Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2022 Publisher: Bayer plc, 400 South Oak Way, Reading, RG2 6AD
Hypersensitivity to gadoteric acid, to meglumine or to any medicinal products containing gadolinium.
Do not use by intrathecal route. Take care to maintain strictly intravenous injection: extravasation may result in local intolerance reactions, requiring the usual local care.
The usual precaution 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.
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 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.
Prior to administration of Dotagraf, 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/1.73m²). 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 Dotagraf, 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 gadoteric acid administration may be useful at removing gadoteric acid 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.
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.
Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age, Dotagraf should only be used in these patients after careful consideration.
In patients with severe cardiovascular disease Dotagraf should only be administrated after careful risk benefit assessment because only limited data are available so far.
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.
No interactions with other medicinal products have been observed. Formal drug interaction studies have not been carried out.
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.
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). Gadoteric acid crosses the placenta slowly. Dotagraf should not be used during pregnancy unless the clinical condition of the woman requires use of gadoteric acid.
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 Dotagraf, should be at the discretion of the doctor and lactating mother.
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.
Side effects in association with the use of gadoteric acid are usually mild to moderate in intensity and transient in nature. Injection site reactions, nausea and headaches are the most frequently observed reactions.
During clinical trials, nausea, headache, injection site reactions, feeling cold, hypotension, somnolence, dizziness, feeling hot, burning sensation, rash, asthenia, dysgeusia and hypertension were the most frequent, uncommonly observed (≥1/1,000 to <1/100) related adverse events.
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, gastrointestinal, articular and/or cardiovascular reactions. Each sign may be a warning sign of a starting shock and leads 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 <1/10), uncommon (≥1/1,000 to <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 involving 2822 patients when available, or from a pool of observational studies involving 185,500 patients.
Uncommon: hypersensitivity
Very rare: anaphylactic reaction, anaphylactoid reaction
Rare: anxiety
Very rare: agitation
Uncommon: headache, dysgeusia, dizziness, somnolence, paraesthesia (including burning sensation)
Rare: presyncope
Very rare: coma, convulsion, syncope, tremor, parosmia
Rare: eyelid oedema
Very rare: conjunctivitis, ocular hyperaemia, vision blurred, lacrimation increased
Rare: palpitations
Very rare: tachycardia, cardiac arrest, arrhythmia, bradycardia
Uncommon: hypotension, hypertension
Very rare: pallor, vasodilatation
Rare: sneezing
Very rare: cough, dyspnoea, nasal congestion, respiratory arrest, bronchospasm, laryngospasm, pharyngeal oedema, dry throat, pulmonary oedema
Uncommon: nausea, abdominal pain
Rare: vomiting, diarrhoea, salivary hypersecretion
Uncommon: rash
Rare: urticaria, pruritus, hyperhidrosis
Very rare: erythema, angioedema, eczema
Not known: nephrogenic systemic fibrosis
Very rare: muscle cramps, muscular weakness, back pain
Uncommon: feeling hot, feeling cold, asthenia, injection site reactions (extravasation, pain, discomfort, oedema, inflammation, coldness)
Rare: chest pain, chills
Very rare: malaise, chest discomfort, pyrexia, face oedema, injection site necrosis (in case of extravasation), phlebitis superficial
Very rare: decreased oxygen saturation
The following adverse reactions were reported with other intravenous contrast agents for MRI:
Haemolysis
Confusion
Blindness transient, eye pain
Tinnitus, ear pain
Asthma
Dry mouth
Dermatitis bullous
Urinary incontinence, renal tubular necrosis, renal failure acute
Electrocardiogram PR prolongation, blood iron increased, blood bilirubin increased, serum ferritin increased, liver function test abnormal
Safety of paediatric patients was considered in clinical trials and postmarketing studies. As compared to the adult, the safety profile of gadoteric acid did not show any specificity in children. Most of the reactions are gastrointestinal symptoms or signs of hypersensitivity.
Reporting suspected adverse reactions after authorization 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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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