Bydureon - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 2 mg of exenatide.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for prolonged-release suspension for injection.

Powder: white to off-white powder.

Solvent: clear, colourless to pale yellow to pale brown solution.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Bydureon is indicated in adults 18 years and older with type 2 diabetes mellitus to improve glycaemic control in combination with other glucose-lowering medicinal products including basal insulin, when the therapy in use, together with diet and exercise, does not provide adequate glycaemic control.

For study results with respect to combinations, effects on glycaemic control and cardiovascular events, and the populations studied, see sections 4.4, 4.5, and 5.1.

4.2 Posology and method of administration

Posology

The recommended dose is 2 mg exenatide once weekly.

Patients switching from immediate-release (Byetta) to prolonged-release (Bydureon or Bydureon BCise) exenatide, may experience transient elevations in blood glucose concentrations, which generally improve within the first two weeks after initiation of therapy. Patients switching between the prolonged-release exenatide products (Bydureon or Bydureon BCise) may do so, with no expected relevant effect on blood glucose concentrations.

When prolonged-release exenatide is added to existing metformin and/or thiazolidinedione therapy, the current dose of metformin and/or thiazolidinedione can be continued. When added to sulphonylurea therapy, a reduction in the dose of sulphonylurea should be considered to reduce the risk of hypoglycaemia (see section 4.4).

Prolonged-release exenatide should be administered once a week on the same day each week. The day of weekly administration can be changed if necessary as long as the last dose was administered at least three days before. Prolonged-release exenatide can be administered at any time of day, with or without meals.

If a dose is missed, it should be administered as soon as practical, provided the next regularly scheduled dose is due in 3 days or more. Thereafter, patients can resume their usual once weekly dosing schedule.

If a dose is missed and the next regularly scheduled dose is due 1 or 2 days later, the patient should not administer the missed dose, but instead resume prolonged-release exenatide on the next regularly scheduled dosing day.

The use of prolonged-release exenatide does not require additional self-monitoring. Blood glucose self-monitoring is necessary to adjust the dose of sulphonylurea and of insulin, particularly when prolonged-release exenatide therapy is started and insulin is reduced. A stepwise approach to insulin dose reduction is recommended.

If a different glucose-lowering treatment is started after the discontinuation of prolonged-release exenatide, consideration should be given to the prolonged release of the medicinal product (see section 5.2).

Special populations

Elderly

No dose adjustment is required based on age. However, as renal function generally declines with age, consideration should be given to the patient’s renal function (see Renal impairment ) (see section 5.2).

Renal impairment

No dose adjustment is necessary for patients with mild or moderate renal impairment.

Prolonged-release exenatide is not recommended for use in patients with end-stage renal disease or severe renal impairment (glomerular filtration rate [GFR] < 30 mL/min) (see section 4.4).

Hepatic impairment

No dose adjustment is necessary for patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of prolonged-release exenatide in children and adolescents aged under

18 years have not yet been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Method of administration

Subcutaneous use

Prolonged-release exenatide is for self-administration by the patient. Each kit should be used by one person only and is for single use.

Prior to initiation of prolonged-release exenatide, it is strongly recommended that patients and caregivers be trained by their healthcare professional. The “Instructions for the User”, provided in the carton, must be followed carefully.

Each dose should be administered in the abdomen, thigh, or the back of the upper arm as a subcutaneous injection immediately after suspension of the powder in the solvent.

When used with insulin, prolonged-release exenatide and insulin must be administered as two separate injections.

For instructions on the suspension of the medicinal product before administration, see section 6.6 and the “Instructions for the User”.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Prolonged-release exenatide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Prolonged-release exenatide is not a substitute for insulin. Diabetic ketoacidosis has been reported in insulin-dependent patients after rapid discontinuation or dose reduction of insulin (see section 4.2).

Prolonged-release exenatide must not be administered by intravenous or intramuscular injection.

Renal impairment

In patients with end-stage renal disease receiving dialysis, single doses of immediate-release exenatide increased frequency and severity of gastrointestinal adverse reactions; therefore, prolonged-release exenatide is not recommended for use in patients with end-stage renal disease or severe renal impairment (GFR < 30 mL/min).

There have been uncommon events of altered renal function with exenatide, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring haemodialysis. Some of these events occurred in patients experiencing events that may affect hydration, including nausea, vomiting, and/or diarrhoea and/or receiving medicinal products known to affect renal function/hydration status. Concomitant medicinal products included angiotensin converting enzymes inhibitors, angiotensin-II antagonists, non-steroidal anti-inflammatory medicinal products and diuretics. Reversibility of altered renal function has been observed with supportive treatment and discontinuation of potentially causative medicinal products, including exenatide.

