GRASUSTEK 6mg 10mg / ml injection solution in pre-filled syringe medication leaflet

Grasustek 6 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 6 mg of pegfilgrastim* in 0.6 ml solution for injection. Theconcentration is 10 mg/ml based on protein only**.

*Produced in Escherichia coli cells by recombinant DNA technology followed by conjugation withpolyethylene glycol (PEG).

** The concentration is 20 mg/ml if the PEG moiety is included.

The potency of this product should not be compared to the potency of another pegylated or non-pegylated protein of the same therapeutic class. For more information, see section 5.1.

Each pre-filled syringe contains 30 mg sorbitol (E 420) (see section 4.4).

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless solution for injection.

Reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patientstreated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemiaand myelodysplastic syndromes).

Pegfilgrastim therapy should be initiated and supervised by physicians experienced in oncology and/orhaematology.

One 6 mg dose (a single pre-filled syringe) of pegfilgrastim is recommended for each chemotherapycycle, given at least 24 hours after cytotoxic chemotherapy.

The safety and efficacy of pegfilgrastim in children has not yet been established. Currently availabledata are described in sections 4.8, 5.1 and 5.2 but no dosing recommendations can be made.

No dose change is recommended in patients with renal impairment, including those with end-stagerenal disease.

Grasustek is injected subcutaneously. The injections should be given into the thigh, abdomen or upperarm.

For instructions on handling of the medicinal product before administration, see section 6.6.

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

In order to improve the traceability of biological medicinal products, the name and batch number ofthe administered product should be clearly recorded.

Limited clinical data suggest a comparable effect on time to recovery from severe neutropenia forpegfilgrastim to filgrastim in patients with de novo acute myeloid leukaemia (AML) (see section 5.1).

However, the long-term effects of pegfilgrastim have not been established in AML; therefore, itshould be used with caution in this patient population.

Granulocyte-colony stimulating factor (G- CSF) can promote growth of myeloid cells in vitro andsimilar effects may be seen on some non-myeloid cells in vitro.

The safety and efficacy of pegfilgrastim have not been investigated in patients with myelodysplasticsyndrome, chronic myelogenous leukaemia, and in patients with secondary AML; therefore, it shouldnot be used in such patients. Particular care should be taken to distinguish the diagnosis of blasttransformation of chronic myeloid leukaemia from AML.

The safety and efficacy of pegfilgrastim administration in de novo AML patients aged < 55 years withcytogenetics t(15;17) have not been established.

The safety and efficacy of pegfilgrastim have not been investigated in patients receiving high-dosechemotherapy. This medicinal product should not be used to increase the dose of cytotoxicchemotherapy beyond established dose regimens.

Pulmonary adverse events

Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSFadministration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higherrisk (see section 4.8).

The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiologicalsigns of pulmonary infiltrates, and deterioration in pulmonary function along with increased neutrophilcount may be preliminary signs of Acute Respiratory Distress Syndrome(ARDS). In suchcircumstances, pegfilgrastim should be discontinued at the discretion of the doctor and the appropriatetreatment given (see section 4.8).

Glomerulonephritis

Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally,events of glomerulonephritis resolved after dose reduction or discontinuation of filgrastim andpegfilgrastim. Urinalysis monitoring is recommended.

Capillary leak syndrome has been reported after G-CSF administration and is characterised byhypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms ofcapillary leak syndrome should be closely monitored and receive standard symptomatic treatment,which may include the need for intensive care (see section 4.8).

Splenomegaly and splenic rupture

Generally asymptomatic cases of splenomegaly and cases of splenic rupture, including some fatalcases, have been reported following administration of pegfilgrastim (see section 4.8). Therefore,spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis ofsplenic rupture should be considered in patients reporting left upper abdominal pain or shoulder tippain.

Thrombocytopenia and anaemia

Treatment with pegfilgrastim alone does not preclude thrombocytopenia and anaemia because fulldose myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring ofplatelet count and haematocrit is recommended. Special care should be taken when administeringsingle or combination chemotherapeutic medicinal products which are known to cause severethrombocytopenia.

