1. Name Of The Medicinal Product
Magnevist® 2 mmol/l solution for injection
2. Qualitative And Quantitative Composition
1ml aqueous solution contains 1.876 mg gadopentetic acid, dimeglumine salt as active ingredient (equivalent to 0.002 mmol gadopentetic acid, dimeglumine, containing 0.32 mg gadolinium).
For excipients see section 6.1.
3. Pharmaceutical Form
Solution for injection.
4. Clinical Particulars
4.1 Therapeutic Indications
For contrast enhancement in direct magnetic resonance arthrography.
4.2 Posology And Method Of Administration
This medicinal product is for diagnostic use by intraarticular administration only.
The usual precautions for MRI (e.g. exclusion of cardiac pacemakers and other ferro-magnetic objects including vascular clips etc) must be observed.
The dose required is administered via intraarticular injection under strict aseptic technique and according to the instructions provided in section 6.6. 'Instructions for use and handling'. Contrast-enhanced MRI can be commenced immediately afterwards.
The recommendations for the use of Magnevist 2 mmol/l apply to a field strength between 0.2 Tesla and 1.5 Tesla.
Intraarticular administrations of contrast agents are to be given with the patient lying or sitting. After the end of the injection, the patient should be kept under supervision for at least half an hour.
Adults:
In general, for all joints the administration of up to 20 ml (knee joint up to 50 ml) Magnevist 2 mmol/l is sufficient for good opacification and to answer all the relevant clinical questions. A volume leading to a slight distension of the joint capsule should be injected. Only so much contrast medium should be injected until discrete resistance is felt and/or the patient experiences a mild feeling of pressure.
Guidelines on volumes to be administered:
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Children:
The product is not recommended in the paediatric age group until further data become available.
4.3 Contraindications
Hypersensitivity to any of the ingredients.
4.4 Special Warnings And Precautions For Use
Strict aseptic technique is required to prevent infection.
Fluoroscopic control should be used to ensure proper needle placement and prevent extracapsular injection. Undue pressure should not be exerted during injection.
Intraarticular injections of Magnevist 2 mmol/l should be avoided in infected joints.
• Hypersensitivity
Severe systemic hypersensitivity reactions cannot be totally excluded (see section 4.8).
Mild angioedema, conjunctivitis, coughing, pruritus, rhinitis, sneezing and urticaria, which can occur irrespective of the amount administered and the mode of administration, may be the first signs of incipient state of shock.
As with other contrast agents, delayed reactions may occur (hours later or up to several days).
As with other contrast enhanced diagnostic procedures, post-procedure observation of the patient is recommended.
Medication for the treatment of hypersensitivity reactions as well as readiness for institution of emergency measures are necessary. Appropriate drugs and instruments (e.g. endotracheal tube and ventilator) must be readily available.
The risk of hypersensitivity reactions is higher in case of;
- previous reaction to contrast media,
- history of bronchial asthma,
- history of allergic disorders
The decision to use Magnevist 2 mmol/l must be made after particularly careful evaluation of the risk-benefit-ratio in patients with an allergic disposition.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
As for all other gadolinium containing contrast media, no interactions with other medicaments have been observed. Formal drug interaction studies have not been carried out. See also section 6.2 Incompatibilities.
Magnevist should be administered without the addition of iodinated contrast media as iodinated contrast media reduce the level of contrast achievable with Magnevist (see Section 6.6 Instructions for use and handling).
4.6 Pregnancy And Lactation
• Pregnancy
For gadopentetic acid, dimeglumine no clinical study data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to embryonal / foetal development (see section 5.3).
Caution should be exercised using Magnevist 2mmol/l in pregnant women.
• Lactation
No data exist concerning intra-articular administration in lactating women. After intravascular use minimal amounts of gadopentetic acid, dimeglumine salt (a maximum of 0.04%) of the intravenously administered dose enters the breast milk. From experience gained so far, harm to the breast-fed infant is considered unlikely.
4.7 Effects On Ability To Drive And Use Machines
No effects of Magnevist 2 mmol/l on driving ability and use of machinery can be expected. However, joint effusion may affect the ability to drive due to a limited joint mobility.
4.8 Undesirable Effects
Frequency of adverse reactions from clinical trial data
Based on experience in more than 4,900 patients, the undesirable effects listed below have been observed and classified by investigators as drug-related.
Adverse reactions with the use of Magnevist 2 mmol are usually of mild to moderate intensity.
The most frequently reported reactions were local injection site reactions, i.e. injection site pain and joint pressure sensations which are mainly related to the procedure itself.
The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs).
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The most appropriate MedDRA term is used to describe a reaction and its synonyms and related conditions.
• Immune system disorders/Hypersensitivity/Allergic reaction
Systemic hypersensitivity may occur rarely in the form of skin reactions. The possibility of a severe hypersensitivity reaction cannot be totally excluded (see section 4.4).
• General disorders and administration site conditions
Injection of Magnevist 2 mmol/l into the joint is commonly associated with transient discomfort, e.g. pressure and pain due to the injected volume. Severe pain may often result from undue use of pressure or the injection of large volumes.
Other adverse reactions commonly known from intravenous injection of gadolinium chelates were so far not observed with Magnevist 2 mmol/l, due to the low dose and the topical administration.
4.9 Overdose
No signs of intoxication secondary to an overdose have so far been observed or reported on clinical use.
