This information is intended for use by health professionals

1. Name of the medicinal product

Magnevist 2 mmol/l solution for injection

2. Qualitative and quantitative composition

1 ml 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).

Excipient with known effect: sodium chloride

Magnevist 2 mmol/l contains 3.4 mg sodium per ml

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection.

Clear, colourless to pale yellow or brownish-yellow solution.

4. Clinical particulars
4.1 Therapeutic indications

For contrast enhancement in direct magnetic resonance arthrography.

This medicinal product is for diagnostic use by intraarticular administration only.

Magnevist 2 mmol/l should be used only when diagnostic information is essential and not available with unenhanced magnetic resonance imaging (MRI) and when another authorised product cannot be used.

4.2 Posology and method of administration

The usual precautions for MRI (e.g. exclusion of cardiac pacemakers and other ferro-magnetic objects including vascular clips etc) must be observed.

Posology

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.

The lowest dose that provides sufficient enhancement for diagnostic purposes should be used.

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:

Joint

Volume required

Shoulder

15-20 ml

Elbow

~ 10 ml

Wrist

4 ml

Finger joint

1-2 ml

Hip

10-20 ml

Knee

25-50 ml

Ankle

12-20 ml

Paediatric population:

The safety and efficacy of Magnevist 2 mmol/l in children aged up to 18 years has not yet been established. No data are available. Magnevist 2 mmol/l is not recommended in the paediatric age group until further data become available.

Method of administration

The dose required is administered via intraarticular injection under strict aseptic technique and according to the instructions provided in section 6.6. Contrast-enhanced MRI can be commenced immediately afterwards.

4.3 Contraindications

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

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.

After intravenous administration of gadopentetic acid, dimeglumine salt, gadolinium can be retained in the brain and in other tissues of the body (bones, liver, kidneys, skin) and can cause dose-dependent increases in T1-weighted signal intensity in the brain, particularly in the dentate nucleus, globus pallidus, and thalamus. Clinical consequences are unknown. Retention of gadolinium in the brain has not been identified for intra-articular administration. The possible diagnostic advantages of using gadopentetic acid, dimeglumine salt in patients who will require repeated scans should be weighed against the potential for deposition of gadolinium in the brain and other tissues.

• Magnevist 2 mmol/l contains sodium

This medicinal product contains 3.4 mg sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

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.

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).

4.6 Fertility, 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 2 mmol/l in pregnant women.

• Breast-feeding

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/l 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).

System Organ Class

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Nervous system disorders

Headache

Dizziness

Vascular disorders

Vasovagal reaction

Gastrointestinal disorders

Nausea

Vomiting

General disorders and administration site conditions

Injection site pain/ Injection site (joint) pressure sensation

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.

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

4.9 Overdose

No signs of intoxication secondary to an overdose have so far been observed or reported on clinical use.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: paramagnetic contrast media, ATC code: V08CA01

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

Contrast medium concentration

(mg/ml)

1.88

Osmolality (Osm/kg H2O)

At 37°C

0.29

Viscosity (mPa·s)

At 20°C

At 37°C

 

1.03

0.71

Density (g/ml)

At 20°C

At 37°C

 

1.01

1.00

pH-value

4.8-8.0

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.

Gadopentetic acid, dimeglumine salt is a linear GdCA. Studies have shown that after exposure to GdCAs given intravenously at significantly higher doses than intra-articular products gadolinium is retained in the body. This includes retention in the brain and in other tissues and organs. With the linear GdCAs this can cause dose-dependent increases in T1-weighted signal intensity in the brain, particularly in the dentate nucleus, globus pallidus, and thalamus. Signal intensity increases and non-clinical data show that gadolinium is released from linear GdCAs.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of systemic toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and contact sensitising potential.

• Local tolerance

Experimental local tolerance studies with gadopentetic acid, dimeglumine (at a concentration of 500 mmol/l) following single subcutaneous and intramuscular administration in animals indicated that slight local intolerance reactions could occur at the injection site after inadvertent administration.

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

Colourless Type I, glass pre-filled syringe with chlorinated butyl rubber stopper and combined luer lock adapter, tip cap (chlorobutyl rubber), safety cap.

Pack size: syringe containing 20 ml of Magnevist solution; individual syringe is blister packaged, with one syringe per carton.

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

400 South Oak Way

Reading

RG2 6AD

8. Marketing authorisation number(s)

PL 00010/0544

9. Date of first authorisation/renewal of the authorisation

Date of First Authorisation:

01 May 2008

Date of Renewal of the Authorisation:

23 February 2009

10. Date of revision of the text

15 January 2019