Forxiga 5 mg film-coated tablets

Forxiga 10 mg film-coated tablets

Forxiga 5 mg film-coated tablets

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin.

Excipient with known effect:

Each 5 mg tablet contains 25 mg of lactose anhydrous.

Forxiga 10 mg film-coated tablets

Each tablet contains dapagliflozin propanediol monohydrate equivalent to 10 mg dapagliflozin.

Excipient with known effect:

Each 10 mg tablet contains 50 mg of lactose anhydrous.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Forxiga 5 mg film-coated tablets

Yellow, biconvex, 0.7 cm diameter round, film-coated tablets with “5” engraved on one side and “1427” engraved on the other side.

Forxiga 10 mg film-coated tablets

Yellow, biconvex, approximately 1.1 x 0.8 cm diagonally diamond-shaped, film-coated tablets with “10” engraved on one side and “1428” engraved on the other side.

Forxiga 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. Forxiga 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

Forxiga 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 listed in section 6.1.

General

Forxiga should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Use in patients with 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. Forxiga 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). Forxiga 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.

Use in patients with 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 anti-hypertensive 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 cases, have been reported in clinical trials and post-marketing 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 anti-hypertensive 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.

Combinations not studied

Dapagliflozin has not been studied in combination with glucagon-like peptide 1 (GLP-1) analogues.

Urine laboratory assessments

Due to its mechanism of action, patients taking Forxiga will test positive for glucose in their urine.

Lactose

The tablets contain lactose anhydrous. 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 (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.

Other interactions

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

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 alternative methods to monitor glycaemic control.

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.

Forxiga 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.