZIN ZYDUS is dependent on renal function. DAPAGLIFLOZIN ZYDUS should not be used in patients with moderate to severe renal impairment (defined as eGFR < 60 mL/min/1.73 mu00b2 by 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:
u2022 Prior to initiation of DAPAGLIFLOZIN ZYDUS and at least annually, thereafter (see section 5.2).
u2022 Prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter.
u2022 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 mu00b2, DAPAGLIFLOZIN ZYDUS treatment should be discontinued.
Hepatic impairment
No dosage adjustment for DAPAGLIFLOZIN ZYDUS is necessary for patients with mild or moderate hepatic impairment. DAPAGLIFLOZIN ZYDUS is not recommended for patients with severe hepatic impairment as efficacy has not been established (see section 5.2).
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 DAPAGLIFLOZIN ZYDUS may be appropriate (see section 4.4).
Elderly
No dosage adjustment for DAPAGLIFLOZIN ZYDUS is required based on age (see section 4.4).
Paediatric and adolescent population
Safety and effectiveness of DAPAGLIFLOZIN ZYDUS in paediatric and adolescent patients have not been established.

Method of administration
For oral administration.

• Hypersensitivity to dapagliflozin or to any of the excipients listed in 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 breastfeeding their infants (see section 4.6).

DAPAGLIFLOZIN ZYDUS IS CONTRAINDICATED FOR USE IN TYPE 1 DIABETES. DAPAGLIFLOZIN ZYDUS IS NOT INDICATED FOR USE IN WEIGHT CONTROL PROGRAMMES AND NOT INDICATED FOR THE TREATMENT OF ANY OTHER CONDITIONS EXCEPT TYPE 2 DIABETES.

There have been reports of metabolic acidosis, including ketoacidosis, which were serious life-threatening or fatal, in patients taking DAPAGLIFLOZIN ZYDUS. Patients who present with signs and symptoms including nausea, vomiting, abdominal pain, malaise and shortness of breath, should be assessed for metabolic acidosis, even if blood glucose levels are below 11 mmol/L. DAPAGLIFLOZIN ZYDUS should be discontinued and the patient should be promptly evaluated and managed accordingly. Predisposing factors for metabolic acidosis include insulin dose reduction, reduced caloric intake, reduced fluid intake or increased insulin requirements due to infections, illness, surgery or alcohol abuse. Caution is advised in treating these patients with DAPAGLIFLOZIN ZYDUS. Predisposing factors for ketoacidosis include low beta-cell function reserve resulting from pancreatic disorders, e.g. history of pancreatitis or pancreatic surgery. DAPAGLIFLOZIN ZYDUS is contraindicated in these patients.

Renal impairment
The glycaemic efficacy of DAPAGLIFLOZIN ZYDUS is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and is likely absent in patients with severe renal impairment (see section 4.2). In subjects with moderate renal impairment (GFR < 60 mL/min), a higher proportion of subjects treated with DAPAGLIFLOZIN ZYDUS had adverse reactions of increase in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension, compared with placebo. DAPAGLIFLOZIN ZYDUS is contraindicated in patients with a GFR < 60 mL/min (see section 4.3). DAPAGLIFLOZIN ZYDUS has not been studied in severe renal impairment (GFR < 30 mL/min) or end-stage renal disease (ESRD) and is contraindicated in these patients. Monitoring of renal function is recommended prior to initiation of DAPAGLIFLOZIN ZYDUS and periodically thereafter (see section 4.2).

Hepatic impairment
There is limited experience in clinical studies in patients with hepatic impairment. DAPAGLIFLOZIN ZYDUS 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
DAPAGLIFLOZIN ZYDUS may cause a decrease in systolic and diastolic blood pressure. Due to its mechanism of action, DAPAGLIFLOZIN ZYDUS increases diuresis which may lead to a modest decrease in blood pressure. It may be more pronounced in patients with very high blood glucose concentrations. Caution should be exercised in patients for whom a DAPAGLIFLOZIN ZYDUS-induced drop in blood pressure could pose a risk, such as patients on antihypertensive therapy with a history of hypotension or elderly patients. A 5 mg starting dose of DAPAGLIFLOZIN ZYDUS may be appropriate in these patients (see section 4.2). 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. DAPAGLIFLOZIN ZYDUS should be permanently discontinued in patients who develop volume depletion (see section 4.8).

Diabetic ketoacidosis (DKA)
Sodium-glucose co-transporter 2 (SGLT2) inhibitors should be used with caution in patients with increased risk of 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. DAPAGLIFLOZIN ZYDUS is contraindicated in patients with type 1 diabetes (see section 4.3).

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. If ketoacidosis is suspected, DAPAGLIFLOZIN ZYDUS should be discontinued and the patient should be promptly evaluated. Before initiating DAPAGLIFLOZIN ZYDUS, 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 DAPAGLIFLOZIN ZYDUS may be restarted when the ketone values are normal, and the patient's condition has stabilised.