Severe gastrointestinal disease

Prolonged-release exenatide has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Its use is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhoea. Therefore, the use of prolonged-release exenatide is not recommended in patients with severe gastrointestinal disease.

Acute pancreatitis

Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. In clinical studies of prolonged-release exenatide, acute pancreatitis occurred in 0.3% of patients. There have been spontaneously reported events of acute pancreatitis with prolonged-release exenatide. Resolution of pancreatitis has been observed with supportive treatment, but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, prolonged-release exenatide should be discontinued; if acute pancreatitis is confirmed, prolonged-release exenatide should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

Concomitant medicinal products

The concurrent use of prolonged-release exenatide with D-phenylalanine derivatives (meglitinides), alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors or other GLP-1 receptor agonists has not been studied. The concurrent use of prolonged-release and immediate-release exenatide has not been studied and is not recommended.

Interaction with warfarin

There have been spontaneously reported cases of increased INR (International Normalised Ratio), sometimes associated with bleeding, with concomitant use of warfarin and exenatide (see section 4.5).

Hypoglycaemia

The risk of hypoglycaemia was increased when prolonged-release exenatide was used in combination with a sulphonylurea in clinical studies. Furthermore, in the clinical studies, patients on a sulphonylurea combination, with mild renal impairment had an increased incidence of hypoglycaemia compared to patients with normal renal function. To reduce the risk of hypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylurea should be considered.

Rapid weight loss

Rapid weight loss at a rate of > 1.5 kg per week has been reported in patients treated with exenatide. Weight loss of this rate may have harmful consequences. Patients with rapid weight loss should be monitored for signs and symptoms of cholelithiasis.

Discontinuation of treatment

After discontinuation, the effect of prolonged-release exenatide may continue as plasma levels of exenatide decline over 10 weeks. Choice of other medicinal products and dose selection should be considered accordingly, as adverse reactions may continue and efficacy may, at least partly, persist until exenatide levels decline.

Excipients

Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

4.5 Interaction with other medicinal products and other forms of interaction

Sulphonylureas

The dose of a sulphonylurea may require adjustment due to the increased risk of hypoglycaemia associated with sulphonylurea therapy (see sections 4.2 and 4.4).

Gastric emptying

The results of a study using paracetamol as a marker of gastric emptying suggest that the effect of prolonged-release exenatide to slow gastric emptying is minor and not expected to cause clinically significant reductions in the rate and extent of absorption of concomitantly administered oral medicinal products. Therefore, no dose adjustments for medicinal products sensitive to delayed gastric emptying are required.

When 1,000 mg paracetamol tablets were administered, either with or without a meal, following 14 weeks of prolonged-release exenatide therapy, no significant changes in paracetamol AUC were observed compared to the control period. Paracetamol Cmax decreased by 16% (fasting) and 5% (fed) and tmax was increased from approximately 1 hour in the control period to 1.4 hours (fasting) and 1.3 hours (fed).

The following interaction studies have been conducted using 10 mcg immediate-release exenatide but not prolonged-release exenatide:

Warfarin

A delay in tmax of about 2 h was observed when warfarin was administered 35 min after immediate-release exenatide. No clinically relevant effects on Cmax or AUC were observed. Increased INR has been spontaneously reported during concomitant use of warfarin and prolonged-release exenatide. INR should be monitored during initiation of prolonged-release exenatide therapy in patients on warfarin and/or cumarol derivatives (see sections 4.4 and 4.8).

Hydroxy methyl glutaryl coenzyme A reductase inhibitors

Lovastatin AUC and Cmax were decreased approximately 40% and 28%, respectively, and tmax was delayed about 4 h when immediate-release exenatide was administered concomitantly with a single dose of lovastatin (40 mg) compared with lovastatin administered alone. In 30-week placebo-controlled clinical studies with immediate-release exenatide, concomitant use of exenatide and HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles (see section 5.1). No predetermined dose adjustment is required; however, lipid profiles should be monitored as appropriate.

Digoxin and lisinopril

In interaction studies of the effect of immediate-release exenatide on digoxin and lisinopril there were no clinical relevant effects on Cmax or AUC, however, a delay in tmax of about 2 h was observed.

