Article Contents
- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBERS
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1.NAME OF THE MEDICINAL PRODUCT
Glyxambi 10 mg/5 mg
Glyxambi 25 mg/5 mg
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Glyxambi 10 mg/5 mg
Each
Glyxambi 25 mg/5 mg
Each
For the full list of excipients, see section 6.1.
3.PHARMACEUTICAL FORM
Glyxambi 10 mg/5 mg
Pale yellow, arc triangular, flat faced,
8 mm each side).
Glyxambi 25 mg/5 mg
Pale pink, arc triangular, flat faced,
4.CLINICAL PARTICULARS
4.1Therapeutic indications
Glyxambi, fixed dose combination of empagliflozin and linagliptin, is indicated in adults aged 18 years and older with type 2 diabetes mellitus:
to improve glycaemic control when metformin and/or sulphonylurea (SU) and one of the monocomponents of Glyxambi do not provide adequate glycaemic control
when already being treated with the free combination of empagliflozin and linagliptin
(See sections 4.2, 4.4, 4.5 and 5.1 for available data on combinations studied)
4.2Posology and method of administration
Posology
The recommended starting dose is 1
In patients who tolerate this starting dose and require additional glycaemic control, the dose can be
increased to 1
When Glyxambi 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 4.4, 4.5 and 4.8).
Patients switching from empagliflozin (either 10 mg or 25 mg daily dose) and linagliptin (5 mg daily dose) to Glyxambi should receive the same daily dose of empagliflozin and linagliptin in the fixed dose combination as in separate tablets. The metformin dose should be continued.
Special populations
Renal impairment
Due to the mechanism of action, decreased renal function will result in reduced glycaemic efficacy of empagliflozin (see sections 4.4 and 5.1).
In patients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 or creatinine clearance (CrCl) ≥60 mL/min, no dose adjustment is required.
In patients with an eGFR <60 mL/min/1.73 m2 or CrCl <60 mL/min, Glyxambi should not be initiated.
In patients tolerating Glyxambi whose eGFR falls persistently below 60 mL/min/1.73 m2 or CrCl below 60 mL/min, the dose of Glyxambi should be adjusted to or maintained at 10 mg empagliflozin plus 5 mg linagliptin once daily.
When eGFR is persistently below 45 mL/min/1.73 m2 or CrCl persistently below 45 mL/min, treatment should be discontinued (see sections 4.4, 4.8, 5.1, and 5.2).
In patients with
Hepatic impairment
No dose adjustment is required in patients with mild to moderate hepatic impairment.
Empagliflozin exposure is increased in patients with severe hepatic impairment and therapeutic experience in such patients is limited (see section 5.2). Therefore, Glyxambi is not recommended for use in this population.
Elderly
No dosage adjustment based on age is required. However, renal function and risk of volume depletion should be taken into account in elderly patients (see sections 4.4 and 4.8). Based on very limited experience in patients 75 years and older, initiation of Glyxambi therapy is not recommended in this population (see sections 4.4 and 5.2).
Paediatric population
Safety and efficacy of Glyxambi in paediatric patients below 18 years of age have not been established. No data are available.
Method of administration
Glyxambi tablets are for oral use and can be taken with or without a meal at any time of the day at regular intervals. The tablets should be swallowed whole with water. If a dose is missed, and it is 12 hours or more until the next dose, the dose should be taken as soon as the patient remembers. The next dose should be taken at the usual time. If a dose is missed, and it is less than 12 hours until the next dose, the dose should be skipped and the next dose should be taken at the usual time. A double dose should not be taken to compensate for a forgotten dose.
4.3Contraindications
Hypersensitivity to the active substances, to any other
4.4Special warnings and precautions for use
Glyxambi should not be used in patients with type 1 diabetes.
Diabetic ketoacidosis (DKA)
Glyxambi should not be used for the treatment of diabetic ketoacidosis.
Rare cases of DKA, including
The risk of DKA must be considered in the event of
In patients where DKA is suspected or diagnosed, treatment with empagliflozin 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 empagliflozin may be restarted once the patient’s condition has stabilised.
Before initiating empagliflozin, 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
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 empagliflozin in patients with type 1 diabetes have not been established and empagliflozin 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.
Use with medicinal products known to cause hypoglycaemia
Empagliflozin and linagliptin as single agents showed an incidence of hypoglycaemia comparable to placebo when used alone or in combination with other antidiabetics not known to cause hypoglycaemia (e.g. metformin, thiazolidinediones). When used in combination with antidiabetics known to cause hypoglycaemia (e.g. sulphonylureas and/or insulin), the incidence of hypoglycaemia
of both agents was increased (see section 4.8).
There are no data about the hypoglycaemic risk of Glyxambi when used with insulin and/or sulphonylurea. However, caution is advised when Glyxambi is used in combination with antidiabetics. A dose reduction of the sulphonylurea or insulin may be considered (see section 4.2 and 4.5).
Acute pancreatitis
Use of a dipeptidyl
If pancreatitis is suspected, Glyxambi should be discontinued; if acute pancreatitis is confirmed, Glyxambi should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Monitoring of renal function
Due to the mechanism of action, the glycaemic efficacy of empagliflozin is dependent on renal function (see sections 4.2, 5.1 and 5.2). Therefore, assessment of renal function is recommended:
prior to Glyxambi initiation and periodically during treatment, i.e. at least yearly,
prior to initiation of any concomitant medicinal product that may have a negative impact on renal function.
