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

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1 1. NAME OF THE MEDICINAL PRODUCT ARTIREM mmol/ml solution for injection in pre-filled syringes. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 ml solution for injection contains mg gadoteric acid (as meglumine salt), equivalent to mmol of gadoteric acid, meglumine, containing 0.39 mg gadolinium) 20 ml solution for injection contains mg gadoteric acid (as meglumine salt), equivalent to 0.05 mmol of gadoteric acid, meglumine, containing 7.86 mg gadolinium). For excipients, see 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. 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

2 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 betaagonists. 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. 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

3 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 intraarticular injection. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: paramagnetic contrast medium ATC code: V08 CA 02 (gadoteric acid). Contrast medium concentration mg/ml mmol/ml Osmolality at 37 C 285 mosm/kg H2O PH ARTIREM is a paramagnetic contrast medium for magnetic resonance imaging. The contrastenhancing 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.

4 The concentration of gadoteric acid 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 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 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

5 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 F 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}

Content (concentration) THE. Applicant Invented name Strength Pharmaceutical Form

Content (concentration) THE. Applicant Invented name Strength Pharmaceutical Form ANNEX I LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTH OF THE MEDICINAL PRODUCTS, ROUTE OF ADMINISTRATION, APPLICANT, MARKETING AUTHORISATION HOLDER IN THE MEMBER STATES 1/14 Member State Marketing Authorisation