Ethinyl estradiol and levonorgestrel

Administration of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) one hour before immediate-release exenatide did not alter the AUC, Cmax or Cmin of either ethinyl estradiol or levonorgestrel. Administration of the oral contraceptive 35 minutes after exenatide did not affect AUC but resulted in a reduction of the Cmax of ethinyl estradiol by 45%, and Cmax of levonorgestrel by 27–41%, and a delay in tmax by 2–4 h due to delayed gastric emptying. The reduction in Cmax is of limited clinical relevance and no adjustment of dosing of oral contraceptives is required.

Paediatric population

Interaction studies with exenatide have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Due to the long washout period of prolonged-release exenatide, women of childbearing potential should use contraception during treatment with prolonged-release exenatide. This medicinal product should be discontinued at least 3 months before a planned pregnancy.

Pregnancy

There are no adequate data from the use of prolonged-release exenatide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Prolonged-release exenatide should not be used during pregnancy and the use of insulin is recommended.

Breast-feeding

It is unknown whether exenatide is excreted in human milk. Prolonged-release exenatide should not be used during breast-feeding.

Fertility

No fertility studies in humans have been conducted.

4.7 Effects on ability to drive and use machines

Prolonged-release exenatide has minor influence on the ability to drive and use machines. When prolonged-release exenatide is used in combination with a sulphonylurea, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines.

4.8 Undesirable effects

Summary of the safety profile

The most frequent adverse reactions were mainly gastrointestinal related (nausea which was the most frequent reaction and associated with the initiation of treatment and decreased over time, and diarrhoea). In addition, injection site reactions (pruritus, nodules, erythema), hypoglycaemia (with a sulphonylurea), and headache occurred. Most adverse reactions associated with prolonged-release exenatide were mild to moderate in intensity.

Tabulated list of adverse reactions

The frequency of adverse reactions of prolonged-release exenatide identified from clinical studies and spontaneous reports (not observed in clinical studies, frequency not known) are summarised in Table 1 below.

In the prolonged-release exenatide clinical studies, background therapies included diet and exercise, metformin, a sulphonylurea, a thiazolidinedione, a combination of oral glucose-lowering medicinal products or a basal insulin.

The reactions are listed below as MedDRA preferred term by system organ class and 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) very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Table 1: Adverse reactions of prolonged-release exenatide identified from clinical studies and spontaneous reports

• 1 Rate based on twelve prolonged-release exenatide completed long-term efficacy and safety studies n = 2868 total (patients on sulphonylurea n = 1002).

• 2 Based on hypoglycaemic events that 1. Result in loss of consciousness, seizure, or coma which resolves after administration of glucagon or glucose OR 2. Require third-party assistance to resolve because of impairment in consciousness or behaviour and has glucose value of < 54 mg/dL (3 mmol/L) OR 3. Result in symptoms consistent with hypoglycaemia with a concomitant glucose < 54 mg/dL (3 mmol/L) prior to treatment.

• 3 Frequency reported from the 28-week controlled treatment period of the prolonged-release exenatide as add-on to insulin glargine study (N=231).

• 4 Rate based on prolonged-release exenatide spontaneous reports data (unknown denominator).

• 5 Rate based on sixteen prolonged-release exenatide completed long term efficacy and safety studies n = 4086 total.

Description of selected adverse reactions

Drug-induced thrombocytopenia

Drug-induced thrombocytopenia (DITP) with exenatide-dependent anti-platelet antibodies has been reported in the postmarketing setting. DITP is an immune-mediated reaction that is caused by drugdependent platelet-reactive antibodies. These antibodies cause destruction of platelets in the presence of the sensitizing drug.

Hypoglycaemia

The incidence of hypoglycaemia was increased when prolonged-release exenatide was used in combination with a sulphonylurea (24.0% versus 5.4%) (see section 4.4). To reduce the risk of hypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylurea may be considered (see sections 4.2 and 4.4).

Prolonged-release exenatide was associated with a significantly lower incidence of episodes of hypoglycaemia than basal insulin in patients also receiving metformin therapy (3% versus 19%) and in patients also receiving metformin plus sulphonylurea therapy (20% versus 42%).

Across 12 studies of prolonged-release exenatide most episodes (99.9% n = 649) of hypoglycaemia were minor, and resolved with oral administration of carbohydrate. One patient was reported with major hypoglycaemia since he had a low blood glucose value (2.2 mmol/L) and requested assistance with oral carbohydrate treatment which resolved the event.