Use in patients with renal impairment
In patients with an eGFR below 60 mL/min/1.73 m2 or CrCl <60 mL/min, avoidance, dose adjustment or discontinuation of Glyxambi may be necessary (for details see section 4.2). Glyxambi should be discontinued when eGFR is persistently below 45 mL/min/1.73 m2 or CrCl is persistenly below
45 mL/min. In patients with
Use in patients at risk for volume depletion
Based on the mode of action of SGLT2 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
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 Glyxambi should be considered until the fluid loss is corrected.
Urinary tract infections
In Glyxambi clinical trials, the incidence of urinary tract infections was overall similar between the patients treated with Glyxambi and the patients treated with empagliflozin or linagliptin. The frequencies were comparable to the incidence of urinary tract infections in empagliflozin clinical trials (see section 4.8).
In a pool of
25 mg and placebo and higher in patients treated with empagliflozin 10 mg (see section 4.8). Complicated urinary tract infections (including serious urinary tract infections, pyelonephritis or urosepsis) occurred at a similar frequency in patients treated with empagliflozin compared to placebo.
Pyelonephritis and urosepsis were not reported from the clinical trials in patients treated with Glyxambi. However, temporary interruption of Glyxambi should be considered in patients with complicated urinary tract infections.
Lower limb amputations
An increase in cases of lower limb amputation (primarily of the toe) has been observed in ongoing
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.
Cardiac failure
Experience with empagliflozin in New York Heart Association (NYHA) class
Urine laboratory assessments
Due to the mechanism of action of empagliflozin, patients taking Glyxambi will test positive for glucose in their urine.
Elevated haematocrit
Haematocrit increase was observed with empagliflozin treatment (see section 4.8).
Elderly
A higher risk of volume depletion adverse reactions were reported in patients aged 75 years and older, treated with empagliflozin, especially at 25 mg/day (see section 4.8). Therefore, special attention should be given to their volume intake in case of
Bullous pemphigoid
There have been
4.5Interaction with other medicinal products and other forms of interaction
No drug interaction studies have been performed with Glyxambi and other medicinal products; however, such studies have been conducted with the individual active substances. Based on results of pharmacokinetic studies, no dose adjustment of Glyxambi is recommended when
Pharmacodynamic interactions
Insulin and sulphonylureas
Insulin and sulphonylureas may increase the risk of hypoglycaemia. Therefore, a lower dose of insulin or sulphonylureas may be required to reduce the risk of hypoglycaemia when used in combination with Glyxambi (see sections 4.2, 4.4 and 4.8).
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).
Pharmacokinetic interactions
Effects of other medicinal products on empagliflozin
Empagliflozin is mainly excreted unchanged. A minor fraction is metabolised via uridine 5'- diphosphoglucuronosyltransferases (UGT); therefore, a clinically relevant effect of UGT inhibitors on empagliflozin is not expected (see section 5.2). The effect of UGT induction on empagliflozin has not been studied.
An interaction study with gemfibrozil, an in vitro inhibitor of OAT3 and OATP1B1/1B3 transporters, showed that empagliflozin Cmax 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
Interaction studies 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
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.
Effects of other medicinal products on linagliptin
than 1 % at the therapeutic dose of linagliptin, were increased 4 to
Interaction studies conducted in healthy volunteers suggest that the pharmacokinetics of linagliptin were not influenced by
Effects of linagliptin on other medicinal products
Linagliptin is a weak competitive and a weak to moderate
Linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin, empagliflozin or oral contraceptives providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8,
4.6Fertility, pregnancy and lactation
The effects of Glyxambi on pregnancy,
Pregnancy
There are no data from the use of empagliflozin and linagliptin in pregnant women.
Animal studies show that empagliflozin and linagliptin cross the placenta during late gestation, but do not indicate direct or indirect harmful effects with respect to early embryonic development with either empagliflozin or linagliptin (see section 5.3). Animal studies with empagliflozin have shown adverse effects on postnatal development (see section 5.3). As a precautionary measure it is preferable to avoid the use of Glyxambi during pregnancy.
No data in humans are available on excretion of empagliflozin and linagliptin into milk. Available
Fertility
No studies on the effect on human fertility have been conducted with Glyxambi or with the individual active substances.
4.7Effects on ability to drive and use machines
Glyxambi 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 Glyxambi is used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. insulin and analogues, sulphonylureas).
4.8Undesirable effects
Summary of the safety profile
The most frequent adverse reaction was urinary tract infection (7.5 % with Glyxambi 10 mg empagliflozin / 5 mg linagliptin and 8.5 % with Glyxambi 25 mg empagliflozin / 5 mg linagliptin) (see Description of selected adverse reactions). The most serious adverse reactions were ketoacidosis
(< 0.1%), pancreatitis (0.2%), hypersensitivity (0.6%), and hypoglycaemia (2.4%) (see section 4.4).
