ANNEX I

LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTH OF THE MEDICINAL PRODUCTS, ROUTE OF ADMINISTRATION, APPLICANT, MARKETING AUTHORISATION HOLDER IN THE MEMBER STATES

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Marketing Authorisation Route of Content Member State Applicant Invented name Strength Pharmaceutical Form Holder administration (concentration)

THE GUERBET ARTIREM 0.0025 mmol/ml Solution for injection Intraarticular use 0.0025 mmol/ml NETHERLANDS GERMANY GUERBET ARTIREM 0.0025 mmol/ml Solution for injection Intraarticular use 0.0025 mmol/ml

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ANNEX II

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS PRESENTED BY THE EMEA

3/14 SCIENTIFIC CONCLUSIONS

OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF ARTIREM (see Annex I)

Contrast-enhanced arthrography using Magnetic Resonance Imaging (MRI) is performed by administering contrast agents by intravenous route (indirect MRI arthrography) or intra-articular injection directly into the joint (i.e. direct MRI arthrography). Contrast agents such as Gd-DTPA (Magnevist®) and Gd-DOTA (DOTAREM®) have been approved for intravenous use at the concentration of 0.5 M in the late 1980’s. In the European Union, DOTAREM is licensed in Austria (1997), Belgium (1989), Denmark (1996), Finland (1995), France (1989), United Kingdom (1996), Greece (1996), Ireland (1996), Italy (1996), Portugal (1991), Luxembourg (1989), Sweden (1995), The Netherlands (1991) and Spain (1998). ARTIREM (a ready-to-use diluted Gd-DOTA, solution for injection in prefilled syringes) has been approved as a line extension of DOTAREM in France (2002), Switzerland (2002), Belgium (2002), Luxembourg (2003), The Netherlands (2003) and Denmark (2004). ARTIREM has the same qualitative formulation as the authorised DOTAREM (Gd-DOTA), but is administered by intra-articular injection directly into the joint, at a much lower concentration of 0.0025 mmol/ml. A referral for Arbitration, under article 29 of Directive 2001/83/EC to the CHMP was triggered by the the German Authorities, BfArM on 5 March 2004. The major objections raised were that the efficacy and safety of ARTIREM 0.0025 mmol/ml had not been sufficiently substantiated and that the claimed indications do not refer to diseases, sufferings, bodily injuries or disease symptoms but solely to the method of arthrography. Additionally, it was considered that there could be potentially serious public health concerns related to the use of this product because of the safety concerns. The CHMP list of questions was issued on 25 March 2004.

• Efficacy issues CHMP considers it well known that the diagnostic performance of Gd complexes depends only on the paramagnetic ion gadolinium (Gd), which is responsible for the efficacy (effect on MRI signal) of such contrast agents. DOTA or DTPA are used only to complex Gd in order to reduce the toxicity of Gd. Gd-DOTA and Gd-DTPA are known to have the same efficacy. Comprehensive references and arguments of Gd-DOTA and Gadolinium-DTPA as being equivalent in terms of safety and efficacy have been presented in view of the comparability of these two compounds, and justify why the diagnostic efficacy of Gd-DOTA could be sufficiently supported by bibliographical listing of clinical studies performed with gadolinium complexes with different chemical structure. The CHMP considers it acceptable that the company did not take into consideration the document “Points to Consider in the Evaluation of Diagnostics Agents” (CPMP/EWP/1119/98) that came into force in November 2001, after the Mutual Recognition Procedure for the present application that was initiated in July 2001 in The Netherlands. Although there are no specific clinical pharmacokinetic data available after the intraarticular injection of Gd-DOTA, the overall systemic exposure is expected to be much lower than the one observed after the

4 intravenous administration. The Company has committed to perform a clinical pharmacokinetic study of Gd-DOTA after intraarticular administration to confirm the available animal data indicating that Gd- DOTA is rapidly and completely cleared from the joint cavity.

