Dotarem Solution For Injection
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Dotarem® Solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
|
Name of ingredients |
Formula per ml |
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Active ingredient: Gadoteric acid * In: |
279.32 mg (equivalent to 0.5 mmol/ml) Bottle |
*Gadoteric acid: 1, 4, 7, 10 tetraazacyclododecane N, N’, N”, N’’’ tetraacetic acid gadolinium complex
Osmolality: 1350 mOsm.kg"1 Viscosity at 20°C: 3.2 mPa.s Viscosity at 37°C: 2.0 mPa.s pH: 6.5 to 8.0
3. PHARMACEUTICAL FORM
Solution for injection.
5, 10, 15, and 20 ml bottles.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Adult population
Enhancement of contrast in Magnetic Resonance Imaging.
Encephalic and spinal MRI: Detection of brain tumours, tumours of the spine and the surrounding tissue, invertebral disc prolapse, infectious diseases.
Whole Body MRI including imaging for renal, cardiac, uterine, ovarian, breast, abdominal and osteo-articular pathology.
Angiography.
Paediatric population (0-18 years)
• Enhancement of contrast in Magnetic Resonance Imaging.
• Encephalic and spinal MRI: Detection of brain tumours, tumours of the spine and the surrounding tissue, invertebral disc prolapse, infectious diseases.
• Whole Body MRI including imaging for renal, cardiac, uterine, ovarian, breast, abdominal and osteo-articular pathology.
4.2 Posology and method of administration
Posology
Adults including the elderly:
Encephalic and Spinal MRI. In most cases the recommended dose is 0.1mmol.kg"1, i.e. 0.2ml.kg"1 which is sufficient to provide diagnostically adequate contrast. If a strong clinical suspicion of a lesion persists despite a normal MRI examination, a further injection of 0.2mmol.kg-1, i.e. 0.4ml.kg-1 within 30 minutes, may improve tumour characterisation and facilitate therapeutic decision making.
Whole body MRI and Angiography. The administration of 0.1mmol.kg"1, i.e. 0.2ml.kg"1 is recommended to provide diagnostically adequate contrast.
Angiography : In exceptional circumstances (e.g. failure to gain satisfactory images of an extensive vascular territory) administration of a second consecutive injection of 0.1mmol.kg-1, i.e 0.2ml.kg-1 may be justified. However, if the use of 2 consecutive doses of Dotarem is anticipated prior to commencing angiography of certain regions (such as leg arteries or lungs), use of 0.05 mmol.kg"1 (i.e. 0.1ml.kg-1) for each dose may be of benefit, depending on the imaging equipment available.
Special populations Impaired renal function
Dotarem should only be used in patients with severe renal impairment (GFR < 30 ml/min/1.73m2) and in patients in the perioperative liver transplantation period after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced MRI (see section 4.4). If it is necessary to use Dotarem, the dose should not exceed 0.1 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of
information on repeated administration, Dotarem injections should not be repeated unless the interval between injections is at least 7 days.
Elderly (aged 65 years and above)
No dosage adjustment is considered necessary. Caution should be exercised in elderly patients (see section 4.4).
Impaired hepatic function
The adult dose applies to these patients. Caution is recommended, especially in the case of perioperative liver transplantation period (see above impaired renal function).
Paediatric population (0-18 years)
Encephalic and Spinal MRI, Whole body MRI: the recommended and maximum dose of Dotarem is 0.1 mmol/kg body weight. More than one dose should not be used during a scan.
Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age, Dotarem should only be used in these patients after careful consideration, at a dose not exceeding 0.1 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Dotarem injections should not be repeated unless the interval between injections is at least 7 days.
Angiography: Dotarem is not recommended for angiography in children under 18 years of age due to insufficient data on its efficacy and safety in this indication.
Method of administration
The product is intended for intravenous administration only.
Paediatric population (0-18 years)
Depending on the amount of Dotarem to be given to the child, it is preferable to use Dotarem vials with a single use syringe of a volume adapted to this amount in order to have a better precision of the injected volume.
In neonates and infants the required dose should be administered by hand.
4.3 Contraindications
Hypersensitivity to gadoteric acid, to meglumine or to any medicinal products containing gadolinium.
Contra-indication related to MRI i.e. patient with pace-makers, vascular clips, infusion pumps, nerve stimulators, cochlear implants, or suspected intracorporeal metallic foreign bodies, particularly in the eye.
4.4 Special warnings and precautions for use
* Dotarem must not be administered by subarachnoid (or epidural) injections.
Hypersensitivity
- As with other gadolinium containing contrast media hypersensitivity reactions can occur, including life-threatening (see section 4.8). Hypersensitivity reactions may be either allergic (described as anaphylactic reactions when serious) or non allergic. They can be either immediate (less than 60 minutes), or delayed (up to 7 days). Anaphylactic reactions occur immediately and can be fatal. They are independent of the dose, can occur after even the first dose of the product, and are often unpredictable.
- There is always a risk of hypersensitivity regardless of the dose injected.