Overall, the safety profile of Glyxambi was in line with the safety profiles of the individual active substances (empagliflozin and linagliptin). No additional adverse reactions were identified with Glyxambi.
The adverse reactions shown in the table below (see Table 1) are listed by system organ class and are based on the safety profiles of empagliflozin and linagliptin monotherapy. The information about adverse reactions not reported in Glyxambi clinical trials is based on the experience from empagliflozin and linagliptin. Adverse reactions marked with an asterisk (*) are further discussed in section “Description of selected adverse reactions” below.
Tabulated list of adverse reactions
Frequency categories 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), very rare (< 1/10,000) and not known (cannot be estimated from the available data).
Table 1 | Adverse reactions |
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System organ class | Frequency | Adverse reaction | |
Infections and infestations | Common | Urinary tract infection1,* | |
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| Common | Vaginal moniliasis, vulvovaginitis, |
|
|
| balanitis and other genital infections1,* |
|
| Common | Nasopharyngitis2 |
Immune system disorders | Uncommon | Hypersensitivity2 | |
|
| Uncommon | Angioedema3, urticaria3,4 |
Metabolism and nutrition | Common | Hypoglycaemia (when used with | |
disorders |
|
| sulphonylurea or insulin)* |
|
| Common | Thirst |
|
| Rare | Diabetic ketoacidosis4,# |
Respiratory, thoracic and | Common | Cough2 | |
mediastinal disorders |
|
| |
Gastrointestinal disorders | Uncommon | Pancreatitis2 | |
|
| Rare | Mouth ulceration3 |
Skin and subcutaneous tissue | Common | Pruritus1 | |
disorders |
| Common | Rash3,4 |
|
| Not known | Bullous pemphigoid3 |
Vascular disorders | Uncommon | Volume depletion1,* | |
Renal and urinary disorders | Common | Increased urination1,* | |
|
| Uncommon | Dysuria1 |
Investigations | Common | Increased amylase2 | |
|
| Common | Lipase increased2 |
|
| Uncommon | Haematocrit increased1,5 |
|
| Uncommon | Serum lipids increased1,6 |
|
| Uncommon | Blood creatinine increased/Glomerular |
|
|
| filtration rate decreased1,* |
1derived from empagliflozin experiences
2derived from linagliptin experiences
3derived from linagliptin postmarketing experience
4derived from empagliflozin postmarketing experience
5Mean changes from baseline in haematocrit were 3.3% and 4.2% for Glyxambi 10 mg/5 mg and 25 mg/5 mg, respectively, compared to 0.2% for placebo. In a clinical trial with empagliflozin, haematocrit values returned towards baseline values after a
6Mean percent increases from baseline for Glyxambi 10 mg/5 mg and 25 mg/5 mg versus placebo, respectively, were total cholesterol 3.2% and 4.6% versus 0.5%;
versus 3.3%; triglycerides
# see section 4.4
Description of selected adverse reactions
Hypoglycaemia
In pooled clinical trials of Glyxambi in patients with type 2 diabetes and inadequate glycaemic control on background metformin, the frequency of the reported hypoglycaemic events was 2.4 %. The incidence of confirmed hypoglycaemic events was low (< 1,5 %). There was no notable difference of the incidence in patients treated with different dose strengths of Glyxambi compared to the treatment with empagliflozin or linagliptin.
One patient administered Glyxambi experienced a confirmed
Based on the experience with empagliflozin and linagliptin, an increase of the risk of hypoglycaemia is expected with the concomitant treatment of insulin and /or sulphonylurea (see section 4.4 and information below)
Hypoglycaemia with empagliflozin
The frequency of hypoglycaemia depended on the background therapy in the respective studies and was similar for empagliflozin and placebo as monotherapy, as
25 mg: 28.4 %, placebo: 20.6 % during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg and 25 mg: 36.1 %, placebo 35.3 % over the 78 week trial), and
Major hypoglycaemia with empagliflozin (events requiring assistance)
The frequency of patients with major hypoglycaemic events was low (< 1 %) and similar for empagliflozin and placebo as monotherapy, as
The frequency of patients with major hypoglycaemic events was increased in patients treated with empagliflozin compared to placebo when given as
Hypoglycaemia with linagliptin
The most frequently reported adverse event in clinical trials with linagliptin was hypoglycaemia observed under the triple combination, linagliptin plus metformin plus sulphonylurea (22.9 % vs 14.8 % in placebo).
Hypoglycaemias in the
Urinary tract infection
In clinical trials with Glyxambi, there was no notable difference of the frequency of urinary tract infections in patients treated with Glyxambi (Glyxambi 25 mg/5 mg: 8.5 %; Glyxambi 10 mg/5 mg: 7.5 %) compared to the patients treated with empagliflozin and linagliptin. The frequencies have been comparable to those reported from the empagliflozin clinical trials (see also section 4.4).
In empagliflozin trials, the overall frequency of urinary tract infection was similar in patients treated with empagliflozin 25 mg and placebo (7.0 % and 7.2 %), and higher in patients treated with empagliflozin 10 mg (8.8 %). 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 of urinary tract infections was similar to placebo for mild, moderate and severe intensity reports. Urinary tract infection was reported more frequently in female patients treated with empagliflozin compared to placebo, but not in male patients.
Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection
In clinical trials with Glyxambi, genital infections in patients treated with Glyxambi (Glyxambi
25 mg/5 mg: 3.0 %; Glyxambi 10 mg/5 mg: 2.5 %) were reported more frequently than for linagliptin but less freqeuntly than for empagliflozin. Overall, the frequencies for Glyxambi have been comparable to those reported from the empagliflozin clinical trials.
In empagliflozin trials, vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently for empagliflozin 10 mg (4.0 %) and empagliflozin 25 mg (3.9 %) compared to placebo (1.0 %). These infections were reported more frequently for empagliflozin compared to placebo in female patients, and the difference in frequency was less pronounced in male patients. The genital tract infections were mild and moderate in intensity, none was severe in intensity.
Increased urination
In clinical trials with Glyxambi, increased urination in patients treated with Glyxambi (Glyxambi
25 mg/5 mg: 2.6 %; Glyxambi 10 mg/5 mg: 1.4 %) was reported more frequently than for linagliptin and with similar frequency than for empagliflozin. Overall, the frequencies for Glyxambi have been comparable to those reported from the empagliflozin clinical trials.
In clinical trials with empagliflozin, increased urination (including the predefined terms pollakiuria, polyuria, nocturia) was observed at higher frequencies in patients treated with empagliflozin (empagliflozin 10 mg: 3.5 %, empagliflozin 25 mg: 3.3 %) compared to placebo (1.4 %). Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was comparable between placebo and empagliflozin (< 1 %).
Volume depletion
In clinical trials with Glyxambi, there was no notable difference in the frequency of volume depletion in patients treated with Glyxambi (Glyxambi 25 mg/5 mg: 0.4 %; Glyxambi 10 mg/5 mg: 0.8 %) compared to the patients treated with empagliflozin and linagliptin. The frequencies have been comparable to those reported from the empagliflozin clinical trials.

In clinical trials with empagliflozin, 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: 0.6 %, empagliflozin 25 mg: 0.4 %) 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 (4.3 %) compared to placebo (2.1 %).
Blood creatinine increased/Glomerular filtration rate decreased
In clinical trials with Glyxambi, the frequency of patients with increased blood creatinine (Glyxambi 25 mg/5 mg: 0.4%; Glyxambi 10 mg/5 mg: 0%) and decreased glomerular filtration rate (Glyxambi 25 mg/5 mg: 0.4%; Glyxambi 10 mg/5 mg: 0.6%) has been comparable to those reported from the empagliflozin clinical trials.
The overall frequency of patients with increased blood creatinine and decreased glomerular filtration rate were similar between empagliflozin and placebo (blood creatinine increased: empagliflozin 10 mg 0.6%, empagliflozin 25 mg 0.1%, placebo 0.5%; glomerular filtration rate decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.3%).
Elderly
In clinical trials, nineteen patients 75 years or older were treated with Glyxambi. No patient was older than 85 years. The safety profile of Glyxambi did not differ in the elderly. Based on empagliflozin experiences, elderly patients may be at increased risk of volume depletion (see sections 4.2, 4.4 and 5.2)
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 the national reporting system listed in Appendix V.
4.9Overdose
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
During controlled clinical trials in healthy subjects, single doses of up to 600 mg linagliptin (equivalent to 120 times the recommended dose) were generally well tolerated. There is no experience with doses above 600 mg in humans.
Treatment
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring and institute clinical measures as required.
The removal of empagliflozin by haemodialysis has not been studied. Linagliptin is not expected to be eliminated to a therapeutically significant degree by haemodialysis or peritoneal dialysis.
5.PHARMACOLOGICAL PROPERTIES
5.1Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering drugs, ATC code: A10BD19
Mechanism of action
Glyxambi combines two antihyperglycaemic medicinal products with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: empagliflozin, a
Empagliflozin
Empagliflozin is a reversible, highly potent (IC50 of 1.3 nmol) and selective competitive inhibitor of SGLT2. Empagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is 5,000 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 mellitus by reducing renal glucose
In patients with type 2 diabetes, urinary glucose excretion increased immediately following the first dose of empagliflozin and was continuous over the
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 diuresis which may contribute to sustained and moderate reduction of blood pressure. The glucosuria, natriuresis and osmotic diuresis observed with empagliflozin may contribute to the improvement in cardiovascular outcomes.
Linagliptin
Linagliptin is an inhibitor of the enzyme
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reversible manner and thus leads to a sustained increase and a prolongation of active incretin levels. Linagliptin
Clinical efficacy and safety
A total of 2,173 patients with type 2 diabetes mellitus and inadequate glycaemic control were treated in clinical studies to evaluate the safety and efficacy of Glyxambi; 1,005 patients were treated with Glyxambi 10 mg empagliflozin/5 mg linagliptin or 25 mg empagliflozin/5 mg linagliptin. In clinical trials, patients were treated for up to 24 or 52 weeks.
