Jardiance 10 mg film-coated tablets

Each tablet contains 10 mg empagliflozin.

Excipient with known effect:

Each tablet contains lactose monohydrate equivalent to 154.3 mg lactose anhydrous.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Round, pale yellow, biconvex, bevel-edged film-coated tablet debossed with “S10” on one side and the Boehringer Ingelheim logo on the other (tablet diameter: 9.1 mm).

Jardiance is indicated in the treatment of type 2 diabetes mellitus to improve glycaemic control in adults 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

The recommended starting dose is 10 mg empagliflozin once daily for monotherapy and add-on combination therapy with other glucose-lowering medicinal products including insulin. In patients tolerating empagliflozin 10 mg once daily who have an eGFR ≥60 ml/min/1.73 m² and need tighter glycaemic control, the dose can be increased to 25 mg once daily. The maximum daily dose is 25 mg (see below and section 4.4).

When empagliflozin is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see sections 4.5 and 4.8).

Special populations

Patients with renal impairment

Due to the mechanism of action, the efficacy of empagliflozin is dependent on renal function. No dose adjustment is required for patients with an eGFR ≥60 ml/min/1.73 m² or CrCl ≥60 ml/min.

Empagliflozin should not be initiated in patients with an eGFR <60 ml/min/1.73 m² or CrCl <60 ml/min. In patients tolerating empagliflozin whose eGFR falls persistently below 60 ml/min/1.73 m² or CrCl below 60 ml/min, the dose of empagliflozin should be adjusted to or maintained at 10 mg once daily. Empagliflozin should be discontinued when eGFR is persistently below 45 ml/min/1.73 m² or CrCl persistently below 45 ml/min (see sections 4.4, 4.8, 5.1, and 5.2).

Empagliflozin should not be used in patients with end stage renal disease (ESRD) or in patients on dialysis as it is not expected to be effective in these patients (see sections 4.4 and 5.2).

Patients with hepatic impairment

No dose adjustment is required for patients with hepatic impairment. Empagliflozin exposure is increased in patients with severe hepatic impairment. Therapeutic experience in patients with severe hepatic impairment is limited and therefore not recommended for use in this population (see section 5.2).

Elderly patients

No dose adjustment is recommended based on age. In patients 75 years and older, an increased risk for volume depletion should be taken into account (see sections 4.4 and 4.8). In patients aged 85 years and older, initiation of empagliflozin therapy is not recommended due to the limited therapeutic experience (see section 4.4).

Paediatric population

The safety and efficacy of empagliflozin in children and adolescents has not yet been established. No data are available.

Method of administration

The tablets can be taken with or without food, swallowed whole with water. If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

General

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

Use in patients with renal impairment

Jardiance should not be initiated in patients with an eGFR below 60 ml/min/1.73 m² or CrCl <60 ml/min. In patients tolerating empagliflozin whose eGFR is persistently below 60 ml/min/1.73 m² or CrCl <60 ml/min, the dose of empagliflozin should be adjusted to or maintained at 10 mg once daily. Empagliflozin should be discontinued when eGFR is persistently below 45 ml/min/1.73 m² or CrCl persistently below 45 ml/min. Empagliflozin should not be used in patients with ESRD or in patients on dialysis as it is not expected to be effective in these patients (see section 4.2 and 5.2).

Monitoring of renal function

Due to the mechanism of action, the efficacy of empagliflozin is dependent on renal function. Therefore assessment of renal function is recommended as follows:

- Prior to empagliflozin initiation and periodically during treatment, i.e. at least yearly (see sections 4.2, 5.1 and 5.2).

- Prior to initiation of any concomitant medicinal product that may have a negative impact on renal function.

Hepatic injury

Cases of hepatic injury have been reported with empagliflozin in clinical trials. A causal relationship between empagliflozin and hepatic injury has not been established.

Elderly patients

The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect the hydration status. Patients aged 75 years and older may be at an increased risk of volume depletion. A higher number of these patients treated with empagliflozin had adverse reactions related to volume depletion as compared to placebo (see section 4.8).

Therapeutic experience in patients aged 85 years and older is limited. Initiation of empagliflozin therapy in this population is not recommended (see section 4.2).

Use in patients at risk for volume depletion

Based on the mode of action of SGLT-2 inhibitors, osmotic diuresis accompanying therapeutic glucosuria may lead to a modest decrease in blood pressure (see section 5.1). Therefore, caution should be exercised in patients for whom an empagliflozin-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 patients aged 75 years and older.

In case of conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended for patients receiving empagliflozin. Temporary interruption of treatment with empagliflozin should be considered until the fluid loss is corrected.