Myelodysplastic syndrome and acute myeloid leukaemia in breast and lung cancer patients

In the post-marketing observational study setting, pegfilgrastim in conjunction with chemotherapyand/or radiotherapy has been associated with development of myelodysplastic syndrome (MDS) andacute myeloid leukaemia (AML) in breast and lung cancer patients (see section 4.8). Monitor breastand lung cancer patients for signs and symptoms of MDS/AML.

Sickle cell anaemia

Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait orsickle cell disease (see section 4.8). Therefore, doctors should use caution when prescribingpegfilgrastim in patients with sickle cell trait or sickle cell disease, should monitor appropriate clinicalparameters and laboratory status and be attentive to the possible association of this medicinal productwith splenic enlargement and vaso-occlusive crisis.

Leucocytosis

White blood cell (WBC) counts of 100 × 109/L or greater have been observed in less than 1 % ofpatients receiving pegfilgrastim. No adverse events directly attributable to this degree of leucocytosishave been reported. Such elevation in white blood cells is transient, typically seen 24 to 48 hours afteradministration and is consistent with the pharmacodynamic effects of this medicinal product.

Consistent with the clinical effects and the potential for leucocytosis, a WBC count should beperformed at regular intervals during therapy. If leukocyte counts exceed 50 × 109/L after the expectednadir, this medicinal product should be discontinued immediately.

Hypersensitivity, including anaphylactic reactions, occurring during initial or subsequent treatmenthave been reported in patients treated with pegfilgrastim. Pegfilgrastim should be permanentlydiscontinued in patients with clinically significant hypersensitivity. Pegfilgrastim should not beadministered to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. If a seriousallergic reaction occurs, appropriate therapy should be administered, with close patient follow-up overseveral days.

Stevens-Johnson syndrome

Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely inassociation with pegfilgrastim treatment. If the patient has developed SJS with the use ofpegfilgrastim, treatment with pegfilgrastim must not be restarted in this patient at any time.

As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation ofantibodies against pegfilgrastim are generally low. Binding antibodies do occur as expected with allbiologics; however, they have not been associated with neutralising activity at present.

Aortitis

Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. Thesymptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatorymarkers (e.g. c-reactive protein and white blood cell count). In most cases aortitis was diagnosed by

CT scan and generally resolved after discontinuation of G-CSF. See also section 4.8.

The safety and efficacy of pegfilgrastim for the mobilisation of blood progenitor cells in patients orhealthy donors has not been adequately evaluated.

Increased haematopoietic activity of the bone marrow in response to growth factor therapy has beenassociated with transient positive bone imaging findings. This should be considered when interpretingbone-imaging results.

Sorbitol

The additive effect of concomitantly administered products containing sorbitol (or fructose) anddietary intake of sorbitol (or fructose) should be taken into account.

This medicinal product contains less than 1 mmol sodium (23 mg) per 6 mg dose, i.e. it is essentially‘sodium-free’.

Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚pegfilgrastim should be administered at least 24 hours after administration of cytotoxic chemotherapy.

In clinical trials, pegfilgrastim has been safely administered 14 days before chemotherapy.

Concomitant use of pegfilgrastim with any chemotherapy has not been evaluated in patients. Inanimal models, concomitant administration of pegfilgrastim and 5-fluorouracil (5-FU) or otherantimetabolites has been shown to potentiate myelosuppression.

Possible interactions with other haematopoietic growth factors and cytokines have not beenspecifically investigated in clinical trials.

The potential for interaction with lithium, which also promotes the release of neutrophils, has not beenspecifically investigated. There is no evidence that such an interaction would be harmful.

The safety and efficacy of Grasustek have not been evaluated in patients receiving chemotherapyassociated with delayed myelosuppression e.g., nitrosoureas.

