Gadoxetic acid Other names: Gd-EOB-DPTA

As transport of gadoxetate to the liver may be mediated by OATP transporters it cannot be excluded that potent OATP inhibitors could cause drug interactions reducing the hepatic contrast effect. However, no clinical data have been presented to support that theory.

Use of gadoxetic acid should be avoided in patients with severe renal impairment (GFR <30 ml/min/1.73m²) and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI. If use of gadoxetic acid cannot be avoided, the dose should not exceed 0.025 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, gadoxetic acid injections should not be repeated unless the interval between injections is at least 7 days.

Elevated levels of bilirubin or ferritin can reduce the hepatic contrast effect of gadoxetic acid.

Allergy-like reactions, including shock, are known to be rare events after administration of gadolinium-based MRI contrast media. Most of these reactions occur within half an hour after administration of contrast media. However, as with other contrast media of this class, delayed reactions may occur after hours to days in rare cases. Medication for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures are necessary.

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 gadoxetic acid must be made after particularly careful evaluation of the risk-benefit ratio.

Hypersensitivity reactions can be more intense in patients on beta-blockers, particularly in the presence of bronchial asthma. It should be considered that patients on beta-blockers may be refractory to standard treatment of hypersensitivity reactions with beta-agonists.

If hypersensitivity reactions occur, injection of the contrast medium must be discontinued immediately.

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 <30ml/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 gadoxetic acid, 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 gadoxetic acid administration may be useful at removing gadoxetic 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.

Gadoxetic acid should not be used in patients with uncorrected hypokalemia.

Gadoxetic acid should be used with special care in patients

• with known congenital long QT syndrome or a family history of congenital long QT syndrome
• with known previous arrhythmias when on drugs that prolong cardiac repolarisation
• who are currently taking a drug that is known to prolong cardiac repolarisation e.g. a class III antiarrhythmic, (e.g. amiodarone, sotalol).

There are no data from the use of gadoxetate in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses. Gadoxetic acid should not be used during pregnancy unless the clinical condition of the woman requires use of gadoxetate.

Gadolinium containing contrast agents are excreted into breast milk in very small amounts. 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 gadoxetic acid, should be at the discretion of the doctor and lactating mother.

Fertility

Animal studies did not indicate impairment of fertility.

Gadoxetic acid has no influence on the ability to drive and use machines.

Summary of the safety profile

The overall safety profile of gadoxetic acid is based on data from more than 1,900 patients in clinical trials, and from post-marketing surveillance.

The most frequently observed adverse drug reactions (≥0.5%) in patients receiving gadoxetic acid are nausea, headache, feeling hot, blood pressure increased, back pain and dizziness.

The most serious adverse drug reaction in patients receiving gadoxetic acid is anaphylactoid shock.

Delayed allergoid reactions (hours later up to several days) have been rarely observed.

Most of the undesirable effects were transient and of mild to moderate intensity.

List of adverse reactions

The adverse drug reactions observed with gadoxetic acid are represented below. They are classified according to System Organ Class (MedDRA version 12.1). 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: common: ≥1/100 to <1/10; 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’.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse drug reactions reported in clinical trials or during post-marketing surveillance in patients treated with gadoxetic acid:

Immune system disorders

Not known: Hypersensitivity/anaphylactoid reaction (e.g. shock*, hypotension, pharyngolaryngeal edema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypoesthesia, sneezing, cough, pallor)

Nervous system disorders

Common: Headache

Uncommon: Vertigo, Dizziness, Dysgeusia, Paresthesia, Parosmia

Rare: Tremor, Akathisia

Not known: Restlessness

Cardiac disorders

Rare: Bundle branch block, Palpitation

Not known: Tachycardia

Vascular disorders

Uncommon: Blood pressure increased, Flushing

Respiratory, thoracic and mediastinal disorders

Uncommon: Respiratory disorders (Dyspnea*, Respiratory distress)

Gastrointestinal disorders

Common: Nausea

Uncommon: Vomiting, Dry mouth

Rare: Oral discomfort, Salivary hypersecretion

Skin and subcutaneous tissue disorders

Uncommon: Rash, Pruritus**

Rare: Maculopapular rash, Hyperhidrosis

Musculoskeletal and connective tissue disorders

Uncommon: Back pain

General disorders and administration site conditions

Uncommon: Chest pain, Injection site reactions (various kinds)***, Feeling hot, Chills, Fatigue, Feeling abnormal

Rare: Discomfort, Malaise

* Life-threatening and/or fatal cases have been reported. These reports originated from post-marketing experience.
** Pruritus (generalized pruritus, eye pruritus)
*** Injection site reactions (various kinds) comprise the following terms: Injection site extravasation, injection site burning, injection site coldness, injection site irritation, injection site pain

Description of selected adverse reactions

Laboratory changes such as elevated serum iron, elevated bilirubin, increases in liver transaminases, decrease of hemoglobin, elevation of amylase, leucocyturia, hyperglycemia, elevated urine albumin, hyponatremia, elevated inorganic phosphate, decrease of serum protein, leucocytosis, hypokalemia, elevated LDH were reported in clinical trials. ECGs were regularly monitored during clinical studies and transient QT prolongation was observed in some patients without any associated adverse clinical events.

Cases of nephrogenic systemic fibrosis (NSF) have been reported with other gadolinium-containing contrast agents.