This information is intended for use by health professionals

1. Name of the medicinal product

Tenkasi 400 mg powder for concentrate for solution for infusion

2. Qualitative and quantitative composition

Each vial contains oritavancin diphosphate equivalent to 400 mg oritavancin.

After reconstitution, 1 ml of the solution contains 10 mg oritavancin.

After dilution, 1 ml of the solution for infusion contains 1.2 mg oritavancin.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder for concentrate for solution for infusion (powder for concentrate).

White to off-white powder.

4. Clinical particulars
4.1 Therapeutic indications

Tenkasi is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults (see sections 4.4 and 5.1).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology

1,200 mg administered as a single dose by intravenous infusion over 3 hours.

Special populations

Elderly (≥ 65 years)

No dosage adjustment is required for patients ≥ 65 years of age (see section 5.2).

Renal impairment

No dosage adjustment is needed in patients with mild or moderate renal impairment (see section 5.2). The pharmacokinetics of oritavancin in patients with severe renal impairment has not been evaluated. Oritavancin is not removed from blood by haemodialysis procedures.

Hepatic impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh Class B) (see section 5.2). The pharmacokinetics of oritavancin in patients with severe hepatic impairment (Child-Pugh Class C) has not been evaluated, however based on pharmacokinetic parameters, severe hepatic impairment is not expected to have an impact on oritavancin exposure. Therefore no dose adjustment is required, even if caution should be exercised when prescribing oritavancin to patients with severe hepatic impariment (Child-Pugh Class C).

Paediatric population

The safety and efficacy of oritavancin in children and adolescents (<18 years) have not yet been established. No data are available.

Method of administration

Intravenous use.

Intravenous infusion over 3 hours (see section 6.6).

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

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

Use of intravenous unfractionated heparin sodium is contraindicated for 120 hours (5 days) after oritavancin administration because the activated partial thromboplastin time (aPTT) test results may remain falsely elevated for up to 120 hours after oritavancin administration (see sections 4.4 and 4.5).

4.4 Special warnings and precautions for use

Hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylactic reactions and anaphylactic shock have been reported with the use of oritavancin. If an acute hypersensitivity reaction occurs during oritavancin infusion, oritavancin should be discontinued immediately and appropriate supportive care should be instituted.

No data are available on cross-reactivity between oritavancin and other glycopeptides, including vancomycin. Before using oritavancin it is important to inquire carefully about previous hypersensitivity reactions to glycopeptides (e.g. vancomycin, telavancin). Due to the possibility of cross-hypersensitivity, there should be careful monitoring of patients with any history of glycopeptide hypersensitivity during and after the infusion.

Infusion related reactions

Oritavancin is given via intravenous infusion over 3 hours to minimise the risk of infusion related reactions. Intravenous infusions of oritavancin can cause reactions that resemble “red man syndrome”, including flushing of the upper body, urticaria, pruritis and/or rash. Infusion-associated reactions characterized by chest pain, chest discomfort, chills, tremor, back pain, neck pain, dyspnoea, hypoxia, abdominal pain and fever have been observed with the use of oritavancin, including after the administration of more than one dose of oritavancin (1200mg) during a single course of therapy. If reactions do occur, stopping or slowing the infusion may result in cessation of these symptoms (see section 4.8).

Need for additional antibacterial agents

Oritavancin is active against Gram positive bacteria only (see section 5.1). In mixed infections where Gram negative and/or certain types of anaerobic bacteria are suspected, oritavancin should be co-administered with appropriate antibacterial agent(s).

Concomitant use of warfarin

Oritavancin has been shown to artificially prolong prothrombin time (PT) and international normalised ratio (INR) for up to 12 hours, making the monitoring of the anticoagulation effect of warfarin unreliable up to 12 hours after an oritavancin dose.

Interference with assay for coagulation tests

Oritavancin has been shown to interfere with certain laboratory coagulation tests (see sections 4.3 and 4.5). Oritavancin concentrations that are found in the blood of patients following administration of a single dose have been shown to artificially prolong:

• aPTT for up to 120 hours,

• PT and INR for up to 12 hours,

• Activated Clotting Time (ACT) for up to 24 hours,

• Silica Clot Time (SCT) for up to 18 hours, and

• Dilute Russell's Viper Venom Test (DRVVT) for up to 72 hours.

These effects result from oritavancin binding to and preventing the action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests. For patients who require aPTT monitoring within 120 hours of oritavancin dosing, a non-phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT monitoring may be considered.

