Magnevist Injection

Document: spc-doc_PL 00010-0542 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Magnevist

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 0.5 mmol gadopentetate dimeglumine (equivalent to 469.01 mg gadopentetate dimeglumine).

For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

This medicinal product is for diagnostic use only as a paramagnetic contrast medium in cranial, spinal and whole body magnetic resonance imaging (MRI).

4.2 Posology and method of administration

Method of administration

Magnevist is to be administered only be intravenous injection.

Nausea and vomiting are known possible adverse reactions of all extracellular MRI contrast media. The patient should therefore refrain from eating for 2 hours prior to investigation to avoid aspiration. The usual precautions for MRI (e.g. exclusion of cardiac pacemakers and other ferro-magnetic objects including vascular clips etc) must be observed.

Instructions for use/handling

Magnevist should only be drawn up into the syringe immediately before use.

The rubber stopper should never be pierced more than once.

Any contrast medium not used in one examination must be discarded.

Contrast-enhanced MRI can start immediately after administration of the medium. Tj-weighted scanning sequences are particularly suitable for contrast-enhanced examinations with Magnevist.

Ideally the patient should be recumbent during administration, and should be kept under supervision for at least 30 minutes after the injection.

Posology

The recommended doses are given in ml of Magnevist per kg body weight.

Adults:

Cranial and spinal MRI

In general, the administration of 0.2ml Magnevist per kg body weight (equivalent to 0.1mmol gadopentetate dimeglumine per kg body weight) is sufficient to provide diagnostically adequate contrast.

If a strong clinical suspicion of a lesion persists despite a normal scan, a further injection of 0.2ml or even 0.4ml Magnevist per kg body weight within 30 minutes may increase the diagnostic yield.

For the exclusion of metastases or recurrent tumours, injection of 0.6ml Magnevist per kg body weight may increase the diagnostic yield.

Maximum single dose: 0.6ml Magnevist per kg of body weight.

Whole body MRI

In general, the administration of 0.2ml Magnevist per kg body weight is sufficient to provide diagnostically adequate contrast.

In special cases, e.g. in lesions with poor vascularisation and/or a small extracellular space, 0.4ml Magnevist per kg body weight may be necessary for an adequate contrast especially with relatively less heavily Tj-weighted scanning sequences.

For the exclusion of a lesion or tumour recurrences the injection of 0.6ml Magnevist per kg body weight may increase the diagnostic yield.

Maximum single dose: 0.6ml Magnevist per kg of body weight.

Special Populations

Renal impairment

Magnevist is contraindicated in patients with severe renal impairment (GFR < 30 ml / min / 1.73 m²) and/or acute kidney injury and in patients in the perioperative liver transplantation period (see section 4.3). Magnevist should only be used after careful risk/benefit evaluation in patients with moderate renal impairment (GFR 30 - 59 ml / min / 1.73 m²) at a dose not exceeding 0.2 ml per kg body weight (see section 4.4). More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Magnevist injections should not be repeated unless the interval between injections is at least 7 days.

Hepatic impairment

Since gadopentetate is almost exclusively eliminated in an unchanged form via the kidneys, no dosage adjustment is considered necessary in patients with moderate hepatic impairment. Data on patients with severe hepatic impairment are not available (see section 5.2).

Elderly (aged 65 years and above)

No dosage adjustment is considered necessary. Caution should be exercised in elderly patients (see section 4.4).

Paediatric Population Cranial and spinal MRI

Children (including infants under the age of 2 years):

0.2ml Magnevist per kg bodyweight is sufficient to provide diagnostically adequate contrast.

In infants (under 2 years of age) the required dose should be administered by hand.

Magnevist is contrainidicated in neonates up to 4 weeks of age (see section 4.3).

Due to immature renal function in infants up to 1 year of age Magnevist should only be used in these patients after careful consideration at a dose not exceeding 0.2 ml per kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Magnevist injections should not be repeated unless the interval between injections is at least 7 days.

If a strong clinical suspicion of a lesion persists despite a normal scan in patients over 1 year of age, a further injection of 0.2ml Magnevist per kg body weight within 30 minutes may increase the diagnostic yield.