Glyxambi added to metformin
In a factorial design study patients inadequately controlled on metformin were treated for
Table 2 Efficacy parameters in clinical study comparing Glyxambi to individual active substances as
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| Glyxambi | Glyxambi | Empagliflozin | Empagliflozin | Linagliptin |
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| 25 mg / 5 mg | 10 mg / 5 mg | 25 mg | 10 mg | 5 mg |
Primary endpoint: HbA1c ( %) – 24 weeks |
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Number of patients analysed | ||||||
Baseline mean (SE) | 7.90 (0.07) | 7.95 (0.07) | 8.02 (0.07) | 8.00 (0.08) | 8.02 (0.08) | |
Change from baseline at |
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week 241: | ||||||
- | adjusted mean2 (SE) | |||||
Comparison vs. empagliflozin1: | vs. 25 mg | vs. 10 mg | ||||
- | adjusted mean2 (SE) |
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- | 95.0 % CI |
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- | <0.0001 | <0.0001 |
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Comparison vs. linagliptin 5 mg1: |
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- | adjusted mean2 (SE) |
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- | 95.0 % CI |
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- | <0.0001 | <0.0001 |
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Last observation (prior to glycaemic rescue ) carried forward (LOCF) Mean adjusted for baseline value and stratification
In a
Overall, the effects on HbA1c reduction observed at 24 weeks were sustained at week 52.
Empagliflozin in patients inadequately controlled on metformin and linagliptin
In patients inadequately controlled on maximally tolerated doses of metformin, open label linagliptin 5 mg was added for 16 weeks. In patients inadequately controlled after this 16 week period, patients received
placebo; all patients continued treatment with metformin and linagliptin 5 mg during the study. A statistically significant greater number of patients with a baseline HbA1c ≥7.0 % treated with both doses of empagliflozin achieved a target HbA1c of <7 % compared to placebo (see Table 3). After
and
After 24 weeks, rescue therapy was used in 4 (3.6 %) patients treated with empagliflozin 25 mg and in 2 (1.8 %) patients treated with empagliflozin 10 mg, compared to 13 (12.0 %) patients treated with placebo (all patients on background metformin + linagliptin 5 mg).
Table 3 | Efficacy parameters in the clinical study comparing empagliflozin to placebo as | ||||
| therapy in patients inadequately controlled on metformin and linagliptin 5 mg | ||||
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| Metformin + linagliptin 5 mg |
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| Empagliflozin 10 mg1 | Empagliflozin 25 mg1 | Placebo2 | |
HbA1c ( %) - 24 weeks3 |
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|
| ||
N |
| ||||
Baseline (mean) | 7.97 | 7.97 | 7.96 | ||
Change from baseline | 0.14 | ||||
(adjusted mean) | |||||
|
|
| |||
Comparison vs. placebo |
| ||||
(adjusted mean) |
| ||||
(95 % CI)2 |
| p<0.0001 | p<0.0001 |
| |
Body |
|
|
| ||
N |
| ||||
Baseline (mean) in kg | 88.4 | 84.4 | 82.3 | ||
Change from baseline (adjusted | |||||
mean) |
|
|
|
| |
Comparison vs. placebo |
| ||||
(adjusted mean) (95 % CI)1 |
| ||||
|
| p<0.0001 | p<0.0001 |
| |
Patients ( %) achieving HbA1c |
|
|
| ||
<7 % with baseline HbA1c |
|
|
| ||
≥7 % - 24 weeks4 |
|
|
| ||
N |
| ||||
Patients ( %) achieving A1C | 37.0 | 32.7 | 17.0 | ||
<7 % |
| ||||
|
|
|
| ||
Comparison vs. placebo (odds | 4.0 | 2.9 |
| ||
ratio) (95 % CI)5 | (1.9, 8.7) | (1.4, 6.1) |
| ||
|
|
|
|
|
1Patients randomized to the empagliflozin 10 mg or 25 mg groups were receiving Glyxambi 10 mg/5 mg or 25 mg/5 mg with background metformin
2Patients randomized to the placebo group were receiving the placebo plus linagliptin 5 mg with background metformin
3
4Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints
5Logistic regression on FAS (NCF) includes baseline HbA1c, baseline eGFR (MDRD), geographical region, and treatment; based on patients with HbA1c of 7 % and above at baseline
In a
Linagliptin 5 mg in patients inadequately controlled on metformin and empagliflozin 10 mg or empagliflozin 25 mg
In patients inadequately controlled on maximally tolerated doses of metformin, open label empagliflozin 10 mg or empagliflozin 25 mg was added for 16 weeks. In patients inadequately controlled after this 16 week period, patients received
Table 4 Efficacy parameters in clinical studies comparing Glyxambi 10 mg/5 mg to empagliflozin 10 mg as well as Glyxambi 25 mg/5 mg to empagliflozin 25 mg as
| Metformin + |
| Metformin + |
| ||
| empagliflozin 10 mg | empagliflozin 25 mg | ||||
| Linagliptin 5 mg |
| Placebo | Linagliptin 5 mg |
| Placebo |
HbA1c ( %) – 24 weeks1 |
|
|
|
|
|
|
N |
|
| ||||
Baseline (mean) | 8.04 |
| 8.03 | 7.82 |
| 7.88 |
Change from baseline |
|
| ||||
(adjusted mean) |
|
| ||||
|
|
|
|
|
| |
Comparison vs. placebo (adjusted |
|
|
|
| ||
mean) (95 % CI) | p=0.0013 |
|
| p<0.0001 |
|
|
Patients ( %) achieving HbA1c |
|
|
|
|
|
|
<7 % with baseline HbA1c ≥7 % – |
|
|
|
|
|
|
24 weeks2 |
|
|
|
|
|
|
N |
|
| ||||
Patients ( %) achieving HbA1c <7 % | 25.9 |
| 10.9 | 36.0 |
| 15.0 |
Comparison vs. placebo (odds ratio) | 3.965 (1.771, |
|
| 4.429 (2.097, 9.353) |
|
|
(95 % CI)3 | 8.876) |
|
| p<0.0001 |
|
|
| p=0.0008 |
|
|
|
|
|
Patients randomized to the linagliptin 5 mg group were receiving either fixed dose combination tablets Glyxambi 10 mg/5 mg plus metformin or fixed dose combination tablets Glyxambi 25 mg/5 mg plus metformin; patients randomized to the placebo group were receiving placebo plus empagliflozin 10 mg plus metformin or placebo plus empagliflozin 25 mg plus metformin
1MMRM model on FAS (OC) includes baseline HbA1c, baseline eGFR (MDRD), geographical region, visit, treatment, and treatment by visit interaction. For FPG, baseline FPG is also included.
2Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints
3Logistic regression on FAS (NCF) includes baseline HbA1c, baseline eGFR (MDRD), geographical region, and treatment; based on patients with HbA1c of 7 % and above at baseline
Cardiovascular safety
The
(empagliflozin 10 mg: 2345, empagliflozin 25 mg: 2342, placebo: 2333) and followed for a median of 3.1 years. The mean age was 63 years, the mean HbA1c was 8.1 %, and 71.5 % were male. At baseline, 74 % of patients were being treated with metformin, 48 % with insulin, and 43 % with a sulfonylurea. About half of the patients (52.2 %) had an eGFR of
At week 12, an adjusted mean (SE) improvement in HbA1c when compared to baseline of 0.11 % (0.02) in the placebo group, 0.65 % (0.02) and 0.71 % (0.02) in the empagliflozin 10 and 25 mg groups was observed. After the first 12 weeks glycaemic control was optimized independent of investigative treatment. Therefore the effect was attenuated at week 94, with an adjusted mean (SE)
improvement in HbA1c of 0.08 % (0.02) in the placebo group, 0.50 % (0.02) and 0.55 % (0.02) in the empagliflozin 10 and 25 mg groups.
Empagliflozin was superior in reducing the primary combined endpoint of cardiovascular death, nonfatal myocardial infarction, or
Table 5 Treatment effect for the primary composite endpoint, its components and mortalitya
| Placebo | Empagliflozinb | |
N | |||
Time to first event of CV death, | 282 (12.1) | 490 (10.5) | |
or | |||
|
| ||
Hazard ratio vs. placebo (95.02% CI)* |
| 0.86 (0.74, 0.99) | |
p−value for superiority |
| 0.0382 | |
CV Death N (%) | 137 (5.9) | 172 (3.7) | |
Hazard ratio vs. placebo (95% CI) |
| 0.62 (0.49, 0.77) | |
| <0.0001 | ||
121 (5.2) | 213 (4.5) | ||
Hazard ratio vs. placebo (95% CI) |
| 0.87 (0.70, 1.09) | |
p−value |
| 0.2189 | |
60 (2.6) | 150 (3.2) | ||
Hazard ratio vs. placebo (95% CI) |
| 1.24 (0.92, 1.67) | |
p−value |
| 0.1638 | |
194 (8.3) | 269 (5.7) | ||
Hazard ratio vs. placebo (95% CI) |
| 0.68 (0.57, 0.82) | |
| <0.0001 | ||
57 (2.4) | 97 (2.1) | ||
Hazard ratio vs. placebo (95% CI) |
| 0.84 (0.60, 1.16) | |
CV = cardiovascular, MI = myocardial infarction |
|
|
aTreated set (TS), i.e. patients who had received at least one dose of study drug
bPooled doses of empagliflozin 10 mg and 25 mg
* Since data from the trial were included in an interim analysis, a
In a prospective,
The efficacy for preventing cardiovascular mortality has not been conclusively established in users of
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Glyxambi in all subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use).
5.2Pharmacokinetic properties
The rate and extent of absorption of empagliflozin and linagliptin in Glyxambi are equivalent to the bioavailability of empagliflozin and linagliptin when administered as individual tablets.The pharmacokinetics of empagliflozin and linagliptin as single agents have been extensively characterized in healthy subjects and patients with type 2 diabetes. Pharmacokinetics were generally similar in healthy subjects and in patients with type 2 diabetes.
Glyxambi showed a similar food effect as the individual active substances. Glyxambi can therefore be
taken with or without food.
Empagliflozin
Absorption
After oral administration, empagliflozin was rapidly absorbed with peak plasma concentrations occurring at a median tmax of 1.5 hours post dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady state mean plasma area under the
259 nmol/L with empagliflozin 10 mg and 4,740 nmol.h and 687 nmol/L with empagliflozin 25 mg once daily. Systemic exposure of empagliflozin increased in a dose proportional manner. The single dose and steady state pharmacokinetic parameters of empagliflozin were similar suggesting linear pharmacokinetics with respect to time.