Urinary tract infections

The overall frequency of urinary tract infection reported as adverse event was similar in patients treated with empagliflozin 25 mg and placebo and higher in patients treated with empagliflozin 10 mg (see section 4.8). Complicated urinary tract infection (e.g. pyelonephritis or urosepsis) occurred at a similar frequency in patients treated with empagliflozin compared to placebo. However, temporary interruption of empagliflozin should be considered in patients with complicated urinary tract infections.

Cardiac failure

Experience in New York Heart Association (NYHA) class I-II is limited, and there is no experience in clinical studies with empagliflozin in NYHA class III-IV.

Urine laboratory assessments

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

Lactose

The tablets contain lactose. 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

Empagliflozin 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, may increase the risk of 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 empagliflozin (see sections 4.2 and 4.8).

Pharmacokinetic interactions

Effects of other medicinal products on empagliflozin

In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by uridine 5'-diphosphoglucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Co-administration of empagliflozin with probenecid, an inhibitor of UGT enzymes and OAT3, resulted in a 26% increase in peak empagliflozin plasma concentrations (C_max) and a 53% increase in area under the concentration-time curve (AUC). These changes were not considered to be clinically meaningful.

The effect of UGT induction on empagliflozin has not been studied. Co-medication with known inducers of UGT enzymes should be avoided due to a potential risk of decreased efficacy.

An interaction study with gemfibrozil, an in vitro inhibitor of OAT3 and OATP1B1/1B3 transporters, showed that empagliflozin C_max increased by 15% and AUC increased by 59% following co-administration. These changes were not considered to be clinically meaningful.

Inhibition of OATP1B1/1B3 transporters by co-administration with rifampicin resulted in a 75% increase in C_max and a 35% increase in AUC of empagliflozin. These changes were not considered to be clinically meaningful.

Empagliflozin exposure was similar with and without co-administration with verapamil, a P-gp inhibitor, indicating that inhibition of P-gp does not have any clinically relevant effect on empagliflozin.

Interaction studies conducted in healthy volunteers suggest that the pharmacokinetics of empagliflozin were not influenced by co-administration with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and hydrochlorothiazide.

Effects of empagliflozin on other medicinal products

Based on in vitro studies, empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Drug-drug interactions involving the major CYP450 and UGT isoforms with empagliflozin and concomitantly administered substrates of these enzymes are therefore considered unlikely.

Empagliflozin does not inhibit P-gp at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Co-administration of digoxin, a P-gp substrate, with empagliflozin resulted in a 6% increase in AUC and 14% increase in C_max of digoxin. These changes were not considered to be clinically meaningful.

Empagliflozin does not inhibit human uptake transporters such as OAT3, OATP1B1, and OATP1B3 in vitro at clinically relevant plasma concentrations and, as such, drug-drug interactions with substrates of these uptake transporters are considered unlikely.

Interaction studies conducted in healthy volunteers suggest that empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, simvastatin, warfarin, ramipril, digoxin, diuretics and oral contraceptives.

Pregnancy

There are no data from the use of empagliflozin in pregnant women. Animal studies show that empagliflozin crosses the placenta during late gestation to a very limited extent but do not indicate direct or indirect harmful effects with respect to early embryonic development. However, animal studies have shown adverse effects on postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Jardiance during early pregnancy. Jardiance is not recommended during the second and third trimester of pregnancy.

Breast-feeding

No data in humans are available on excretion of empagliflozin into milk. Available toxicological data in animals have shown excretion of empagliflozin in milk. A risk to the newborns/infants cannot be excluded. Jardiance should not be used during breast-feeding.

Fertility

No studies on the effect on human fertility have been conducted for Jardiance. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

Jardiance has minor influence on the ability to drive and use machines. Patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines, in particular when Jardiance is used in combination with a sulphonylurea and/or insulin.

Summary of the safety profile

A total of 13,076 patients with type 2 diabetes were included in clinical studies to eva luate the safety of empagliflozin. 2856 patients received empagliflozin 10 mg and 3,738 patients received empagliflozin 25 mg for at least 24 weeks and 601 or 881 patients for at least 76 weeks, either alone or in combination with metformin, a sulphonylurea, pioglitazone, DPP-4 inhibitors, or insulin.

In 5 placebo-controlled trials of 18 to 24 weeks duration, 2,971 patients were included of which 995 were treated with placebo and 1,976 with empagliflozin. The overall incidence of adverse events in patients treated with empagliflozin was similar to placebo. The most frequently reported adverse reaction was hypoglycaemia when used with sulphonylurea or insulin (see description of selected adverse reactions).