Whole body MRI

Children (over the age of 2 years):

In general, 0.2ml Magnevist per kg body weight is sufficient to provide diagnostically adequate contrast.

Neonates and Infants under the age of 2 years:

Magnevist is contraindicated in neonates up to 4 weeks of age (see section 4.3).

Experience in children under the age of 2 years is limited. However, this limited experience has shown that 0.2ml Magnevist per kg body weight may be used in this particular age group. In infants (under 2 years of age) the required dose should be administered by hand.

4.3 Contraindications

Hypersensitivity or allergy to the active substance or to any of the excipients listed in section 6.1 (see also Section 4.4).

Use of Magnevist is contraindicated in patients with severe renal impairment

(GFR <30 ml/min/1.73m²) and/or acute kidney injury, in patients in the perioperative liver

transplantation period and in neonates up to 4 weeks of age (see section 4.4).

4.4 Special warnings and precautions for use

• Hypersensitivity and hypersensitivity reactions

Particularly careful risk-benefit assessment is required in patients with known hypersensitivity to Magnevist.

As with other intravenous contrast agents, Magnevist can be associated with anaphylactoid / hypersensitivity or other idiosyncratic reactions (characterised by cardiovascular, respiratory or cutaneous manifestations) ranging to severe reactions including shock.

The risk of hypersensitivity reactions is higher in case of:

• previous reaction to contrast media,

• history of bronchial asthma,

• history of allergic disorders

In patients with an allergic disposition (especially with a history of the above-mentioned conditions) the decision to use Magnevist must be made after particularly careful evaluation of the risk-benefit ratio.

Most of these reactions occur within half an hour of administration. Therefore, 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.

Delayed reactions (hours later or up to several days) have been rarely observed (see section 4.8 Undesirable effects).

Patients who experience hypersensitivity reactions while taking beta blockers may be resistant to treatment effects of beta agonists.

Patients with cardiovascular disease are more susceptible to serious or even fatal outcomes of severe hypersensitivity reactions.

• Patients with impaired renal function

Prior to administration of Magnevist, all patients should be screened for renal dysfunction by obtaining laboratory tests.

There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of Magnevist and some other gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment (GFR <30ml/min/1.73 m²) and/or acute kidney injury. Magnevist is contraindicated in these patients (see section 4.3). Patients undergoing liver transplantation are at particular risk since the incidence of acute renal failure is high in this group. Therefore Magnevist must not be used in patients in the perioperative liver transplantation period and in neonates (see section 4.3).

The risk for development of NSF in patients with moderate renal impairment (GFR 3059 ml/min/1.73m²) is unknown, therefore, Magnevist should only be used after careful risk-benefit evaluation in patients with moderate renal impairment.

Haemodialysis shortly after Magnevist administration may be useful at removing Magnevist from the body. Approximately 70% of the administered dose is removed with each dialysis session, such that after 3 dialysis sessions of 3 hours each, about 97% of the total administered dose is eliminated from the body. There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in patients not already undergoing haemodialysis.

• Neonates and infants

Magnevist is contraindicated in neonates up to 4 weeks of age (see section 4.3). Due to immature renal function in infants up to 1 year of age, Magnevist should only be used in these patients after careful consideration (see section 4.2).

• Elderly

As the renal clearance of gadopentetate may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction.

• Seizure disorders

Patients with seizure disorders or intracranial lesions may be at increased risk of seizure activity, as this has been reported rarely in association with Magnevist administration (see section 4.8).

For patients predisposed to seizures, precautionary measures should be taken, e.g. close monitoring; all equipment and drugs necessary to counter any convulsions which may occur must be made ready for use beforehand.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies with other medicinal products have been conducted.

The results of serum iron determinations using complexometric methods (e.g. bathophenanthroline) may result in falsely low values for up to 24 hours after the administration of Magnevist because of the free DTPA contained in the contrast-medium solution.

4.6 Pregnancy and lactation

• Pregnancy

There are no data from the use of gadopentetate in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3). Magnevist should not be used during pregnancy unless the clinical condition of the woman requires use of gadopentetate.