- Patients who have already experienced a reaction during previous administration of a gadolinium-containing MRI contrast agent present an increased risk of experiencing another reaction on subsequent administration of the same product, or possibly other products, and are therefore considered to be at high risk.
- The injection of gadoteric acid may aggravate symptoms of an existing asthma. In patients with asthma unbalanced by the treatment, the decision to use gadoteric acid 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 on beta-blockers, and particularly in the presence of bronchial asthma. These patients may be refractory to standard treatment of hypersensitivity reactions with beta-agonists.
- Before any contrast medium is injected, the patient should be questioned for a history of allergy (e.g. seafood allergy, hay fever, hives), sensitivity to contrast media and bronchial asthma as the reported incidence of adverse reactions to contrast media is higher in patients with these conditions and premedication with antihistamines and/or glucocorticoids may be considered.
- 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 instituted. A venous access should thus be kept during the entire examination. To permit immediate emergency countermeasures, appropriate drugs (e.g. epinephrine and antihistamines), an endotracheal tube and a respirator should be ready at hand.
* Impaired renal function
Prior to administration of Dotarem, it is recommended that all patients are screened for renal dysfunction by obtaining laboratory tests.
There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of some gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment (GFR < 30 ml/min/1.73m ). Patients undergoing liver transplantation are at particular risk since the incidence of acute renal failure is high in this group. As there is a possibility that NSF may occur with Dotarem, it should therefore only be used in patients with severe renal impairment and in patients in the perioperative liver transplantation period after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced MRI.
Haemodialysis shortly after Dotarem administration may be useful at removing Dotarem 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.
* Elderly
As the renal clearance of gadoteric acid may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction.
* Paediatric population
Neonates and infants
Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age, gadoteric acid should only be used in these patients after careful consideration.
* CNS disorders
Like with other gadolinium containing contrast agents special precaution is necessary in patients with a low threshold for 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 interactions with other medicinal products have been observed. Formal drug interaction studies have not been carried out.
Concomitant medications to be taken into account
Beta-blockers, vasoactive substances, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists: these medicinal products decrease the efficacy of the mechanisms of cardiovascular compensation for blood pressure disorders: the radiologist must be informed before injection of gadolinium complexes, and resuscitation equipment must be at hand.
4.6 Fertility, pregnancy and lactation Pregnancy
There are no data from the use of gadoteric acid in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Dotarem should not be used during pregnancy unless the clinical condition of the woman requires use of gadoteric acid.
Lactation
Gadolinium containing contrast agents are excreted into breast milk in very small amounts (see section 5.3). At clinical doses, no effects on the infant are anticipated due to the small amount excreted in milk and poor absorption from the gut. Continuing or discontinuing breast feeding for a period of 24 hours after administration of Dotarem, should be at the discretion of the doctor and lactating mother.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. Ambulant patients while driving vehicles or operating machinery should take into account that nausea may incidentally occur
4.8 Undesirable effects
Side effects in association with the use of gadoteric acid are usually mild to moderate in intensity and transient in nature. A sensation of heat, cold and/or pain at the injection site are the most frequently observed reactions.
During clinical trials, headache and paresthesia were very commonly observed (>1/10), and nausea, vomiting and skin reactions such as erythematous rash and pruritus were commonly observed (>1/100 - <1/10).
Since post-marketing, the most commonly reported adverse reactions following administration of gadoteric acid are nausea, vomiting, pruritus and hypersensitivity reactions.
In hypersensitivity reactions, the reactions most frequently observed are skin reactions, which can be localized, extended or generalized.
These reactions occur most often immediately (during the injection or within one hour after the start of injection) or sometimes delayed (one hour to several days after injection), presenting as skin reactions in this case.
Immediate reactions include one or more effects, which appear simultaneously or sequentially, which are most often cutaneous, respiratory and/or cardiovascular reactions. Each sign may be a warning sign of a starting shock and go very rarely to death.
Isolated cases of nephrogenic systemic fibrosis (NSF) have been reported with gadoteric acid, most of which were in patients co-administered other gadolinium-containing contrast agents (see section 4.4).
The adverse reactions are listed in the table below by SOC (System Organ Class) and by frequency with the following
guidelines: very common (>1/10), common (>1/100 to 1<1/10), uncommon (>1/1000 to 1<1/100), rare (>1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data). The data presented are from clinical trials when available, or from an observational study involving 82,103 patients.