Specific interaction or metabolism studies have not been performed; however, clinical trials have notindicated an interaction of pegfilgrastim with any other medicinal products.

There are no or limited data on the use of pegfilgrastim in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). Grasustek is not recommended during pregnancy and inwomen of childbearing potential not using contraception.

There is insufficient information on the excretion of pegfilgrastim/metabolites in breast milk.

Therefore a risk for new-borns/infants cannot be ruled out. A decision must be made whether todiscontinue breast-feeding or to discontinue/abstain from Grasustek therapy taking into account thebenefit of breast-feeding for the child and the benefit of therapy for the mother.

Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulativeweekly doses approximately 6 to 9 times higher than the recommended human dose (based on bodysurface area) (see section 5.3).

Pegfilgrastim has no or a negligible influence on the ability to drive and use machines.

The most frequently reported adverse reactions were bone pain (very common [≥ 1/10]) andmusculoskeletal pain (common) [≥ 1/100 to < 1/10]). Bone pain was generally of mild to moderateseverity, transient and could be controlled in most patients with standard analgesics.

Hypersensitivity-type reactions, including skin rash, urticaria, angioedema dyspnoea, erythema,flushing, and hypotension occurred on initial or subsequent treatment with pegfilgrastim (uncommon[≥ 1/1,000 to < 1/100]). Serious allergic reactions, including anaphylaxis can occur in patientsreceiving pegfilgrastim (uncommon) (see section 4.4).

Capillary Leak Syndrome, which can be life-threatening if treatment is delayed, has been reported asuncommon (≥ 1/1,000 to < 1/100) in cancer patients undergoing chemotherapy followingadministration of G-CSF; see section 4.4 and section “Description of selected adverse reactions”below.

Splenomegaly, generally asymptomatic, is uncommon.

Splenic rupture including some fatal cases is uncommonly reported following administration ofpegfilgrastim (see section 4.4).

Uncommon pulmonary adverse reactions including interstitial pneumonia, pulmonary oedema,pulmonary infiltrates and pulmonary fibrosis have been reported. Uncommonly, cases have resulted inrespiratory failure or ARDS, which may be fatal (see section 4.4).

Isolated cases of sickle cell crises have been reported in patients with sickle cell trait or sickle celldisease (uncommon in sickle cell patients) (see section 4.4).

The data in the table below describe adverse reactions reported from clinical trials and spontaneousreporting. Within each frequency grouping, undesirable effects are presented in order of decreasingseverity.

MedDRA Adverse reactionssystem organ class Very Common Uncommon Rare Very rarecommon (≥ 1/100 to < 1/10) (≥ 1/1,000 to (≥1/10,000 (<(≥ 1/10) < 1/100) to 1/10,000)< 1/1,000)

Neoplasms benign, Myelodysplasticmalignant and syndrome1unspecified (incl cysts Acute myeloidand polyps) leukaemia1

Blood and Thrombocytopenia1; Sickle cell anaemialymphatic Leukocytosis1 with crisis2;system disorders Splenomegaly2;

Splenic rupture2

Immune system Hypersensitivity

Disorders reactions;

Anaphylaxis

Metabolism and Elevations in uricnutrition aciddisorders

Nervous system Headache1

Disorders

Vascular Capillary leak Aortitis

Disorders syndrome1

Respiratory, Acute Respiratory Pulmonarythoracic and DistressSyndrome2; haemorrhagemediastinal Pulmonary adversedisorders reactions(interstitialpneumonia,pulmonary oedema,pulmonaryinfiltrates andpulmonary fibrosis)

Haemoptysis

Gastrointestinal Nausea1disorders

Skin and Sweet’s syndrome Stevens-subcutaneous (acute febrile Johnsontissue disorders neutrophilic syndromedermatosis)1, 2;

Cutaneous

Vasculitis1,2

Musculoskeletal Bone pain Musculoskeletaland connective pain (myalgia,tissue disorders arthralgia, pain inextremity, backpain,musculoskeletalpain, neck pain)

Renal and urinary Glomerulonephritis2disorders

General Injection site pain1 Injection sitedisorders and Non-cardiac chest Reactions2administration painsite conditions

Investigations Elevations in lactatedehydrogenase andalkalinephosphatase1;

Transient elevationsin LFTs for ALT or

AST11 See section “Description of selected adverse reactions” below.2 This adverse reaction was identified through post-marketing surveillance of pegfilgrastim but not observed in randomised,controlled clinical trials in adults. The frequency category was estimated from a statistical calculation based upon 1,576patients receiving pegfilgrastim in nine randomised clinical trials.