• Lactation

Small amounts of gadopentetate dimeglumine (up to 0.04% of the administered dose) are excreted in human milk. A risk to the suckling child

cannot be excluded. Breast-feeding should be discontinued for at least 24 hours after the administration of Magnevist.

4.7 Effects on ability to drive and use machines

None stated.

4.8 Undesirable effects

The overall safety profile of Magnevist is based on data from post-marketing surveillance and from more than 11,000 patients in clinical trials.

The most frequently observed adverse drug reactions (> 0.4%) in patients receiving Magnevist in clinical trials are various injection site reactions, headache and nausea.

Most of the adverse drug reactions in clinical trials were of mild to moderate intensity.

Overall, the most serious adverse drug reactions in patients receiving Magnevist are:

• Nephrogenic systemic fibrosis

• Anaphylactoid reactions/anaphylactoid shock

Delayed hypersensitivity/anaphylactoid reactions (hours later up to several days) have been rarely observed (see section 4.4).

The adverse drug reactions observed with Magnevist are represented in the table below. They are classified according to System Organ Class (MedDRA). The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Adverse drug reactions from clinical trials are classified according to their frequencies. Frequency groupings are defined according to the following convention: uncommon: > 1/1,000 to < 1/100; rare: >1/10,000 to <1/1,000. The adverse drug reactions identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under ‘not known’.

Table 1: Adverse drug reactions reported in clinical trials or during postmarketing surveillance in patients treated with Magnevist.

System organ class	Uncommon	Rare	Not known
Blood and lymphatic system disorders			Serum iron increased*
Immune system disorders		Hypersensitivity /anaphylactoid reaction (e.g. anaphylactoid shock, Anaphylactoid reaction§ , Hypersensitivity reactions§ , Shock§ , Hypotension§ , Conjunctivitis, Loss of consciousness§ , Throat

		tightness, Sneezing, Urticaria, Pruritus, Rash, Erythema, Dyspnoea, Respiratory arrest⁸ , Bronchospasm⁸ , Wheezing, Laryngospasm⁸ , Laryngeal oedema⁸ , Pharyngeal oedema⁸ , Cyanosis⁸ , Rhinitis⁸, Angioedema⁸ , Oedema face, Reflex tachycardia⁸)
Psychiatric disorders		Disorientation	Agitation Confusion
Nervous system disorders	Dizziness Headache Dysgeusia	Convulsion* Paraesthesia Burning sensation Tremor	Coma* Somnolence* Speech disorder Parosmia
Eye disorders			Visual disturbance Eye pain Lacrimation
Ear and labyrinth disorders			Hearing impaired Ear pain
Cardiac disorders		Tachycardia* Arrhythmia	Cardiac arrest* Heart rate decreased/bradycardia*
Vascular disorders		Thrombophlebitis Flushing Vasodilatation	Syncope* Vasovagal reaction Blood pressure increased
Respiratory, thoracic and mediastinal disorders		Throat irritation Pharyngolaryngeal pain / pharynx discomfort Cough	Respiratory distress Respiratory rate increased or Respiratory rate decreased Pulmonary oedema*
Gastrointestinal disorders	Vomiting Nausea	Abdominal pain Stomach discomfort Diarrhoea Toothache Dry mouth Oral soft tissue pain and paraesthesia	Salivation
Hepatobiliary disorders			Blood bilirubin increased Hepatic enzyme increased
Skin and subcutaneous tissue disorders			Nephrogenic Systemic Fibrosis (NSF), **
Musculoskeletal, connective tissue and bone disorders		Pain in extremity	Back pain Arthralgia
Renal and urinary disorders			Acute renal failure,* Increased serum creatinine** Urinary incontinence Urinary urgency
General disorders and administration site conditions	Pain Feeling hot Feeling cold	Chest pain Pyrexia Oedema peripheral	Chills Sweating Body temperature

Life-threatening and/or fatal cases have been reported.

Injection site	Malaise	increased or Body
reactions (e.g.	Fatigue	temperature decreased
Injection site	Thirst
coldness, paraesthesia, swelling, warmth, pain, oedema, irritation, haemorrhage, erythema, discomfort, necrosis^§, thrombophlebitis^§, phlebitis^§, inflammation^§, extravasation§)	Asthenia

***

In patients with pre-existing renal impairment.