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Organ Class System |
Frequency : adverse reaction |
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Immune system disorders |
Uncommon: hypersensitivity, anaphylactic reaction, anaphylactoid reaction |
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Psychiatric disorders |
Very rare: agitation, anxiety |
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Nervous system disorders |
Very common: paraesthesia, headache Rare: dysgeusia Very rare: coma, convulsion, syncope, presyncope, dizziness, parosmia, tremor |
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Eye disorders |
Very rare: conjunctivitis, ocular hyperaemia, vision blurred, lacrimation increased, eyelid oedema |
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Cardiac disorders |
Very rare: cardiac arrest, bradycardia, tachycardia, arrhythmia, palpitations |
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Vascular disorders |
Very rare: hypotension, hypertension, vasodilatation, pallor |
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Respiratory, thoracic and mediastinal disorders |
Very rare: respiratory arrest, pulmonary oedema, bronchospasm, laryngospasm, pharyngeal oedema, dyspnoea, nasal congestion, sneezing, cough, dry throat |
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Gastrointestinal disorders |
Common: nausea, vomiting Very rare: diarrhoea, abdominal pain, salivary hypersecretion |
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Skin and subcutaneous tissue disorders |
Common: pruritus, erythema, rash Rare: urticaria, hyperhidrosis, Very rare: eczema, angioedema Not known: nephrogenic systemic fibrosis |
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Musculoskeletal and connective tissue disorders |
Very rare: muscle contracture, muscular weakness, back pain |
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General disorders and administration site conditions |
Common: feeling hot, feeling cold, injection site pain Very rare : malaise, thoracic pain, chest discomfort, fever, chills, face oedema, asthenia, injection site discomfort, injection site reaction, injection site oedema, injection site extravasation, injection site inflammation (in case of extravasation), injection site necrosis (in case of extravasation), superficial phlebitis |
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Investigations |
Very rare: decreased oxygen saturation |
The following adverse reactions were reported with other intravenous contrast agents for MRI :
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Organ Class System |
Adverse reaction |
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Blood and lymphatic system disorders |
Haemolysis |
|
Psychiatric disorders |
Confusion |
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Eye disorders |
Blindness transient, eye pain |
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Ear and labyrinth disorders |
Tinnitus, ear pain |
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Respiratory, thoracic and mediastinal disorders |
Asthma |
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Gastrointestinal disorders |
Dry mouth |
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Skin and subcutaneous tissue disorders |
Dermatitis bullous |
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Renal and urinary disorders |
Urinary incontinence, renal tubular necrosis, renal failure acute |
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Investigations |
Electrocardiogram PR prolongation, blood iron increased, blood bilirubin increased, serum ferritin increased, liver function test abnormal |
Adverse reaction in Children
Adverse events related to gadoteric acid are uncommon in children. The expectedness of these events is identical to that of the events reported in adults.
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 national reporting system:
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
There is no experience to date of overdose with DOTAREM®.
Dotarem can be removed by haemodialysis. However there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic Properties
Gadoteric acid has paramagnetic properties which increase contrast enhancement in MRI. It has no specific pharmacodynamic activity and is highly biologically inert.
5.2 Pharmacokinetic properties
After intravenous injection, gadoteric acid is distributed in the extracellular fluids of the body. It does not bind to plasmatic albumin.
In patients with normal renal function, the plasmatic half-life is approximately 90 minutes. It is eliminated by glomerular filtration in unchanged form. Plasmatic clearance is retarded in the event of renal failure.
In animals, gadoteric acid excretion in milk is low and crossing of the placental barrier is slow.
To date no data exist concerning the kinetics in the elderly, children, pregnant or lactating women or hepatically impaired.
5.3 Preclinical Safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or toxicity to reproduction.
The acute toxicity of DOTAREM® injected intravenously (2ml.min-1) was studied in mice (at doses between 16 and 26 ml/kg) and in rats (at a dose of 25ml/kg). The manifestations observed were convulsive signs and transient respiratory disorders. Deaths occurred in the two studies, from a dose of 18ml/kg upwards in mice. Necropsy revealed a hemorrhagic appearance in the lungs and sometimes in the kidney. In another specific study in mice a minor proconvulsive effect was observed after IV administration of a dose of 4ml/kg.
The administration of DOTAREM® in rats and in dogs at daily doses up to 3ml/kg, i.e. 15 times the dose laid down in clinical conditions, and for 28 days cause no other effect than a reversible vacuolisation of the proximal tubular cells of the kidney.
DOTAREM® is non-toxic for gestating females, non embryo-toxic and non teratogenic for the foetus. No prior peri- and post-natal toxicity and fertility studies have been carried out.
DOTAREM® showed no cytotoxic or mutagenic action in the in vivo and in vitro tests used.
Animal studies have shown negligible (less than 1 % of the administered dose) secretion of gadoteric acid in maternal milk.
6. PHARMACEUTICAL PARTICULARS
6.1 List of Excipients
Meglumine Water for injection Nitrogen Gas
6.2 Incompatibilities
There are no known incompatibilities.
6.3 Shelf life
3 years.
6.4 Special Precautions for Storage
There are no special precautions for storage.
6.5 Nature and Contents of Container
Type II colourless glass bottle 5, 10, 15, and 20 ml closed by an elastomer stopper.
6.6 Special precautions for disposal
Vial : Prepare a syringe and needle. Raise the plastic disk. Puncture the latter with the needle after cleaning the stopper with a cloth soaked in alcohol. Remove the quantity of product necessary for the examination and inject intravenously.
The peel-off tracking label on the vials 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.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Guerbet B.P.57400
95943 Roissy CdG Cedex France
Tel.: +33 1 45 91 50 00
E-mail: brigitte. gayet@ guerbet-group. com
8 MARKETING AUTHORISATION NUMBER(S)
PL 12308/0016
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
29/11/2002
10 DATE OF REVISION OF THE TEXT
18/05/2016