Tabulated list of adverse reactions

Adverse reactions classified by system organ class and MedDRA preferred terms reported in patients who received empagliflozin in placebo-controlled studies are presented in the table below (Table 1).

The adverse reactions are listed by absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), or very rare (<1/10,000), and not known (cannot be estimated from the available data).

Table 1: Adverse reactions reported in placebo-controlled studies

^a see subsections below for additional information

Description of selected adverse reactions

Hypoglycaemia

The frequency of hypoglycaemia depended on the background therapy in the respective studies.

Minor hypoglycaemia

The frequency of patients with minor hypoglycaemia was similar for empagliflozin and placebo as monotherapy, add-on to metformin, and add-on to pioglitazone with or without metformin. An increased frequency was noted when given as add-on to metformin and a sulfonylurea (empagliflozin 10 mg: 16.1%, empagliflozin 25 mg: 11.5%, placebo: 8.4%), and as add-on to insulin with or without metformin and with or without a sulphonylurea (empagliflozin 10 mg: 19.5%, empagliflozin 25 mg: 27.1%, placebo: 20.6% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 36.1%, empagliflozin 25 mg: 34.8%, placebo 35.3% over the 78-week trial).

Major hypoglycaemia (hypoglycaemia requiring assistance)

No increase in major hypoglycaemia was observed with empagliflozin compared to placebo as monotherapy, add-on to metformin, add-on to metformin and a sulfonylurea, and add-on to pioglitazone with or without metformin. An increased frequency was noted when given as add-on to insulin with or without metformin and with or without a sulfonylurea (empagliflozin 10 mg: 0%, empagliflozin 25 mg: 1.3%, placebo: 0% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 0%, empagliflozin 25 mg: 1.3%, placebo 0% over the 78-week trial).

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently in patients treated with empagliflozin (empagliflozin 10 mg: 4.1%, empagliflozin 25 mg: 3.7%) compared to placebo (0.9%). These infections were reported more frequently in females treated with empagliflozin compared to placebo, and the difference in frequency was less pronounced in males. The genital tract infections were mild or moderate in intensity.

Increased urination

Increased urination (including the predefined terms pollakiuria, polyuria, and nocturia) was observed at higher frequencies in patients treated with empagliflozin (empagliflozin 10 mg: 3.4%, empagliflozin 25 mg: 3.2%) compared to placebo (1.0%). Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was similar for placebo and empagliflozin (<1%).

Urinary tract infection

The overall frequency of urinary tract infection reported as adverse event was similar in patients treated with empagliflozin 25 mg and placebo (7.6%) and higher in empagliflozin 10 mg (9.3%). Similar to placebo, urinary tract infection was reported more frequently for empagliflozin in patients with a history of chronic or recurrent urinary tract infections. The intensity (mild, moderate, severe) of urinary tract infection was similar in patients treated with empagliflozin and placebo. Urinary tract infection was reported more frequently in females treated with empagliflozin compared to placebo; there was no difference in males.

Volume depletion

The overall frequency of volume depletion (including the predefined terms blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolaemia, orthostatic hypotension, and syncope) was similar in patients treated with empagliflozin (empagliflozin 10 mg: 0.5%, empagliflozin 25 mg: 0.3%) and placebo (0.3%). The frequency of volume depletion events was increased in patients 75 years and older treated with empagliflozin 10 mg (2.3%) or empagliflozin 25 mg (4.4%) compared to placebo (2.1%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

Ireland - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

Symptoms

In controlled clinical studies single doses of up to 800 mg empagliflozin (equivalent to 32 times the highest recommended daily dose) in healthy volunteers and multiple daily doses of up to 100 mg empagliflozin (equivalent to 4 times the highest recommended daily dose) in patients with type 2 diabetes did not show any toxicity. Empagliflozin increased urine glucose excretion leading to an increase in urine volume. The observed increase in urine volume was not dose-dependent and is not clinically meaningful. There is no experience with doses above 800 mg in humans.

Therapy

In the event of an overdose, treatment should be initiated as appropriate to the patient's clinical status. The removal of empagliflozin by haemodialysis has not been studied.

Pharmacotherapeutic group: Drugs used in diabetes, Other blood glucose lowering drugs, excl. insulins, ATC code: A10BX12

Mechanism of action

Empagliflozin is a reversible, highly potent (IC₅₀ of 1.3 nmol) and selective competitive inhibitor of sodium-glucose co-transporter 2 (SGLT2). Empagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is 5000 times more selective for SGLT2 versus SGLT1, the major transporter responsible for glucose absorption in the gut. SGLT2 is highly expressed in the kidney, whereas expression in other tissues is absent or very low. It is responsible, as the predominant transporter, for the reabsorption of glucose from the glomerular filtrate back into the circulation. In patients with type 2 diabetes and hyperglycaemia a higher amount of glucose is filtered and reabsorbed.

