GADOVIST Solution for injection in prefilled syringe/cartridge Ref.[8839] Active ingredients: Gadobutrol

While injecting Gadovist into veins with a small lumen there is the possibility of adverse effects such as reddening and swelling.

The usual safety requirements for magnetic resonance imaging, especially the exclusion of ferromagnetic materials, also apply when using Gadovist.

Hypersensitivity reactions

As with other intravenous contrast agents, Gadovist can be associated with anaphylactoid/hypersensitivity or other idiosyncratic reactions, characterized by cardiovascular, respiratory or cutaneous manifestations, and ranging to severe reactions including shock. In general, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes of severe hypersensitivity reactions.

The risk of hypersensitivity reactions may be higher in case of:

• previous reaction to contrast media
• history of bronchial asthma
• history of allergic disorders

In patients with an allergic disposition the decision to use Gadovist 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 preparedness for institution of emergency measures are necessary (see section 4.2).

Delayed reactions (after hours up to several days) have been rarely observed (see section 4.8).

Impaired renal function

Prior to administration of Gadovist, 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 Gadovist, 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 magnetic resonance imaging (MRI).

Haemodialysis shortly after Gadovist administration may be useful at removing Gadovist 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

Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age, Gadovist should only be used in these patients after careful consideration.

Elderly

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

Seizure disorders

Like with other gadolinium containing contrast agents special precaution is necessary in patients with a low threshold for seizures.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose (based on the average amount given to a 70 kg person), i.e. essentially ‘sodium-free’.

No interaction studies have been performed.

Pregnancy

There are no data from the use of gadobutrol in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3).

Gadovist should not be used during pregnancy unless the clinical condition of the woman requires use of gadobutrol.

Breast-feeding

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 of breast feeding for a period of 24 hours after administration of Gadovist, should be at the discretion of the doctor and lactating mother.

Fertility

Animal studies do not indicate impairment of fertility.

Not relevant.

The overall safety profile of Gadovist is based on data from more than 6,300 patients in clinical trials and from post-marketing surveillance.

The most frequently observed adverse drug reactions (≥0.5%) in patients receiving Gadovist are headache, nausea and dizziness.

The most serious adverse drug reactions in patients receiving Gadovist are cardiac arrest and severe anaphylactoid reactions (including respiratory arrest and anaphylactic shock).

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

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

The adverse drug reactions observed with Gadovist 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: 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.

Table 1. Adverse drug reactions reported in clinical trials or during post-marketing surveillance in patients treated with Gadovist:

Immune system disorders

Uncommon: Hypersensitivity/anaphylactoid reaction^#* (e.g. anaphylactoid shock^§*, circulatory collapse^§*, respiratory arrest^§*, pulmonary oedema^§*, bronchospasm^§, cyanosis^§, oropharyngeal swelling^§*, laryngeal oedema^§, hypotension^*, blood pressure increased^§, chest pain^§, urticaria, face oedema, angioedema^§, conjunctivitis^§, eyelid oedema, flushing, hyperhidrosis^§, cough^§, sneezing^§, burning sensation^§, pallor^§)

Nervous system disorders

Common: Headache

Uncommon: Dizziness, Dysgeusia, Paresthesia

Rare: Loss of consciousness^*, Convulsion, Parosmia

Cardiac disorders

Rare: Tachycardia, Palpitations

Not known: Cardiac arrest^*

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea^*

Gastrointestinal disorders

Common: Nausea

Uncommon: Vomiting

Rare: Dry mouth

Skin and subcutaneous tissue disorders

Uncommon: Erythema, Pruritus (including generalised pruritus), Rash (including generalised, macular, papular, pruritic rash)

Not known: Nephrogenic Systemic Fibrosis (NSF)

General disorders and administration site conditions

Uncommon: Injection site reaction⁰, Feeling hot

Rare: Malaise, Feeling cold

* There have been reports of life-threatening and/or fatal outcomes from this ADR
# None of the individual symptoms ADRs listed under hypersensitivity/anaphylactoid reactions identified in clinical trials reached a frequency greater than rare (except for urticarial)
^§ Hypersensitivity/anaphylactoid reactions identified only during post-marketing surveillance (frequency not known)
⁰ Injection site reactions (various kinds) comprise the following terms: Injection site extravasation, injection site burning, injection site coldness, injection site warmth, injection site erythema or rash, injection site pain, injection site hematoma

Patients with an allergic disposition suffer more frequently than others from hypersensitivity reactions.

Isolated cases of nephrogenic systemic fibrosis (NSF) have been reported with Gadovist (see section 4.4).

Fluctuations of renal function parameters including increases of serum creatinine have been observed after administration of Gadovist.

Paediatric population

Based on two single dose phase I/III studies in 138 subjects aged 2-17 years and 44 subjects aged 0 - <2 years (see section 5.1) the frequency, type and severity of adverse reactions in children of all ages (including term neonates) are consistent with the adverse drug reaction profile known in adults. This has been confirmed in a phase IV study including more than 1,100 paediatric patients and postmarketing surveillance.

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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.