Type 2 diabetes mellitus
Rare cases of DKA, including life-threatening and fatal cases, have been reported in patients treated with SGLT inhibitors, including DAPAGLIFLOZIN ZYDUS. 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, DAPAGLIFLOZIN ZYDUS treatment should be stopped immediately. Restarting SGLT2 inhibitor treatment in patients experiencing a DKA while on SGLT2 inhibitor treatment is not recommended.

Pharmacodynamic interactions
Diuretics
DAPAGLIFLOZIN ZYDUS 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 ZYDUS in patients with type 2 diabetes mellitus (see section 4.2).

Pharmacokinetic interactions
The metabolism of DAPAGLIFLOZIN ZYDUS 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 ZYDUS is not expected to alter the metabolic clearance of co-administered medicines that are metabolised by these enzymes.

Effect of other medicines on DAPAGLIFLOZIN ZYDUS
Interaction studies conducted in healthy subjects, using mainly a single-dose design, suggest that the pharmacokinetics of DAPAGLIFLOZIN ZYDUS 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 ZYDUS 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-glycoprotein substrate) or warfarin (S-warfarin, a CYP2C9 substrate), or the anticoagulatory effects of warfarin as measured by international normalised ratio (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 ZYDUS have not been studied.

Pregnancy
DAPAGLIFLOZIN ZYDUS is contraindicated in pregnancy (see section 4.3). There are no data from the use of DAPAGLIFLOZIN ZYDUS 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. When pregnancy is detected, treatment with DAPAGLIFLOZIN ZYDUS should be discontinued.

Breastfeeding
Mothers on DAPAGLIFLOZIN ZYDUS should not breastfeed their infants. It is unknown whether DAPAGLIFLOZIN ZYDUS is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk. DAPAGLIFLOZIN ZYDUS should not be used while breastfeeding and exposure to DAPAGLIFLOZIN ZYDUS should be avoided during the first 2 years of life (see section 4.2).

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

DAPAGLIFLOZIN ZYDUS causes dizziness and may have an influence on the ability to drive and use machines. Patients should also be alerted to the risk of hypoglycaemia when DAPAGLIFLOZIN ZYDUS is used in combination with a sulphonylurea or insulin. Patients should therefore be warned to be cautious when driving a vehicle or operating machinery.

Summary of the safety profile
During clinical studies in type 2 diabetes, the most frequently reported adverse reactions were genital infections.

Tabulated list of adverse reactions
The following adverse reactions have been reported during clinical studies. None were found to be dose related.

System organ class
Frequent
Less frequent
Infections and infestations
Vulvovaginitis, balanitis and related genital infections, urinary tract infection.
Fungal infection, necrotising fasciitis of the perineum (Fournieru2019s gangrene).
Metabolism and nutrition disorders
Hypoglycaemia (when used with SU or insulin).
Volume depletion, dehydration, hypovolaemia, hypotension, thirst, diabetic ketoacidosis (when used in type 2 diabetes mellitus).
Nervous system disorders
Dizziness.
Gastrointestinal disorders
Constipation, dry mouth.
Skin and subcutaneous disorders
Hyperhidrosis.
Musculoskeletal and connective tissue disorders
Back pain.
Renal and urinary disorders
Glycosuria, dysuria, polyuria (including pollakiuria, polyuria, increased urine output, osmotic diuresis. Nocturia.
Reproductive system and breast disorders
Vulvovaginal pruritis, genital pruritis.
Investigations
Haematocrit increased, creatinine renal clearance decreased during initial treatment, dyslipidaemia. Blood creatinine increased during initial treatment, blood urea increased, weight decreased.

Additional adverse reactions were reported when DAPAGLIFLOZIN ZYDUS 10 mg was included in the following treatment regimens:
u2022 add-on to metformin studies: headache,
u2022 add-on to thiazolidinedione study: nasopharyngitis, diarrhoea.

In patients with moderate renal impairment, a higher frequency of bone fractures may be observed when treated with DAPAGLIFLOZIN ZYDUS (see section 4.3).

Post-marketing adverse events
Spontaneous reports
Skin and subcutaneous disorders: Rash, generalised rash, pruritic rash, macular rash, maculopapular rash, pustular rash, vesicular rash, erythematous rash.

Description of selected adverse reactions
Vulvovaginitis, balanitis and related genital infections
In clinical studies, the most vulvovaginitis, balanitis and related genital infections reported were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from treatment. These infections are more frequent in females and subjects with a prior history are more likely to have a recurrent infection. Vulvovaginitis, balanitis and related genital infections includes 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.

Urinary tract infections
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.

Necrotising fasciitis of the perineum (Fournier's gangrene)
Cases of Fournier's gangrene have been reported post marketing in patients taking SGLT2 inhibitors, including DAPAGLIFLOZIN ZYDUS (see section 4.4).

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 DAPAGLIFLOZIN ZYDUS is important. It allows continued monitoring of the benefit/risk balance of DAPAGLIFLOZIN ZYDUS. Health care providers are asked to report any suspected adverse reactions via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Symptoms of overdose
In overdose, side effects may be elicited or exacerbated (see section 4.8). Studies indicate that DAPAGLIFLOZIN ZYDUS did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times the maximum recommended human dose).

Treatment of overdose
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.