In patients with acute or chronic severe renal impairment

Reactions identified only during post-marketing surveillance (frequency not known).

Cases of nephrogenic systemic fibrosis (NSF) have been reported with Magnevist (see section 4.4).

In patients with dialysis-dependent renal failure who received Magnevist, delayed and transient inflammatory-like reactions such as fever, chills and C-reactive protein increase have been commonly observed. These patients had the MRI examination with Magnevist on the day before haemodialysis.

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.

4.9 Overdose

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

Accidental overdose may cause the following effects due to the hyperosmolality of Magnevist: increase of pulmonary artery pressure, osmotic diuresis, hypervolaemia and dehydration.

In case of inadvertent overdose, renal function should be monitored in patients with renal impairment.

Magnevist can be removed by haemodialysis (see section 4.4). However, there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: paramagnetic contrast media ATC Code: V08CA01

• Mechanism of action

Magnevist is a paramagnetic contrast agent for magnetic resonance imaging.

When T1-weighted scanning sequences are used in magnetic resonance imaging, the gadopentetate-induced shortening of the spin-lattice relaxation time (T1) of excited water protons leads to an increase of the signal intensity and, hence, to an increase of the image contrast of certain tissues.

• Pharmacodynamic effects

Gadopentetate is a highly paramagnetic compound which leads to distinct shortening of the relaxation times even at low concentrations. The paramagnetic efficacy at a magnetic field strength of 1.5 T and 37°C, the relaxivity (r1) - determined from the influence on the T1 relaxation time of the water protons in plasma and the relaxivity (r₂) - determined from the influence on the T2 relaxation time - is about 4.1 ± 0.2 l/(mmol-sec) and 4.6 ± 0.8 l/(mmol-sec), respectively. The relaxivities display only slight dependency on the strength of the magnetic field.

Diethylene triamine pentaacetic acid (DTPA) forms a complex with the paramagnetic gadolinium ion with high in-vivo and in-vitro stability (thermodynamic stability constant: log K_GdL = 22-23). Gadopentetate dimeglumine is a highly water-soluble, hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of about 0.0001. When tested in vitro with the enzymesacetylcholinesterase and lysozyme at clinically relevant concentrations gadopentetate dimeglumine did not display significant inhibitory interaction. Magnevist does not activate the complement system and, therefore, probably has a very low potential for inducing anaphylactoid reactions.

In higher concentrations and on prolonged incubation, gadopentetate dimeglumine has a slight in-vitro effect on erythrocyte morphology. After intravenous administration of Magnevist in man, the reversible process could lead to weak intravascular haemolysis, which might explain the slight increase of serum bilirubin and iron occasionally observed in the first few hours after injection.

Physico-chemical properties of Magnevist 0.5 mmol/ml are listed below:

Magnevist 0.5 mmol/ml (0.5 mol/l)

Contrast medium concentration (mg/ml)		469.01
Contrast medium content (g) per vial of		2.3
5ml		4.7
	10ml	7.0
	15ml	9.4
	20ml	14.1
	30ml
Osmolarity at 37°C (mosmol/l solution)		1440.0
Osmolality at 37°C (mosmol/kg H₂0)		1960.0
Osmotic pressure at 37°C	(atm)	49.8
	(MPa)	5.06
Density (g/ml or kg/l)	at	1.210
20°C		1.195
	at
37°C
Viscosity (mPa.s)	at	4.9
20°C		2.9
	at
37°C
pH		7.0 - 7.9

5.2 Pharmacokinetic properties

Gadopentetate behaves in the organism like other highly hydrophilic biologically inert compounds (e.g mannitol or inulin).

• Absorption and distribution

After intravenous administration of Magnevist, plasma levels decline rapidly bi-exponentially with a terminal half-life of about 90 minutes.

Gadopentetate is rapidly distributed in the extracellular space. The total distribution volume of gadopentetate is about 0.26 l per kg. Protein binding is negligible.