When prolonged-release exenatide was added to basal insulin, no initial dose adjustment of insulin was required. Prolonged-release exenatide in combination with basal insulin showed no clinically significant differences in the incidence of hypoglycaemic episodes compared to insulin. There were no episodes of major hypoglycaemia in the prolonged-release exenatide with insulin group.

Nausea

The most frequently reported adverse reaction was nausea. In patients treated with prolonged-release exenatide, generally 20% reported at least one episode of nausea compared to 34% of immediate-release exenatide patients. Most episodes of nausea were mild to moderate. With continued therapy, the frequency decreased in most patients who initially experienced nausea.

The incidence of withdrawal due to adverse events during the 30-week controlled study was 6% for prolonged-release exenatide treated patients, 5% for immediate-release exenatide treated patients. The most common adverse events leading to withdrawal in either treatment group were nausea and vomiting. Withdrawal due to nausea or vomiting each occurred in < 1% for prolonged-release exenatide treated patients and 1% for immediate-release exenatide treated patients.

Injection site reactions

Injection site reactions were observed more frequently in prolonged-release exenatide treated patients versus comparator-treated patients (16% versus range of 2–7%) during the 6-month controlled phase of studies. These injection site reactions were generally mild and usually did not lead to withdrawal from studies. Patients may be treated to relieve symptoms, while continuing treatment. Subsequent injections should use a different site of injection each week. In postmarketing experiences, cases with injection site abscesses and cellulitis have been reported.

Small subcutaneous injection site nodules were observed very frequently in clinical studies, consistent with the known properties of poly (D,L-lactide co-glycolide) polymer microsphere formulations. Most individual nodules were asymptomatic, did not interfere with study participation and resolved over 4 to 8 weeks.

Immunogenicity

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop antibodies to exenatide following treatment with prolonged-release exenatide. In most patients who develop antibodies, antibody titres diminish over time.

The presence of antibodies (high or low titres) is not predictive of glycaemic control for an individual patient.

In clinical studies of prolonged-release exenatide, approximately 45% of patients had low titre antibodies to exenatide at study endpoint. Overall, the percentage of antibody positive patients was consistent across clinical studies. Overall, the level of glycaemic control (HbA1c) was comparable to that observed in those without antibody titres. On average in the phase 3 studies, 12% of the patients had higher titre antibodies. In a proportion of these the glycaemic response to prolonged-release exenatide was absent at the end of the controlled period of studies; 2.6% of patients showed no glucose improvement with higher titre antibodies whereas 1.6% showed no improvement while antibody negative.

Patients who developed antibodies to exenatide tend to have more injection site reactions (for example: redness of skin and itching), but otherwise similar rates and types of adverse events as those with no antibodies to exenatide.

For prolonged-release exenatide treated patients, the incidence of potentially immunogenic injection site reactions (most commonly pruritus with or without erythema) during the 30-week and the two 26-week studies was 9%. These reactions were less commonly observed in antibody-negative patients (4%) compared with antibody-positive patients (13%), with a greater incidence in those with higher titre antibodies.

Examination of antibody-positive specimens revealed no significant cross-reactivity with similar endogenous peptides (glucagon or GLP-1).

Rapid weight loss

In a 30-week study, approximately 3% (n = 4/148) of prolonged-release exenatide treated patients experienced at least one time period of rapid weight loss (recorded body weight loss between two consecutive study visits of greater than 1.5 kg/week).

Increased heart rate

A mean increase in heart rate (HR) of 2.6 beats per minute (bpm) from baseline (74 bpm) was observed in pooled prolonged-release exenatide clinical studies. Fifteen percent of prolonged-release exenatide treated patients had mean increases in HR of >10 bpm; approximately 5% to 10% of subjects within the other treatment groups had mean increases in HR of > 10 bpm.

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.

4.9 Overdose

5.  PHARMACOLOGICAL PROPERTIES

5.1  Pharmacodynamic properties

5.2 Pharmacokinetic properties

The absorption properties of exenatide reflect the extended release properties of the prolonged-release exenatide formulation. Once absorbed into the circulation, exenatide is distributed and eliminated according to its known systemic pharmacokinetic properties (as described in this section).

Absorption

Following weekly administration of 2 mg prolonged-release exenatide, mean exenatide concentrations exceeded minimal efficacious concentrations (~ 50 pg/mL) in 2 weeks with gradual increase in the average plasma exenatide concentration over 6 to 7 weeks. Subsequently, exenatide concentrations of approximately 151–265 pg/mL were maintained indicating that steady state was achieved. Steady-state exenatide concentrations are maintained during the one-week interval between doses with minimal peak to trough fluctuation from this average therapeutic concentration.