The Chromogenic Factor Xa Assay, the Thrombin Time (TT) assay and the assays used for the diagnosis of Heparin Induced Thrombocytopenia (HIT) are not affected by oritavancin. In vitro, oritavancin 46.6 μg/mL did not affect an assay for activated protein C resistance (APCR), suggesting that there is a low likelihood that oritavancin will interfere with this test. However, APCR is a phospholipid-based test and it cannot be ruled out that higher concentrations of oritavancin that may occur during clinical use could interfere with this test.

No effect of oritavancin on the in vivo coagulation system was observed in nonclinical and clinical studies.

Clostridioides difficile-associated diarrhoea

Antibacterial-associated colitis and pseudomembranous colitis have been reported for oritavancin and may range in severity from mild to life threatening diarrhoea. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of oritavancin (see section 4.8). In such a circumstance, the use of supportive measures together with the administration of specific treatment for Clostridioides difficile should be considered.

Superinfection

The use of antibacterial medicinal products may increase the risk of overgrowth of non-susceptible micro-organisms. If superinfection occurs, appropriate measures should be taken.

Osteomyelitis

In Phase 3 ABSSSI clinical trials, more cases of osteomyelitis were reported in the oritavancin-treated arm than in the vancomycin-treated arm (see section 4.8). Patients should be monitored for signs and symptoms of osteomyelitis after administration of oritavancin. If osteomyelitis is suspected or diagnosed, appropriate alternative antibacterial therapy should be instituted.

Abscess

In the Phase 3 clinical trials, slightly more cases of newly emergent abscesses were reported in the oritavancin-treated arm than in the vancomycin-treated arm (4.6% vs 3.4%, respectively) (see section 4.8). If newly emergent abscesses occur, appropriate measures should be taken.

Limitations of the clinical data

In the two major trials in ABSSSI the types of infections treated were confined to cellulitis, abscesses and wound infections only. Other types of infections have not been studied. There is limited experience in clinical studies in patients with bacteraemia, peripheral vascular disease or neutropenia, in immunocompromised patients, in patients aged > 65 years and in infections due to S. pyogenes.

4.5 Interaction with other medicinal products and other forms of interaction

Substances metabolised by cytochrome P450

A screening drug-drug interaction study was conducted in healthy volunteers (n=16) evaluating the concomitant administration of a single 1,200 mg dose of oritavancin with probe substrates for several CYP450 enzymes. Oritavancin was found to be a nonspecific, weak inhibitor (CYP2C9 and CYP2C19) or a weak inducer (CYP3A4 and CYP2D6) of several CYP isoforms.

Caution should be used when administering oritavancin concomitantly with medicinal products with a narrow therapeutic window that are predominantly metabolised by one of the affected CYP450 enzymes(e.g., warfarin), as co-administration may increase (e.g., for CYP2C9 substrates) or decrease (e.g., for CYP2D6 substrates) concentrations of the narrow therapeutic range medicinal product. Patients should be closely monitored for signs of toxicity or lack of efficacy if they have been given oritavancin while on a potentially affected compound (e.g. patients should be monitored for bleeding, if concomitantly receiving oritavancin and warfarin) (see section 4.4). A study to assess the drug-drug interaction effect of a single 1,200mg dose of oritavancin on the pharmacokinetics of S-warfarin following a single dose was conducted in 36 healthy subjects. S-warfarin pharmacokinetics were evaluated following a single dose of warfarin 25 mg given alone, or administered at the start, 24, or 72 hours after a single 1,200mg dose of oritavancin. The results showed no effect of oritavancin on S-warfarin AUC and Cmax.

Drug-laboratory test interactions (see sections 4.3 and 4.4)

Oritavancin binds to and prevents the action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests. Oritavancin concentrations achieved in the blood after 1,200 mg doses may produce falsely elevated results from certain laboratory tests (see Table 1).

Table 1: Coagulation tests affected by oritavancin

Assay

Duration of interference

Prothrombin time (PT)

Up to 12 hours

International normalized ratio (INR)

Up to 12 hours

Activated partial thromboplastin time (aPTT)

Up to 120 hours

Activated clotting time (ACT)

Up to 24 hours

Silica clot time (SCT)

Up to 18 hours

Dilute Russell's viper venom time (DRVVT)

Up to 72 hours

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of oritavancin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of oritavancin during pregnancy unless the potential benefit justifies the potential risk to the foetus.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of oritavancin in milk (see section 5.3). It is unknown whether oritavancin/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from oritavancin therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Animal studies have revealed no evidence of impaired fertility due to oritavancin at the highest concentrations administered, however, there is no data on the effects of oritavancin on human fertility.