In studies in rats and dogs, relatively high concentrations of the intact gadolinium complex were found in the kidneys amounting to about 0.15% of administered dose seven days after intravenous administration of radioactively labelled gadopentetate. Less than 1% of the administered dose was found in the remaining parts of the body of both species.

Gadopentetate neither penetrates nor passes a blood-testis barrier. The small amount which overcomes the placental barrier is quickly eliminated by the foetus.

In a clinical study in lactating women (aged 23-38 years), less than 0.04% of administered gadopentetate was excreted into human breast milk. In rats, absorption from the gastrointestinal tract after oral administration was found to be small (4%).

• Metabolism

Gadopentetate is not metabolised.

• Elimination

Gadopentetate is eliminated in unchanged form via the kidneys by glomerular filtration. The fraction eliminated extra-renally is less than 1% of the administered dose.

An average of 83% of the dose was eliminated within 6 hours post-injection. About 91% of the dose was recovered in the urine within the first 24 hours. The renal clearance of

gadopentetate was about 120ml/min/1.73m² and is therefore comparable to substances that are exclusively excreted by glomerular filtration (e.g. inulin or ⁵¹Cr-EDTA).

• Characteristics in special patient populations

Elderly population (aged 65 years and above)

Magnevist is excreted renally and its clearance is reduced with age as expected due to the age-related physiological reduction in renal function. Magnevist urinary recovery remains similar to non-elderly subjects.

Renal impairment

In patients with impaired renal function; the serum half-life of gadopentetate is prolonged due to the reduced glomerular filtration rate. After administration of a single intravenous dose to 10 patients with impaired renal function (4 patients with mild renal impairment [creatinine clearance > 60 to < 90 ml/min] and 6 patients with moderate renal impairment [creatinine clearance > 30 to < 60 ml/min]), mean half-lives were 2.6 ± 1.2 hours and 4.2 ± 2.0 hours for the mildly and moderately impaired patients, respectively, as compared to 1.6 ± 0.13 hours in healthy subjects.

Gadopentetate is completely renally excreted within two days in patients with slightly to moderately impaired renal function (creatinine clearance > 30 ml/min).

Paediatric population

In a study with paediatric patients aged 2 months to < 2 years the pharmacokinetics (body weight-normalised clearance, distribution volume, area under the concentration-time curve and terminal half-life) of gadopentetate were similar to adults.

5.3 Preclinical safety data

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

• Reproduction toxicity

Reproduction-toxicological studies with Magnevist gave no indication of a teratogenic potential following the administration of Magnevist during pregnancy.

With daily dosage in the pregnant rat for 10 days of 12.5 times, and in the pregnant rabbit for 13 days of at least 7.5 times the human dose per unit weight, there was slight retardation of foetal growth and ossification.

• Local tolerance

Experimental local tolerance studies following a single paravenous, subcutaneous as well as intramuscular application indicated that slight local intolerance reactions could occur at the administration site after inadvertent paravenous administration.

6 PHARMACEUTICAL PARTICULARS

List of excipients

6.1

Meglumine Pentetic acid (DTPA) 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

5 years.

6.4 Special precautions for storage

Keep the container (vials, ampoules) in the outer carton in order to protect from light.

This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

Pack size

Colourless glass injection vials with 5ml, 10ml, 15ml, 20ml and 30ml

chlorinated butyl rubber stoppers and pure aluminium lacquered flange caps

Colourless glass ampoules 10ml, 15ml, and 20ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

This medicinal product should be visually inspected before use.

Magnevist should not be used in case of severe discolouration, the occurrence of particulate matter or a defective container.

The peel-off tracking label on the vials/ampoules should be stuck onto the patient record to enable accurate recording of the gadolinium contrast agent used. The dose used should also be recorded. If electronic patient records are used, the name of the product, the batch number and the dose should be entered into the patient record.

Please also refer to section 4.2.

7 MARKETING AUTHORISATION HOLDER

Bayer plc Bayer House Strawberry Hill Newbury

Berks RG14 1JA

8 MARKETING AUTHORISATION NUMBER(S)

PL 00010/0542

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/12/1988 / 09/01/2009

10 DATE OF REVISION OF THE TEXT

19/05/2016