Distribution

The mean apparent volume of distribution of exenatide following subcutaneous administration of a single dose of exenatide is 28 L.

Biotransformation and elimination

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide is 9 L/h. These pharmacokinetic characteristics of exenatide are independent of the dose. Approximately 10 weeks after discontinuation of prolonged-release exenatide therapy, mean plasma exenatide concentrations fell below minimal detectable concentrations.

Special populations

Renal impairment

Population pharmacokinetic analysis of renal impaired patients receiving 2 mg prolonged-release exenatide indicate that there may be an increase in systemic exposure of approximately 74% and 23% (median prediction in each group) in moderate (N = 10) and mild (N = 56) renal impaired patients, respectively as compared to normal (N = 84) renal function patients.

Hepatic insufficiency

No pharmacokinetic study has been performed in patients with hepatic insufficiency. Exenatide is cleared primarily by the kidney; therefore hepatic dysfunction is not expected to affect blood concentrations of exenatide.

Gender, race and body weight

Gender, race and body weight have no clinically relevant influence on exenatide pharmacokinetics.

Elderly

Data in elderly are limited, but suggest no marked changes in exenatide exposure with increased age up to about 75 years old.

In a pharmacokinetic study of immediate-release exenatide in patients with type 2 diabetes, administration of exenatide (10 mcg) resulted in a mean increase of exenatide AUC by 36% in 15 elderly subjects aged 75 to 85 years compared to 15 subjects aged 45 to 65 years likely related to reduced renal function in the older age group (see section 4.2).

Paediatric population

In a single-dose pharmacokinetic study of immediate-release exenatide in 13 patients with type 2 diabetes and between the ages of 12 and 16 years, administration of exenatide (5 mcg) resulted in slightly lower mean AUC (16% lower) and Cmax (25% lower) compared to those observed in adults. No pharmacokinetics study of prolonged-release exenatide has been conducted in the paediatric population.

5.3 Preclinical safety data

Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, or genotoxicity conducted with immediate-release exenatide or prolonged-release exenatide.

Thyroid tumours have been observed in rats and mice with long acting GLP-1 receptor agonists. In a 2-year rat carcinogenicity study with prolonged-release exenatide, an increased incidence of C-cell adenomas and C-cell carcinomas was observed at doses > 2-fold the human systemic exposure based on AUC. The clinical relevance of these findings is currently unknown.

Animal studies with exenatide did not indicate harmful effects with respect to fertility; high doses of exenatide caused skeletal effects and reduced foetal and neonatal growth.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Powder

poly (D,L-lactide-co-glycolide)

sucrose

Solvent

carmellose sodium

sodium chloride

polysorbate 20

sodium dihydrogen phosphate monohydrate

disodium phosphate heptahydrate water for injections

6.2 Incompatibilities

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

3 years

After suspension

The suspension must be injected immediately after mixing the powder and the solvent.

6.4 Special precautions for storage

Store in a refrigerator (2 °C – 8 °C).

Do not freeze.

The kit may be kept for up to 4 weeks below 30 °C prior to use.

Store in the original package in order to protect from light.

For storage conditions after mixing of the medicinal product, see section 6.3.

6.5 Nature and contents of container

The powder is packaged in a 3 mL Type I glass vial sealed with a chlorobutyl rubber stopper and an aluminium seal with a plastic flip-off cap.

The solvent is packaged in a 1.5 mL Type 1 glass pre-filled syringe sealed with a bromobutyl rubber cap and a rubber plunger.

Each single-dose kit contains one vial of 2 mg exenatide, one pre-filled syringe of 0.65 mL solvent, one vial connector, and two injection needles (one spare).

Pack size of 4 single-dose kits and a multipack consisting of 12 (3 packs of 4) single-dose kits. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The patient should be instructed to discard the syringe safely, with the needle still attached after each injection. The patient does not need to save any part of the single-use kit.

The solvent should be visually inspected prior to use. The solvent should only be used if it is clear and free of particulate matter. After suspension, the mixture should only be used if it is white to off white and cloudy.

Prolonged-release exenatide must be injected immediately after suspension of the powder in the solvent.

Prolonged-release exenatide that has been frozen must not be used.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB

SE-151 85 Sodertalje

Sweden

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/11/696/001–002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 June 2011

Date of latest renewal: 18 February 2016