4.7 Effects on ability to drive and use machines

Oritavancin has a minor influence on the ability to drive and use machines. Dizziness may occur and this may have an effect on driving and use of machines (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions (≥5%) were: nausea, hypersensitivity reactions, infusion site reactions, and headache. The most commonly reported serious adverse reaction was cellulitis (1.1%). The most common reported reasons for discontinuation were cellulitis (0.4%) and osteomyelitis (0.3%). Female patients had a higher reporting rate for adverse reactions than male patients.

Tabulated list of adverse reactions

Adverse reactions for oritavancin from the pooled Phase 3 ABSSSI clinical trials with single dose oritavancin are listed by system organ class in the following table.

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); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2: Frequency of adverse reactions by system organ class

System organ class

Frequency

Adverse Reactions

Infections and infestations

Common

Cellulitis, abscess (limb and subcutaneous)

Uncommon

Osteomyelitis

Blood and lymphatic system disorders

Common

Anaemia

Uncommon

Eosinophilia, thrombocytopenia

Immune system disorders

Uncommon

Hypersensitivity (see sections 4.3 and 4.4) , anaphylactic reaction

Unknown

Anaphylactic shock

Metabolism and nutrition disorders

Uncommon

Hypoglycaemia, hyperuricaemia

Nervous system disorders

Common

Headache, dizziness

Rare

Tremor*

Cardiac disorders

Common

Tachycardia

Respiratory, thoracic and mediastinal disorders

Uncommon

Bronchospasm, wheezing, dyspnoea*

Rare

Hypoxia*

Gastrointestinal disorders

Common

Nausea, vomiting, diarrhoea, constipation

Uncommon

Abdominal pain*

Hepatobiliary disorders

Common

Liver function test abnormal (Alanine aminotransferase increased, Aspartate aminotransferase increased)

Uncommon

Blood bilirubin increased

Skin and subcutaneous tissue disorders

Common

Urticaria, rash, pruritis

Uncommon

Leucocytoclastic vasculitis, angioedema, erythema multiforme, flushing

Musculoskeletal and connective tissue disorders

Common

Myalgia

Uncommon

Tenosynovitis

Rare

Back pain*, neck pain*

General disorders and administration site conditions

Common

Infusion site reactions, including the following symptoms infusion site phlebitis, infusion site erythema, extravasation, induration, pruritis, rash, oedema peripheral

Uncommon

Chest pain*, pyrexia*

Rare

Red man syndrome, chest discomfort*, chills*

*These reactions may be infusion-related (see section 4.4)

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

In the clinical programme of 3,017 oritavancin-treated subjects; there was no incidence of accidental overdose of oritavancin.

Oritavancin is not removed from blood by haemodialysis procedures. In the event of overdose, supportive measures should be taken.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, glycopeptide antibacterials, ATC code: J01XA05

Mechanism of action

Oritavancin has three mechanisms of action: (i) inhibition of the transglycosylation (polymerization) step of cell wall biosynthesis by binding to the stem peptide of peptidoglycan precursors; (ii) inhibition of the transpeptidation (crosslinking) step of cell wall biosynthesis by binding to the peptide bridging segments of the cell wall; and (iii) disruption of bacterial membrane integrity, leading to depolarization, permeabilization, and rapid cell death.

Resistance

Gram-negative organisms are intrinsically resistant to all glycopeptides, including oritavancin.

Resistance to oritavancin was observed in vitro in vancomycin-resistant isolates of Staphylococcus aureus. There is no known cross-resistance between oritavancin and non-glycopeptide classes of antibiotics.

Oritavancin exhibits reduced in vitro activity against certain Gram-positive organisms of the genera Lactobacillus, Leuconostoc and Pediococcus that are intrinsically resistant to glycopeptides.

Susceptibility testing break points

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

Table 3: Susceptibility Interpretive Criteria for Oritavancin

Organism group

MIC breakpoints

(mg/L)

S

R >

Staphylococcus aureus

0.125

0.125

Beta-haemolytic streptococci Groups A, B, C, G

0.25

0.25

Viridans group streptococci (S. anginosus group only)

0.25

0.25

S=Susceptible, R=Resistant

Pharmacokinetic/Pharmacodynamic (PK/PD) relationship

The area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) ratio of oritavancin for the infecting organism has been shown to be the parameter that best correlates with efficacy.