Uncommon cases of Sweet's syndrome have been reported, although in some cases underlyinghaematological malignancies may play a role.

Uncommon events of cutaneous vasculitis have been reported in patients treated with pegfilgrastim.

The mechanism of vasculitis in patients receiving pegfilgrastim is unknown.

Injection site reactions, including injection-site erythema (uncommon) as well as injection-site pain(common events) have occurred during initial or subsequent treatment with pegfilgrastim.

Common cases of leucocytosis (White Blood Count [WBC] > 100 × 109/l) have been reported (seesection 4.4).

Reversible, mild to moderate elevations in uric acid and alkaline phosphatase, with no associatedclinical effects, were uncommon; reversible, mild to moderate elevations in lactate dehydrogenase,with no associated clinical effects, were uncommon in patients receiving pegfilgrastim followingcytotoxic chemotherapy.

Nausea and headaches were very commonly observed in patients receiving chemotherapy.

Uncommon elevations in liver function tests (LFTs) for alanine aminotransferase (ALT) or aspartateaminotransferase (AST),, have been observed in patients after receiving pegfilgrastim followingcytotoxic chemotherapy. These elevations are transient and return to baseline.

An increased risk of MDS/AML following treatment with pegfilgrastim in conjunction withchemotherapy and/or radiotherapy has been observed in an epidemiological study in breast and lungcancer patients (see section 4.4).

Common cases of thrombocytopenia have been reported.

Cases of capillary leak syndrome have been reported in the post marketing setting G-CSF use. Thesehave generally occurred in patients with advanced malignant diseases, sepsis, taking multiplechemotherapy medicinal products or undergoing apheresis (see section 4.4).

Experience in children is limited. A higher frequency of serious adverse reactions in younger childrenaged 0-5 years (92 %) has been observed compared to older children aged 6-11 and 12-21 yearsrespectively (80 % and 67 %) and adults. The most common adverse reaction reported was bone pain(see sections 5.1 and 5.2).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Single doses of 300 μg/kg have been administered subcutaneously to a limited number of healthyvolunteers and patients with non-small cell lung cancer without serious adverse reactions. The adverseevents were similar to those in subjects receiving lower doses of pegfilgrastim.

Pharmacotherapeutic group: immunostimulants, colony stimulating factors; ATC Code: L03AA13.

Grasustek is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency http://www.ema.europa.eu.

Human granulocyte colony stimulating factor (G-CSF) is a glycoprotein, which regulates theproduction and release of neutrophils from the bone marrow. Pegfilgrastim is a covalent conjugate ofrecombinant human G-CSF (r-metHuG-CSF) with a single 20 kd polyethylene glycol (PEG) molecule.

Pegfilgrastim is a sustained duration form of filgrastim due to decreased renal clearance. Pegfilgrastimand filgrastim have been shown to have identical modes of action, causing a marked increase inperipheral blood neutrophil counts within 24 hours, with minor increases in monocytes and/orlymphocytes. Similar to filgrastim, neutrophils produced in response to pegfilgrastim show normal orenhanced function as demonstrated by tests of chemotactic and phagocytic function. As with otherhaematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelialcells. G-CSF can promote growth of myeloid cells, including malignant cells, in vitro and similareffects may be seen on some non-myeloid cells in vitro.