Empagliflozin improves glycaemic control in patients with type 2 diabetes by reducing renal glucose reabsorption. The amount of glucose removed by the kidney through this glucuretic mechanism is dependent on blood glucose concentration and GFR. Inhibition of SGLT2 in patients with type 2 diabetes and hyperglycaemia leads to excess glucose excretion in the urine.

In patients with type 2 diabetes, urinary glucose excretion increased immediately following the first dose of empagliflozin and is continuous over the 24 hour dosing interval. Increased urinary glucose excretion was maintained at the end of the 4-week treatment period, averaging approximately 78 g/day. Increased urinary glucose excretion resulted in an immediate reduction in plasma glucose levels in patients with type 2 diabetes.

Empagliflozin improves both fasting and post-prandial plasma glucose levels. The mechanism of action of empagliflozin is independent of beta cell function and insulin pathway and this contributes to a low risk of hypoglycaemia. Improvement of surrogate markers of beta cell function including Homeostasis Model Assessment-β (HOMA-β) was noted. In addition, urinary glucose excretion triggers calorie loss, associated with body fat loss and body weight reduction. The glucosuria observed with empagliflozin is accompanied by mild diuresis which may contribute to sustained and moderate reduction of blood pressure.

Clinical efficacy and safety

A total of 11,250 patients with type 2 diabetes were treated in 10 double-blind, placebo- and active-controlled clinical studies, of which 7,015 received empagliflozin (empagliflozin 10 mg: 3021 patients; empagliflozin 25 mg: 3994 patients). Four studies had treatment durations of 24 weeks; extensions of those and other studies had patients exposed to empagliflozin for up to 102 weeks.

Treatment with empagliflozin as monotherapy and in combination with metformin, pioglitazone, a sulphonylurea, DPP-4 inhibitors, and insulin lead to clinically relevant improvements in HbA1c, fasting plasma glucose (FPG), body weight, and systolic and diastolic blood pressure. Administration of empagliflozin 25 mg resulted in a higher proportion of patients achieving HbA1c goal of less than 7% and fewer patients needing glycaemic rescue compared to empagliflozin 10 mg and placebo. Higher baseline HbA1c was associated with a greater reduction in HbA1c.

Monotherapy

The efficacy and safety of empagliflozin as monotherapy was eva luated in a double-blind, placebo- and active-controlled study of 24 weeks duration in treatment-naïve patients. Treatment with empagliflozin resulted in a statistically significant (p<0.0001) reduction in HbA1c compared to placebo (Table 2) and a clinically meaningful decrease in FPG.

In a prespecified analysis of patients (N=201) with a baseline HbA1c ≥8.5%, treatment resulted in a reduction in HbA1c from baseline of -1.44% for empagliflozin 10 mg, -1.43% for empagliflozin 25 mg, -1.04% for sitagliptin, and an increase of 0.01% for placebo.

In the double-blind placebo-controlled extension of this study, reductions of HbA1c, body weight and blood pressure were sustained up to Week 52.

Table 2: Efficacy results of a 24 week placebo-controlled study of empagliflozin as monotherapy^a

^a Full analysis set (FAS) using last observation carried forward (LOCF) prior to glycaemic rescue therapy

¹ Mean adjusted for baseline value

² Not eva luated for statistical significance as a result of the sequential confirmatory testing procedure

³ 95% CI

⁴ LOCF, values after antihypertensive rescue censored

*p-value <0.0001

Combination therapy

Empagliflozin as add on to metformin, sulphonylurea, pioglitazone

Empagliflozin as add-on to metformin, metformin and a sulphonylurea, or pioglitazone with or without metformin resulted in statistically significant (p<0.0001) reductions in HbA1c and body weight compared to placebo (Table 3). In addition it resulted in a clinically meaningful reduction in FPG, systolic and diastolic blood pressure compared to placebo.

In the double-blind placebo-controlled extension of these studies, reduction of HbA1c, body weight and blood pressure were sustained up to Week 52.

Table 3: Efficacy results of 24 week placebo-controlled studies^a

Tags： 责任编辑：admin
【大 中 小】【打印】 【繁体】【投稿】【收藏】 【推荐】【举报】【评论】 【关闭】 【返回顶部】
分享到:
上一篇：Jardiance 25 mg film-coated tab..	下一篇：RoActemra 162 mg Solution for I..