Source: European Medicines Agency (EU) Revision Year: 2011 Publisher: TMC Pharma Services Ltd., Finchampstead, Berkshire RG40 4LJ, UK
Hypersensitivity to the active substance or to any of the excipients.
Diagnostic procedures involving the use of MRI contrast agents should be carried out under the supervision of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. Appropriate facilities should be available for coping with any complication of the procedure, as well as for emergency treatment of potential severe reactions to the contrast agent itself. The usual safety precautions for magnetic resonance imaging must be observed, e.g., exclusion of cardiac pacemakers and ferromagnetic implants. As with other contrast enhanced diagnostic procedures, post-procedure observation of the patient is recommended, in particular in patients with a history of allergy, renal insufficiency, or adverse reaction.
The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid, or cardiovascular reactions, or other idiosyncratic reactions should always be considered especially in those patients with a known clinical hypersensitivity, previous reaction of contrast media, a history of asthma, or other allergic disorders. Experience with other contrast media shows that the risk of hypersensitivity reactions is higher in those patients. Delayed reactions may occur (after hours to days).
Caution should also be exercised in the following cases:
Hypersensitivity reactions: If hypersensitivity reactions occur (see section 4.8), administration of the contrast medium must be discontinued immediately and – if necessary – specific therapy instituted via a venous access. It is therefore advisable to use a flexible indwelling cannula for intravenous contrast medium administration. Due to the possibility of severe hypersensitivity reactions after intravenous contrast administration, preparedness for institution of emergency measures is necessary, e.g., appropriate medicinal products, an endotracheal tube, and a respirator should be at hand.
Renal impairment: Since gadofosveset is cleared from the body primarily by urinary excretion, caution should be exercised in patients with impaired renal function (see section 4.2 and 5.2).
Prior to administration of Ablavar, 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/1.73 m²). 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 Ablavar, it should therefore be avoided in patients with severe renal impairment and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI.
Haemodialysis shortly after Ablavar administration may be useful at removing Ablavar 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 gadofosveset may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction.
Haemodialysis shortly after Ablavar administration in patients currently receiving haemodialysis may be useful at removing Ablavar from the body. In a clinical trial it was shown that gadofosveset can effectively be removed from the body by dialysis using high flux filters.
There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in patients not already undergoing haemodialysis.
Elevated levels of gadofosveset (e.g. repeated use in the short term [within 6-8 hours], or an inadvertent overdose >0.05 mmol/kg) may be associated with mild QT prolongation (8.5 msec by Fridericia correction). In the situation of elevated levels of gadofosveset or underlying QT prolongation the patient should be carefully observed including cardiac monitoring.
It has been shown in published studies that MRA in the presence of metallic stents causes artefacts. The reliability of lumen visualisation in a stented vessel with Ablavar has not been evaluated.
This medicine contains 6.3 mmol sodium (or 145 mg) per dose.
To be taken into consideration by patients on a controlled sodium diet.
Because gadofosveset is bound to albumin, an interaction with other plasma protein bound active substances (e.g., ibuprofen and warfarin) is generally possible, i.e., a competition for the protein binding site can occur. However, in a series of in vitro drug interaction studies (in 4.5% human serum albumin and human plasma), gadofosveset demonstrated no adverse interaction with digitoxin, propranolol, verapamil, warfarin, phenprocoumon, ibuprofen, diazepam, ketoprofen, naproxen, diclofenac and piroxicam at clinically relevant concentrations. In vitro studies using human liver microsomes did not indicate any potential to inhibit the cytochrome P 450 enzyme system.
In a clinical study, it was shown that gadofosveset does not affect the unbound fraction of warfarin in plasma. The anticoagulant activity of warfarin was not altered and the efficacy of the medicinal product was not influenced.
In clinical trials using Ablavar, no specific trends were observed that would signify a potential interaction of the medicinal product with laboratory test methods.
There are no data from the use of Ablavar in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3). Ablavar should not be used during pregnancy unless the clinical condition of the woman requires use of the medicinal product.
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 breastfeeding or discontinuing Ablavar for a period of 24 hours after administration should be at the discretion of the physician and breast-feeding mother.
No studies on the effects on the ability to drive and use machine have been performed. Uncommonly, dizziness or vision problems may occur with this medicine. If a patient experiences these effects he/she should not drive or use machines.
The most common adverse reactions were pruritus, paresthesia, headache, nausea, vasodilatation, burning sensation and dysgeusia. Most of the adverse reactions were mild to moderate in intensity. Most of the adverse reactions (80%) occurred within 2 hours. Delayed reactions (after hours to days) may occur.
Based on clinical trial experience in more than 1,800 patients, the following adverse reactions have been observed.
The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Common (≥1/100), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000)
Uncommon: Nasopharyngitis
Rare: Cellulitis, Urinary tract infection
Uncommon: Hypersensitivity
Uncommon: Hyperglycaemia, Electrolyte imbalance (incl. Hypocalcemia)
Rare: Hyperkalemia, Hypokalemia, Hypernatremia, Appetite decreased
Uncommon: Anxiety, Confusion
Rare: Hallucination, Abnormal dreams
Common: Headache, Paraesthesia, Dysgeusia, Burning sensation
Uncommon: Dizziness (excl. Vertigo), Tremor, Hypoesthesia, Parosmia, Ageusia, Muscle contractions involuntary
Uncommon: Vision abnormal, Lacrimation increased
Rare: Abnormal sensation in eye, Asthenopia
Rare: Ear pain
Uncommon: Atrioventricular block first degree, Electrocardiogram QT prolonged, Tachycardia, Electrocardiogram abnormal
Rare: Cardiac flutter, Myocardial ischaemia, Bradycardia, Atrial fibrillation, Palpitations, Electrocardiogram ST segment depression, Electrocardiogram T wave amplitude decreased
Common: Vasodilatation (incl. Flushing)
Uncommon: Phlebitis, Hypertension, Peripheral coldness
Rare: Anaphylactoid reaction, Hypotension, Arteriosclerosis
Uncommon: Dyspnea, Cough
Rare: Respiratory depression
Common: Nausea
Uncommon: Vomiting, Retching, Diarrhea, Abdominal pain, Pharyngolaryngeal pain, Abdominal discomfort, Flatulence, Hypoesthesia lips, Salivary hypersecretion, Dyspepsia, Dry mouth, Pruritus ani
Common: Pruritus
Uncommon: Urticaria, Rash, Erythema, Sweating increased
Rare: Swelling face, Clamminess
Uncommon: Pain in limb, Neck pain, Muscle cramps, Muscle spasms
Rare: Muscle tightness, Sensation of heaviness
Uncommon: Haematuria, Microalbuminuria, Glycosuria
Rare: Micturition urgency, Renal pain, Urinary frequency
Uncommon: Genital pruritus, Genital burning sensation
Rare: Pelvic pain
Common: Feeling cold
Uncommon: Pain, Chest pain, Groin pain, Fatigue, Feeling abnormal, Feeling hot, Injection site pain, Injection site erythema, Injection site coldness
Rare: Pyrexia, Rigors, Weakness, Chest pressure sensation, Injection site thrombosis, Injection site bruising, Injection site inflammation, Injection site burning, Injection site extravasation, Injection site haemorrhage, Injection site pruritus, Sensation of pressure
Rare: Phantom limb pain
Cases of nephrogenic systemic fibrosis (NSF) have been reported with other gadolinium-containing contrast agents (see section 4.4).
As with other intravenous contrast agents, this medicinal product can be associated with anaphylactoid/hypersensitivity reactions characterised by cutaneous, respiratory and/or cardiovascular manifestations which may lead to shock.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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