Administration of empagliflozin 25 mg after intake of a
Distribution
The apparent
Biotransformation
No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates
Elimination
Based on the population pharmacokinetic analysis, the apparent terminal elimination half life of empagliflozin was estimated to be 12.4 hours and apparent oral clearance was 10.6 L/hour. The inter subject and residual variabilities for empagliflozin oral clearance were 39.1 % and 35.8 %, respectively. With once daily dosing, steady state plasma concentrations of empagliflozin were reached by the fifth dose. Consistent with the half life, up to 22 % accumulation, with respect to plasma AUC, was observed at steady state.
Following administration of an oral
Linagliptin
Absorption
After oral administration of a 5 mg dose to healthy volunteers or patients, linagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1.5 hours
After once daily dosing of 5 mg linagliptin,
compared to the first dose. The
The absolute bioavailability of linagliptin is approximately 30 %.
The steady state plasma AUCτ,ss and Cmax,ss concentrations of linagliptin were 153 nmol*hr/L and 12.9 nmol/L for linagliptin 5 mg once daily for 7 days.
Distribution
As a result of tissue binding, the mean apparent volume of distribution at
Biotransformation
Following a [14C] linagliptin oral 10 mg dose, approximately 5 % of the radioactivity was excreted in urine. Metabolism plays a subordinate role in the elimination of linagliptin. One main metabolite with a relative exposure of 13.3 % of linagliptin at
Elimination
Plasma concentrations of linagliptin decline in a triphasic manner with a long terminal
Following administration of an oral [14C] linagliptin dose to healthy subjects, approximately 85 % of the administered radioactivity was eliminated in faeces (80 %) or urine (5 %) within 4 days of dosing. Renal clearance at
Renal impairment
Empagliflozin
In patients with mild, moderate or severe renal impairment (eGFR <30 to <90 mL/min/1.73 m2) and patients with kidney failure or end stage renal disease (ESRD), AUC of empagliflozin increased by approximately 18 %, 20 %, 66 %, and 48 %, respectively compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in subjects with moderate renal impairment and kidney failure/ESRD compared to patients with normal renal function. Peak plasma levels of empagliflozin were roughly 20 % higher in subjects with mild and severe renal impairment as compared to subjects with normal renal function. The population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased with a decrease in eGFR leading to an increase in drug exposure (see section 4.2).
Linagliptin
A
Under
Hepatic impairment
Empagliflozin
In patients with mild, moderate and severe hepatic insufficiency
AUC and Cmax of empagliflozin increased (AUC by 23 %, 47 %, 75 % and Cmax by 4 %, 23 %,48 %) compared to subjects with normal hepatic function (see section 4.2).
Linagliptin
In
Body mass index
No dosage adjustment is necessary for Glyxambi based on body mass index. Body mass index had no clinically relevant effect on the pharmacokinetics of empagliflozin or linagliptin based on population pharmacokinetic analysis.
Gender
Gender had no clinically relevant effect on the pharmacokinetics of empagliflozin or linagliptin based on population pharmacokinetic analysis.
Race
No clinically relevant difference in pharmacokinetics of empagliflozin and linagliptin were seen in population pharmacokinetic analysis and dedicated phase I studies.
Elderly
Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin or linagliptin based on population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had comparable plasma concentrations of linagliptin compared to younger subjects.
Paediatric patients
Empagliflozin
A paediatric Phase 1 study examined the pharmacokinetics and pharmacodynamics of empagliflozin (5 mg, 10 mg and 25 mg) in children and adolescents ≥10 to <18 years of age with type 2 diabetes mellitus. The observed pharmacokinetic and pharmacodynamic responses were consistent with those
found in adult subjects.
Linagliptin
A paediatric Phase 2 study examined the pharmacokinetics and pharmacodynamics of 1 mg and 5 mg linagliptin in children and adolescents ≥10 to <18 years of age with type 2 diabetes mellitus. The observed pharmacokinetic and pharmacodynamic responses were consistent with those found in adult subjects. Linagliptin 5 mg showed superiority over 1 mg with regard to trough
Drug interactions
No drug interaction studies have been performed with Glyxambi and other medicinal products; however, such studies have been conducted with the individual active substances.
In vitro assessment of empagliflozin
Based on in vitro studies, empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7.
In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by uridine
Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not Organic Anion Transporter 1 (OAT1) and Organic Cation Transporter 2 (OCT2). Empagliflozin is a substrate of
Empagliflozin does not inhibit
Empagliflozin does not inhibit human uptake transporters such as OAT3, OATP1B1, and OATP1B3 in vitro at clinically relevant plasma concentrations and, as such,
In vitro assessment of linagliptin
Linagliptin was a substrate for
5.3Preclinical safety data
General toxicity studies in rats up to 13 weeks were performed with the combination of empagliflozin and linagliptin.
Focal areas of hepatocellular necrosis were found in the combination groups at ≥15: 30 mg/kg linagliptin: empagliflozin (3.8 times the clinical exposure for linagliptin and 7.8 times the clinical exposure for empagliflozin) as well as in the group treated with empagliflozin alone but not in the control group. The clinical relevance of this finding remains uncertain.