On the basis of the results of the acute toxicity studies with higher concentrated solutions of gadopentetic acid, dimeglumine, a risk of acute intoxication is highly unlikely after intraarticular injection of Magnevist 2 mmol/l.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Magnevist 2 mmol/l is a paramagnetic contrast agent for magnetic resonance imaging. The contrast-enhancing effect is mediated by the di-N-methylglucamine salt of gadopentetic acid, dimeglumine - the gadolinium complex of pentetic acid (diethylene triamine pentaacetic acid = DTPA). When a suitable scanning sequence (e.g. T1-weighted spin-echo technique) is used in proton magnetic resonance imaging, the gadolinium ion-induced shortening of the spin-lattice relaxation time of excited atomic nuclei leads to an increase of the signal intensity and, hence, to an increase of the image contrast of certain tissues.
Gadopentetic acid, dimeglumine is a highly paramagnetic compound which leads to distinct shortening of relaxation times, even in low concentrations. The paramagnetic efficacy, the relaxivity (determined from the influence on the spin-lattice relaxation time of protons) is 3.67 in water and about 4.95 l/mmol/sec in plasma, and displays only slight dependency on the strength of the magnetic field.
The concentration of Magnevist 2 mmol/l corresponds to 1/250 of the concentration used for i.v. administration. This concentration is sufficient to allow adequate imaging efficacy even after further dilution with joint effusion. If the joint cavity is filled with gadolinium-containing fluid, the signal in the cavity increases on use of T1-weighted sequences, i.e. it becomes bright and contrasts clearly with all structures with a weak or intermediate signal (i.e. all intraarticular structures: hyaline and fibrous cartilage, all ligaments, tendons and the joint capsule). While normal, or even increased, joint fluid does not differ in its signal behaviour in T1-weighted images from all the other anatomical structures apart from fibrocartilage, the intraarticular administration of Magnevist 2 mmol/l leads to distinctly improved contrast situations.
DTPA forms a firm complex with the paramagnetic gadolinium ion with extremely high in vivo and in vitro stability (log K = 22 - 23). The dimeglumine salt of gadopentetic acid, dimeglumine is a highly water-soluble, extremely hydrophilic compound with a distribution coefficient between n-butanol and buffer at pH 7.6 of about 0.0001. The substance does not display any particular protein binding or inhibitory interaction with enzymes (e.g. myocardial Na+ and K+ ATPase). Magnevist 2 mmol/l does not activate the complement system and, therefore, probably has a very low potential for inducing anaphylactoid reactions.
Based on clinical experience, impairment of hepatic, renal or cardiovascular function is not expected.
The physico-chemical properties of Magnevist 2 mmol/l listed below are:
Magnevist 2 mmol/l |
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5.2 Pharmacokinetic Properties
The pharmacokinetic properties of gadopentetic acid, dimeglumine have been extensively studied after intravenous and oral administration in doses exceeding the amount injected intraarticularly.
After intraarticular injection the compound distributes in the synovial fluid and diffuses into the interstitial space. Marginal uptake into the cartilage is completely reversible.
After distribution in the extracellular space primarily through diffusion controlled processes, the gadopentetic acid, dimeglumine is eliminated unmetabolised via the kidneys by glomerular filtration.
5.3 Preclinical Safety Data
• Systemic toxicity
Animal systemic tolerance studies following repeated daily intravenous administration, after doses much higher than that given intraarticularly, produced no findings which object to a single diagnostic administration of Magnevist 2 mmol/l to humans.
• Genotoxicity, tumorigenicity
Animal studies into genotoxic effects (gene, chromosomal and genome mutation tests) of gadopentetic acid, dimeglumine in vivo and in vitro gave no indication of a mutagenic potential.
In a tumorigenicity study with gadopentetic acid, dimeglumine in rats no compound-related tumours could be observed. Due to this fact, the absence of genotoxic effects and taking into account the pharmacokinetics and the absence of indications of toxic effects on fast-growing tissues, as well as the fact that Magnevist 2 mmol/l is clinically only administered once, there is no evident risk of a tumorigenic effect on humans.
• Local tolerance and contact-sensitising potential
Local tolerance studies with Magnevist 2 mmol/l following single intraarticular administration in animals gave no indication that adverse local effects can be expected in joints of humans.
Local tolerance studies with gadopentetic acid, dimeglumine following single subcutaneous and intramuscular administration in animals indicated that slight local intolerance reactions could occur at the injection site after inadvertent administration.
No indication of a contact-sensitising potential of gadopentetic acid, dimeglumine was observed during animal sensitisation studies.
6. Pharmaceutical Particulars
6.1 List Of Excipients
pentetic acid
meglumine
sodium chloride
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
6.4 Special Precautions For Storage
None
6.5 Nature And Contents Of Container
Prefilled syringe of 20ml
Glass barrel: glass type I, colourless
Plunger stopper: chlorinated butyl rubber
Tip cap: chlorinated butyl rubber
Luer Lock Adaptor: polysulphone
6.6 Special Precautions For Disposal And Other Handling
The prefilled syringe must be taken from the pack and prepared for the injection immediately before the examination and injected under sterile conditions.
The tip cap should be removed from the prefilled syringe immediately before use.
Any contrast medium solution not used in one examination must be discarded.
Mixture of Magnevist 2 mmol/l with X-ray contrast media before injection is not recommended as it may reduce efficacy. The minimal amount of X-ray contrast medium required for control of the needle position in the joint may be separately injected prior to the administration of Magnevist 2 mmol/l (0.5 ml to a maximum of 1.0 ml).
7. Marketing Authorisation Holder
Bayer plc
Bayer House
Strawberry Hill
Newbury
Berkshire
RG 14 1JA
Trading as Bayer plc, Bayer Schering Pharma
8. Marketing Authorisation Number(S)
PL 00010/0544
9. Date Of First Authorisation/Renewal Of The Authorisation
01 May 2008
10. Date Of Revision Of The Text
11 August 2008
Legal category: POM
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