- Safety issues The CHMP considers that company has provided sufficient data about the safety profile of diluted Gd-DOTA by the intraarticular route. Since ARTIREM 0.0025 mmol/ml in prefilled syringes was first approved in Europe (2002), 12,000 patients have been exposed to this product. On the basis of the PSURs provided during this period, no severe adverse events (SAEs) have been reported. Additionally, no adverse reactions were reported for diluted Gd-DOTA in vials in Switzerland since available on the market (1992). Therefore the available post-marketing information on the safety of intraarticular Gd-DOTA does not raise any additional safety concern. Direct MRI arthrography with diluted Gd chelate solutions has been performed off-label by physicians using a self-prepared dilution, since no ready-to-use diluted product was available on the market. The CHMP considers that the availability of gadolinium complex formulations specifically aimed for direct MRI arthrography is regarded as an improvement by removing the septic risk related to the on-site preparation of a concentrated product. - Benefit/Risk considerations Overall, from the data provided it is concluded that the efficacy and safety of ARTIREM have been sufficiently established. The company has committed to perform a clinical pharmacokinetic study of Gd- DOTA after intraarticular administration to confirm the available animal data indicating that Gd-DOTA is rapidly and completely cleared from the joint cavity. Consequently, a positive risk/benefit conclusion for ARTIREM is concluded with the available data.

GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS

Whereas,

the scope of the referral was to grant a Marketing Authorisation for ARTIREM, and to amend the Summary of Products Characteristics in view of the available efficacy and safety data. ARTIREM is administered to the patients by intraarticular injection according to routine clinical practice. The volume range of Gd-DOTA administered by intraarticular route in the studies of the provided literature review and the Swiss postmarketing survey is that which appears in the proposed SPC for ARTIREM. the Summary of Products Characteristics proposed by the company has been assessed based on the documentation submitted and the scientific discussion within the CHMP. In line with published literature and clinical practice, sections 4.3 and 4.4 of the Summary of Products Characteristics on Contraindications and Special warnings and special precautions for use have been amended.

5 the CHMP has recommended the granting of the Marketing Authorisation for which the Summary of Product Characteristics is set out in Annex III for ARTIREM 0.0025 mmol/ml solution for injection in pre-filled syringes (see Annex I), under the conditions set out in Annex IV.

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ANNEX III

SUMMARY OF PRODUCT CHARACTERISTICS

7 1. NAME OF THE MEDICINAL PRODUCT

ARTIREM 0.0025 mmol/ml solution for injection in pre-filled syringes.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution for injection contains 1.397 mg gadoteric acid (as meglumine salt), equivalent to 0.0025 mmol of gadoteric acid, meglumine, containing 0.39 mg gadolinium)

20 ml solution for injection contains 27.932 mg gadoteric acid (as meglumine salt), equivalent to 0.05 mmol of gadoteric acid, meglumine, containing 7.86 mg gadolinium).

For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Solution for injection in pre-filled syringes. Clear, colourless to light yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Arthrography using magnetic resonance imaging (MRI) for the following joints and diseases : - Shoulder : diagnosis of rotator cuff partial-thickness tears, diagnosis of glenoid labrum and labral ligamentous complex tears - Hip : diagnosis of labral tears, loose bodies and chondral lesions - Elbow : diagnosis of ligaments tears - Knee : Detection of residual or recurrent meniscal tears, diagnosis of loose bodies, synovial plicae, and osteochondral lesion stability - Wrist : Evaluation of the ligaments and triangular fibrocartilage - Ankle : diagnosis of ligamentous damage, impingement, and loose bodies - In general, for all articulations : detection of intraarticular osteochondral bodies

4.2 Posology and method of administration

- General Information ARTIREM must be administered by intraarticular injection under strict aseptic conditions. The recommendations for the use of ARTIREM are made with reference to a field strength of 0.2 Tesla, 1.0 and 1.5 Tesla. The product is for single use only. Optimal imaging: within 45 minutes after injection Optimal image sequence: T1-weighted

- Dosage A volume should be injected, which causes a slight extension of the joint capsule. The recommended dosage depends on the joint to be examined and its size.

8 Joint Recommended volume Shoulder 5 to 25 ml Hip 5 to 25 ml Elbow 4 to 10 ml Knee 20 to 40 ml Wrist 3 to 9 ml Ankle 4 to 19 ml

4.3 Contraindications

Hypersensitivity to gadoteric acid, to meglumine or to any medicinal products containing gadolinium.

Iodinated contrast media must not be administered simultaneously with ARTIREM, since the efficacy of ARTIREM may be reduced (see section 6.6 “Instructions for use and handling”).

4.4 Special warnings and special precautions for use

ARTIREM is for strict intraarticular injection. Precautions must be taken to avoid accidental extraarticular injection. ARTIREM must not be administered by subarachnoid (or epidural) injection.