In two randomised, double-blind, pivotal studies in patients with high risk stage II-IV breast cancerundergoing myelosuppressive chemotherapy consisting of doxorubicin and docetaxel, use ofpegfilgrastim, as a single once per cycle dose, reduced the duration of neutropenia and the incidence offebrile neutropenia similarly to that observed with daily administrations of filgrastim (a median of11 daily administrations). In the absence of growth factor support, this regimen has been reported toresult in a mean duration of grade 4 neutropenia of 5 to7 days, and a 30-40 % incidence of febrileneutropenia. In one study (n = 157), which used a 6 mg fixed dose of pegfilgrastim the mean durationof grade 4 neutropenia for the pegfilgrastim group was 1.8 days compared with 1.6 days in thefilgrastim group (difference 0.23 days, 95 % CI -0.15, 0.63). Over the entire study, the rate of febrileneutropenia was 13 % of pegfilgrastim-treated patients compared with 20 % of filgrastim-treatedpatients (difference 7 %, 95 % CI of-19 %, 5 %). In a second study (n = 310), which used aweight-adjusted dose (100 μg /kg), the mean duration of grade 4 neutropenia for the pegfilgrastimgroup was 1.7 days, compared with 1.8 days in the filgrastim group (difference 0.03 days, 95 % CI

- 0.36, 0.30).

The overall rate of febrile neutropenia was 9 % of patients treated with pegfilgrastim and 18 % ofpatients treated with filgrastim (difference 9 %, 95 % CI of-16.8 %, -1.1 %).

In a placebo-controlled, double-blind study in patients with breast cancer the effect of pegfilgrastim onthe incidence of febrile neutropenia was evaluated following administration of a chemotherapyregimen associated with a febrile neutropenia rate of 10-20 % (docetaxel 100 mg/m2 every 3 weeks for4 cycles). Nine hundred and twenty-eight patients were randomised to receive either a single dose ofpegfilgrastim or placebo approximately 24 hours (day 2) after chemotherapy in each cycle. Theincidence of febrile neutropenia was lower for patients randomised to receive pegfilgrastim comparedwith placebo (1% versus 17 %, p < 0.001). The incidence of hospitalisations and intravenousanti-infective use associated with a clinical diagnosis of febrile neutropenia was lower in thepegfilgrastim group compared with placebo (1 % versus 14 %, p < 0.001; and 2 % versus 10 %, p <0.001).

A small (n = 83), phase II, randomised, double-blind study in patients receiving chemotherapy for denovo acute myeloid leukaemia compared pegfilgrastim (single dose of 6 mg) with filgrastim,administered during induction chemotherapy. Median time to recovery from severe neutropenia wasestimated as 22 days in both treatment groups. Long-term outcome was not studied (see section 4.4).

In a phase II (n = 37) multicentre, randomised, open-label study of paediatric sarcoma patientsreceiving 100 μg/kg pegfilgrastim following cycle 1 of vincristine, doxorubicin and cyclophosphamide(VAdriaC/IE) chemotherapy, a longer duration of severe neutropenia (neutrophils < 0.5 × 109/L) wasobserved in younger children aged 0-5 years (8.9 days) compared to older children aged 6-11 yearsand 12-21 years (6 days and 3.7 days, respectively) and adults. Additionally, a higher incidence offebrile neutropenia was observed in younger children aged 0-5 years (75 %) compared to olderchildren aged 6-11 years and 12-21 years (70 % and 33 %, respectively) and adults (see sections 4.8and 5.2).

After a single subcutaneous dose of pegfilgrastim, the peak serum concentration of pegfilgrastimoccurs at 16 to 120 hours after dosing and serum concentrations of pegfilgrastim are maintainedduring the period of neutropenia after myelosuppressive chemotherapy. The elimination ofpegfilgrastim is non-linear with respect to dose; serum clearance of pegfilgrastim decreases withincreasing dose. Pegfilgrastim appears to be mainly eliminated by neutrophil mediated clearance,which becomes saturated at higher doses. Consistent with a self-regulating clearance mechanism, theserum concentration of pegfilgrastim declines rapidly at the onset of neutrophil recovery (see figure1).