Clinical efficacy against specific pathogens

Efficacy has been demonstrated in clinical studies against the following pathogens that were susceptible to oritavancin in vitro.

Gram-positive microorganisms:

Staphylococcus aureus

Streptococcus pyogenes

Streptococcus agalactiae

Streptococcus dysgalactiae

Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus)

Antibacterial activity against other relevant pathogens

Clinical efficacy has not been established against the following pathogens although in vitro studies suggest that they would be susceptible to oritavancin in the absence of acquired mechanisms of resistance:

• Beta-haemolytic streptococci of Group G

Clostridium perfringens

Peptostreptococcus spp.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with oritavancin in one or more subsets of the paediatric population in the treatment of acute bacterial skin and skin structure infections (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Oritavancin exhibits linear pharmacokinetics at a dose up to 1,200 mg. The mean (CV%) maximum oritavancin concentration (Cmax) and AUC0-∞ in patients receiving a single 1,200 mg dose in ABSSSI patients is 138 (23) μg/ml and 2,800 (28.6) μg•h/mL respectively.

Distribution

Oritavancin is approximately 85% bound to human plasma proteins. Based on population PK analysis, the population mean total volume of distribution is estimated to be approximately 87.6 L, indicating oritavancin is extensively distributed into the tissues.

Exposures (AUC0-24) of oritavancin in skin blister fluid were 20% of those in plasma after a single 800 mg dose in healthy subjects.

Biotransformation

No metabolites were observed in plasma or bile from oritavancin treated dogs and rats, respectively. Additionally, in vitro human liver microsome studies indicated that oritavancin is not metabolized.

Elimination

No mass balance study has been conducted in humans. In humans, less than 1% to 5% of the dose was recovered as parent drug in faeces and urine respectively after 2 weeks of collection indicating that oritavancin is slowly excreted unchanged.

The mean terminal elimination plasma half-life of oritavancin is 245 hours (14.9% CV) based on population PK analysis of ABSSSI patients receiving a single 1,200 mg dose. The population mean total clearance is estimated at 0.445 L/h (27.2 % CV).

In a population PK analysis, a relationship between height and clearance was identified, where clearance increased with increasing height. Dose modification based on height is not necessary.

Special populations

Renal impairment

The pharmacokinetics of oritavancin was examined in the single dose Phase 3 ABSSSI studies in patients with normal renal function, CrCL ≥90 mL/min (n=213), mild renal impairment, CrCL 60-89 mL/min (n=59), moderate renal impairment, CrCL 30-59 mL/min (n=22), and severe renal impairment CrCL <30 mL/min (n=3). Population pharmacokinetic analysis indicated that renal impairment had no clinically relevant effect on the exposure of oritavancin. No dedicated studies in dialysis patients have been conducted.

Dosage adjustment of oritavancin is not needed in patients with mild or moderate renal impairment. The pharmacokinetics of oritavancin in patients with severe renal impairment has not been evaluated.

Hepatic impairment

The pharmacokinetics of oritavancin were evaluated in a study of subjects with moderate hepatic impairment (Child-Pugh Class B, n=20) and compared with healthy subjects (n=20) matched for gender, age and weight. There were no relevant changes in pharmacokinetics of oritavancin in subjects with moderate hepatic impairment.

Dosage adjustment of oritavancin is not needed in patients with mild and moderate hepatic impairment. The pharmacokinetics of oritavancin in patients with severe hepatic impairment has not been studied.

Effects of age, weight, gender and race

Population PK analysis from the single dose Phase 3 ABSSSI studies in patients indicated that gender, age, weight, or race had no clinically relevant effect on the exposure of oritavancin. No dosage adjustment is warranted in these subpopulations.

5.3 Preclinical safety data

The primary adverse effect of oritavancin administration to rats and dogs was a dose related accumulation of eosinophilic granules in tissue macrophages including hepatocytes, renal cortical epithelial cells, adrenal cells and macrophages of the reticulo endothelial system. The appearance of the eosinophilic granules did not occur following single dose administration and did not significantly affect innate macrophage function in vitro at intracellular levels anticipated from a single 1,200 mg dose.