Intraarticular injection of ARTIREM in infected joints should be avoided.

As there is no clinical experience with children, ARTIREM must not be administered to children and adolescents (< 18 years).

The usual precautionary measures for MRI examination should be taken, such as exclusion of patients with pacemakers, ferromagnetic vascular clips, infusion pumps, nerve stimulators, cochlear implants, or suspected intracorporal metallic foreign bodies, particularly in the eye.

Hypersensitivity (see section 4.3 “Contra-indications”) • As with other gadolinium-containing contrast media, hypersensitivity reactions can occur (see 4.8 Undesirable effects). Most of these reactions appear within at least half an hour after injection of the contrast medium. However, as with other contrast media in this group, the occurrence of delayed reactions up to several days after administration cannot be ruled out. • Patients with hypersensitivity or a previous reaction to contrast media are at increased risk of having a severe reaction. Patients should be asked if they have a history of allergy (e.g. hay fever, hives, asthma, etc.) before any contrast medium is injected. In such patients, the decision to use ARTIREM must be made after careful evaluation of the risk/benefit ratio. • As known from the use of iodinated contrast media, hypersensitivity reactions can be aggravated in patients taking beta-blockers, particularly in the presence of bronchial asthma. These patients may be refractory to standard treatment of hypersensitivity reactions with beta-agonists. • During the examination, supervision by a physician is necessary. If hypersensitivity reactions occur, administration of the contrast medium must be discontinued immediately and - if necessary - specific therapy given. To permit immediate emergency countermeasures, appropriate drugs (e.g. epinephrine and antihistamines), an endotracheal tube and a respirator should be ready to hand.

4.5 Interaction with other medicinal products and other forms of interaction

No interactions with other medicinal products have been observed. Formal drug interaction studies have not been carried out. ARTIREM should not be mixed with other compounds.

9 4.6 Pregnancy and lactation

No data are available on the use of ARTIREM in pregnant women. Animal studies to date have given no indication of a noxious effect. ARTIREM passes the placenta. Administration during pregnancy should be avoided unless absolutely necessary.

There are no data available on excretion of ARTIREM into human breast milk. Animal studies have shown negligible excretion of ARTIREM into maternal milk. If application during lactation is necessary, it is advisable to discontinue breastfeeding for at least 24 hours.

4.7 Effects on ability to drive and use machines

No studies of the effects on the ability to drive and use machines have been performed. Effects on the ability to drive and use machines are not expected. However, joint effusions may impair the ability to drive because of a reduced mobility of the joint.

4.8 Undesirable effects

General disorders and administration site conditions :

-commonly reported (>1/100, <1/10): Mild pain in the joint being examined -uncommonly reported (>1/1,000, <1/100): discomfort in the joint being examined.

However, rare anaphylactoid reactions have been reported with meglumine gadoterate that may be very rarely severe, life-threatening or have a fatal outcome, particularly in patients with a history of allergy. These allergoid reactions can occur irrespective of the amount administered and the mode of administration and may take the form of one or more of the following symptoms: Angioedema, anaphylactic shock, circulatory and cardiac arrest, hypotension, larynx oedema, bronchospasm, laryngospasm, pulmonary oedema, dyspnoea, stridor , coughing, pruritus, rhinitis, sneezing, conjunctivitis, urticaria and rash. Some of these symptoms may be the first signs of incipient state of anaphylactic shock. Delayed contrast medium reactions are possible (see “4.4. Special warnings...“).

4.9 Overdose

No signs of intoxication secondary to an overdose have so far been observed or reported in clinical practice with ARTIREM. On the basis of the results of the toxicity studies conducted with gadoteric acid solutions at higher concentrations, a risk of acute intoxication is highly unlikely following the use of ARTIREM by intra- articular injection.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: paramagnetic contrast medium ATC code: V08 CA 02 (gadoteric acid).

Contrast medium 1.397 mg/ml concentration: 0.0025 mmol/ml Osmolality at 37°C 285 mOsm/kg H2O PH 6.0 – 9.0

10 ARTIREM is a paramagnetic contrast medium for magnetic resonance imaging. The contrast-enhancing effect is mediated by gadoteric acid, which is an ionic gadolinium complex composed of gadolinium oxide and 1,4,7,10-tetraazacyclododecane- N,N’,N’’,N’’’-tetraacetic acid (Dota), which is present as meglumine salt.