At exposures sufficiently in excess of exposure in humans after therapeutic doses, the combination of empagliflozin and linagliptin was not teratogenic and did not show maternal toxicity. Adverse effects
on renal development were not observed after administration of empagliflozin alone, linagliptin alone or after administration of the combined products.
Empagliflozin
Non clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, fertility and early embryonic development.
In
In a 2 year carcinogenicity study, empagliflozin did not increase the incidence of tumours in female rats up to the highest dose of 700 mg/kg/day, which corresponds to approximately 72 times the maximal clinical AUC exposure to empagliflozin. In male rats, treatment related benign vascular proliferative lesions (haemangiomas) of the mesenteric lymph node were observed at the highest dose, but not at 300 mg/kg/day, which corresponds to approximately 26 times the maximal clinical exposure to empagliflozin. Interstitial cell tumours in the testes were observed with a higher incidence in rats at 300 mg/kg/day and above, but not at 100 mg/kg/day which corresponds to approximately 18 times the maximal clinical exposure to empagliflozin. Both tumours are common in rats and are unlikely to be relevant to humans.
Empagliflozin did not increase the incidence of tumours in female mice at doses up to
1,000 mg/kg/day, which corresponds to approximately
empagliflozin. The mode of action for these tumours is dependent on the natural predisposition of the male mouse to renal pathology and a metabolic pathway not reflective of humans. The male mouse renal tumours are considered not relevant to humans.
At exposures sufficiently in excess of exposure in humans after therapeutic doses, empagliflozin had no adverse effects on fertility or early embryonic development. Empagliflozin administered during the period of organogenesis was not teratogenic. Only at maternally toxic doses, empagliflozin also caused bent limb bones in the rat and increased embryofetal loss in the rabbit.
In pre- and postnatal toxicity studies with empagliflozin in rats, reduced weight gain in offspring was observed at maternal exposures approximately 4 times the maximal clinical exposure to empagliflozin. No such effect was seen at systemic exposure equal to the maximal clinical exposure to empagliflozin. The relevance of this finding to humans is unclear.
In a juvenile toxicity study in the rat, when empagliflozin was administered from postnatal day 21 until postnatal day 90,
Linagliptin
Non clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, fertility and early embryonic development.
In
Liver, kidneys and gastrointestinal tract are the principal target organs of toxicity in mice and rats. At exposures greater than
Liver, kidneys, stomach, reproductive organs, thymus, spleen, and lymph nodes were target organs of toxicity in Cynomolgus monkeys at more than
Oral
Linagliptin had no adverse effects on fertility or early embryonic development at exposures greater than
In the pre- and postnatal toxicity study with linagliptin in rats, reduced weight gain in offspring was observed at maternal exposures approximately
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
Glyxambi 10 mg/5 mg
Tablet core
Mannitol (E421)
Maize starch
Copovidone
Crospovidone (Type B)
Talc
Magnesium stearate
Film coating
Hypromellose 2910
Mannitol (E421)
Talc
Titanium dioxide (E171)
Macrogol 6000
Iron oxide yellow (E172)
Glyxambi 25 mg/5 mg
Tablet core
Mannitol (E421)
Maize starch
Copovidone
Crospovidone (Type B)
Talc
Magnesium stearate
Film coating
Hypromellose 2910
Mannitol (E421)
Talc
Titanium dioxide (E171)
Macrogol 6000
Iron oxide red (E172)
6.2Incompatibilities
Not applicable.
6.3Shelf life
3 years.
6.4Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5Nature and contents of container
PVC/PVDC/aluminium perforated unit dose blisters.
Pack sizes of 7 x 1, 10 x 1, 14 x 1, 28 x 1, 30 x 1, 60 x 1, 70 x 1, 90 x 1 and 100 x 1
Not all pack sizes may be marketed.
6.6Special precautions for disposal
No special requirements for disposal.
7.MARKETING AUTHORISATION HOLDER
Boehringer Ingelheim International GmbH
Binger Str. 173
Germany
8.MARKETING AUTHORISATION NUMBERS
Glyxambi 10 mg/5 mg
EU/1/16/1146/001 (7 x 1
EU/1/16/1146/002 (10 x 1
EU/1/16/1146/003 (14 x 1
EU/1/16/1146/004 (28 x 1
EU/1/16/1146/005 (30 x 1
EU/1/16/1146/006 (60 x 1
EU/1/16/1146/007 (70 x 1
EU/1/16/1146/008 (90 x 1
EU/1/16/1146/009 (100 x 1

Glyxambi 25 mg/5 mg
EU/1/16/1146/010 (7 x 1
EU/1/16/1146/011 (10 x 1
EU/1/16/1146/012 (14 x 1
EU/1/16/1146/013 (28 x 1
EU/1/16/1146/014 (30 x 1
EU/1/16/1146/015 (60 x 1
EU/1/16/1146/016 (70 x 1
EU/1/16/1146/017 (90 x 1
EU/1/16/1146/018 (100 x 1
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: {DD month YYYY}
- Lyxumia
- Pergoveris
- Aldara
- Pecfent
- Duloxetine lilly
- Temozolomide sun
Prescription drugs listed:
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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