Moderate, dose-related increases in liver enzymes (alanine transaminase and aspartate transaminase) were observed in rats and dogs and were shown to be reversible upon cessation of treatment. Biochemistry changes associated with kidney function including decreases in urine-specific gravity and pH and slight increases in blood urea nitrogen and sporadic increases in creatinine were present in both rat and dog after treatment of two weeks. Extramedullary haematopoiesis in the spleen was observed in rats. This histopathological finding correlated with an enlargement and an increase in the weight of the spleen. The exposure in rats at the no observed adverse effect level (NOAEL) was less to only slightly higher than the human exposure based on the AUC.

Histamine-like infusion reactions following immediately or shortly after dosing with oritavancin occurred in both rats and dogs. These reactions were associated with mortality at lower dosages in male than in female rats in single dose studies; however, the same gender-related differences were not observed in other species. Studies in neonatal rats and dogs for 30 days showed the same tissue effects as those seen in adult animals including sensitivity to the oritavancin-mediated histamine-like infusion reactions. Mortality was observed in neonatal rats at slightly lower dosage levels than in adults.

A standard battery of in vitro and in vivo tests on the genotoxic potential did not reveal any clinically relevant findings. Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of oritavancin.

When administered intravenously at doses up to 30 mg/kg, oritavancin did not affect the fertility or reproductive performance of male and female rats. Studies in pregnant rats and rabbits do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. There was no evidence of transplacental transfer of oritavancin in pregnant rats. The exposure in rats at the NOAEL was less to only slightly higher than the human exposure based on the AUC.

Following a single intravenous infusion in lactating rats, radio-labelled [14C]oritavancin was excreted in milk and absorbed by nursing pups.

6. Pharmaceutical particulars
6.1 List of excipients

Mannitol

Phosphoric acid (for pH-adjustment)

6.2 Incompatibilities

Sodium chloride solution should not be used for dilution as it is incompatible with oritavancin and may cause precipitation of the medicinal product. Therefore, other substances, additives or other medicinal products mixed in sodium chloride solution for intravenous use should not be added to oritavancin single-use vials or infused simultaneously through the same intravenous line or through a common intravenous port. In addition, medicinal products formulated at a basic or neutral pH may be incompatible with oritavancin (see section 6.6).

6.3 Shelf life

4 years

After reconstitution

The reconstituted solution should be further diluted in glucose 50 mg/ml (5%) intravenous infusion bag immediately.

After dilution

The diluted solution should be used immediately.

From a microbiological point of view, the product should be used immediately. If not used immediately storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 12 hours at 25°C and 24 hours at 2-8°C following dilution in a glucose 5% intravenous infusion bag, unless reconstitution and dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not store above 25°C.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Single-use 50 ml Type 1 glass vials with rubber stoppers and aluminium flip off cap.

3 individual vials are packaged in a carton.

6.6 Special precautions for disposal and other handling

For single use only. Tenkasi should be prepared under aseptic techniques in a pharmacy.

The powder must be reconstituted with water for injections and the resulting concentrate must be diluted in a glucose 5% intravenous infusion bag prior to use. Both the reconstituted solution and the diluted solution for infusion should be clear, colourless to pale yellow solution. Parenteral medicinal products should be inspected visually for particulate matter after reconstitution.

Reconstitution:.

• 40 mL of water for injections (WFI) should be added using a sterile syringe to reconstitute each vial to provide a 10 mg/mL solution per vial.

• To avoid excessive foaming, it is recommended that WFI should be added carefully, along the walls of the vials.

• Each vial should be swirled gently to avoid foaming and ensure that all of the powder is completely reconstituted in solution.

Dilution: Three reconstituted vials are needed for dilution for administration of a single 1,200 mg intravenous infusion. Only glucose 5% intravenous bag (D5W) should be used for dilution. Sodium chloride solution should not be used for dilution (see section 6.2).

Dilution:

• Withdraw and discard 120 mL from a 1,000 mL D5W intravenous bag.

• Withdraw 40 mL from each of the three reconstituted vials and add to D5W intravenous bag to bring the bag volume to 1,000 mL. This yields a concentration of 1.2 mg/mL of oritavancin. PP (Polypropylene) or PVC (Polyvinyl chloride) bags should be used for administration preparation.

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

7. Marketing authorisation holder

Menarini International Operations Luxembourg S.A.

1, Avenue de la Gare

L-1611, Luxembourg

Luxembourg

8. Marketing authorisation number(s)

EU/1/15/989/001

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 19/03/2015

Date of latest renewal: 13/01/2020

10. Date of revision of the text

July 2021

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.