The paramagnetic effect (relaxivity) is determined from the effect on spin-lattice relaxation time (T1), about 3.4 mmol-1.L.sec-1, and on spin-spin relaxation time (T2), about 4.27 mmol-1.L.sec-1.

The concentration of gadoteric acid 0.0025 mmol/ml equals a dilution of 1/200 of the concentration used for intravenous application. This concentration is sufficient for a significant shortening of the T1- relaxation time even after further dilution by a joint effusion. Using T1-weighted sequences will lead to an increase in signal intensity in the articular space, which thereby becomes brighter in colour (intraarticular structures like hyaline and fibrous cartilage, ligaments, tendons and articular capsule). The normal synovial fluid does not differ in its signal behaviour in T1-weighted pictures from all other anatomical structures (except fibrous cartilage). By intraarticular application of gadoteric acid 0.0025 mmol/ml, however, the contrast is markedly better.

5.2 Pharmacokinetic properties

The pharmacological properties of gadoteric acid were extensively investigated after intravenous application of doses which were definitely higher than the intraarticular injected doses. After intraarticular injection the compound is distributed in the articular space and diffuses into the adjoining tissues. A marginal absorption into the articular cartilage is fully reversible. After diffusion into extracellular space, gadoteric acid is eliminated rapidly (89% after 6 hours, 95% after 24 hours) in unchanged form via the kidneys by glomerular filtration. Excretion via the feces is negligible. No metabolites have been detected. The elimination half-life is about 1.6 hours in patients with normal renal function. In patients with renal impairment the elimination half-life is increased to approximately 5 hours for a creatinine clearance between 30 and 60 ml/min and approximately 14 hours for a creatinine clearance between 10 and 30 ml/min. Animal experiments have shown that gadoteric acid can be removed by dialysis.

5.3 Preclinical safety data

Preclinical data showed no special risk for humans based on data obtained after intravenous injections of gadoteric acid in repeated dose toxicity, reproduction toxicity and genotoxicity studies.

Studies of the local safety of gadoteric acid after intraarticular injection in dogs showed no effects on bones, cartilage or the composition of synovial fluid.

6. PHARMACEUTICAL PARTICULARS.

6.1 List of excipients

Meglumine Sodium chloride Sodium hydroxide (E 524) for pH adjustment Hydrochloric acid 0.1N (E 507) for pH adjustment Water for injection.

6.2 Incompatibilities

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

6.3 Shelf life

3 years After first opening the medicinal product should be use immediately.

6.4 Special precautions for storage

Do not freeze

6.5 Nature and contents of container

Type I colourless, siliconized 20 ml glass pre-filled syringes (containing a solution of 20 ml) graduated per ml, sealed with a synthetic polyisoprene/ bromobutyl stopper and a siliconized chlorobutyl-isoprene rubber plunger and packed in a unit box.

6.6 Instructions for use and handling

Instructions for use/handling by the doctor or health personnel: Screw the plunger rod onto the rubber plunger and inject intraarticularly the quantity of product required for the examination. For single use only. Any unused solution should be discarded. The solution for injection should be inspected visually prior to use. Only clear solutions free of visible particles should be used. The patients should remain under observation for half an hour after injection.

If administration of radiological contrast media is necessary to control the correct needle position into the joint, this contrast media should be injected before the administration of ARTIREM and not simultaneously because the efficacy of ARTIREM may be reduced.

7. MARKETING AUTHORIZATION HOLDER

Guerbet BP 57400 F-95943 Roissy CdG Cedex

8. MARKETING AUTHORIZATION NUMBER

Registered under {number}

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION

{date}

10. DATE OF REVISION OF THE TEXT

{date}

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ANNEX IV

CONDITIONS OF THE MARKETING AUTHORISATION

13 Conditions of the Marketing Authorisation

CHMP requirements in relation to the follow-up clinical pharmacokinetic study for assessing the time-course of an intra-articularly injected Gd-DOTA

Guerbet will conduct a clinical trial on ARTIREM entitled “MR arthrography: time-course of an intraarticularly injected gadolinium contrast agent” in January 2005, in line with the provided protocol. The study will focus on large and small joints “of importance” (shoulder, wrist, hip). ARTIREM will be injected in the joint and MR images will be acquired at several time-points to describe the fate of the contrast after injection. Guerbet commits to submit the results of this study to the CHMP members by December 2005.

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