Figure 1. Profile of median pegfilgrastim serum concentration and absolute neutrophil count(ANC) in chemotherapy treated patients after a single 6 mg injection

Due to the neutrophil-mediated clearance mechanism, the pharmacokinetics of pegfilgrastim is notexpected to be affected by renal or hepatic impairment. In an open label, single dose study (n = 31)various stages of renal impairment, including end-stage renal disease, had no impact on thepharmacokinetics of pegfilgrastim.

Limited data suggest that the pharmacokinetics of pegfilgrastim in elderly subjects (> 65 years) issimilar to that in adults.

The pharmacokinetics of pegfilgrastim were studied in 37 paediatric patients with sarcoma, whoreceived 100 μg/kg pegfilgrastim after the completion of VAdriaC/IE chemotherapy. The youngestage group (0-5 years) had a higher mean exposure to pegfilgrastim (AUC) (± Standard Deviation)(47.9 ± 22.5 μgꞏhr/ml) than older children aged 6-11 years and 12-21 years (22.0 ± 13.1 μgꞏhr/ml and29.3 ± 23.2 μgꞏhr/ml, respectively) (see section 5.1). With the exception of the youngest age group(0 5 years), the mean AUC in paediatric subjects appeared similar to that for adult patients withhigh-risk stage II-IV breast cancer and receiving 100 μg/kg pegfilgrastim after the completion ofdoxorubicin/docetaxel (see sections 4.8 and 5.1).

Preclinical data from conventional studies of repeated dose toxicity revealed the expectedpharmacological effects including increases in leukocyte count, myeloid hyperplasia in bone marrow,extramedullary haematopoiesis and splenic enlargement.

There were no adverse effects observed in offspring of pregnant rats given pegfilgrastimsubcutaneously, but in rabbits pegfilgrastim has been shown to cause embryo/foetal toxicity (embryoloss) at cumulative doses approximately 4 times the recommended human dose, which were not seenwhen pregnant rabbits were exposed to the recommended human dose. In rat studies, it was shown thatpegfilgrastim may cross the placenta. Studies in rats indicated that reproductive performance, fertility,oestrous cycling, days between pairing and coitus, and intrauterine survival were unaffected bypegfilgrastim given subcutaneously. The relevance of these findings for humans is not known.

Sodium acetate *

Sorbitol (E420)

Polysorbate 20

Water for injections

*Sodium acetate is formed by titrating glacial acetic acid with sodium hydroxide.

This medicinal product must not be mixed with other medicinal products, particularly with sodiumchloride solutions.

3 years.

Store in a refrigerator (2 °C-8 °C).

Grasustek may be exposed to room temperature (not above 30 °C) for a maximum single period of upto 72 hours. Grasustek left at room temperature for more than 72 hours should be discarded.

Do not freeze. Accidental exposure to freezing temperatures for a single period of less than 24 hoursdoes not adversely affect the stability of Grasustek.

Keep the container in the outer carton to protect from light.

Pre-filled syringe (Type I glass), with a (butyl) rubber stopper and a stainless-steel needle withautomatic needle guard. The needle has flexible, rigid needle shield.

Each pre-filled syringe contains 6 mg of pegfilgrastim in 0.6 ml of solution for injection.

Pack size of one pre-filled syringe with automatic needle guard (0.6 ml) and supplied in a dispensingpack containing one syringe.

Before administration, Grasustek solution should be visually inspected for particulate matter. Only asolution that is clear and colourless should be injected.

Excessive shaking may aggregate pegfilgrastim, rendering it biologically inactive.

Allow the pre-filled syringe for manual administration to come to room temperature for 30 minutesbefore using the syringe.

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

Juta Pharma GmbH,

Gutenbergstr. 13,24941 Flensburg,

Germany

EU/1/19/1375/001

Date of first authorisation: 20 June 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.