Ioversol

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

There are, however, no adequate and well controlled studies in pregnant women.

It is not known whether ioversol crosses the placental barrier or reaches foetal tissues. However, many injectable contrast agents cross the placental barrier in humans and appear to enter foetal tissue passively.

Because animal teratology studies are not always predictive of human response, caution should be exercised when prescribing to pregnant women. Since any X-ray investigation during pregnancy may involve a potential risk, the risk/benefit ratio should be carefully weighed. If a better and safer alternative is available, an X-ray investigation involving X-ray contrast media should be avoided.

It is not known whether ioversol is excreted in human milk. However, many injectable X-ray contrast agents are excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in breastfed infants, caution should be exercised when intravascular contrast media are administered to breastfeeding women because of potential adverse reactions, and consideration should be given to temporarily discontinuing breastfeeding.

Fertility

Animal studies did not indicate direct or indirect harmful effects with respect to fertility in humans. There are, however, no adequate and well controlled clinical studies on fertility.

There is no known effect on the ability to drive and operate machines. However, because of the risk of early reactions driving or operating machinery is not advisable for 1 hour following the time of injection.

Frequencies for adverse drug reactions are defined as follows:

Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1000 to <1/100)
Rare (≥1/10,000 to <1/1000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)

a. Summary of the safety profile

Adverse reactions following the use of ioversol formulations are generally independent of the dose administered. Usually, they are mild to moderate, of short duration and resolve spontaneously (without treatment). However, even mild adverse reactions may be the first indication of a serious, generalized reaction that can occur rarely after iodinated contrast media. Such serious reactions may be life-threatening and fatal, and usually affect the cardiovascular system. Most adverse drug reactions to ioversol formulations occur within minutes after administration, however contrast related hypersensitivity reactions may occur with a delay of some hours up to several days.

b. Summary of adverse reactions

From clinical studies, mild discomfort, including sensation of heat or cold, pain during the injection, and/or transient taste perversion, was noted in 10% to 50% of patients. In a large post-marketing study, other side effects occurred in a total of 1.1% of the patients; the most frequent were nausea (0.4%), skin reactions such as urticaria or erythema (0.3%), and vomiting (0.1%). All other events occurred in less than 0.1% of the patients.

Immune system disorders

Very rare: anaphylactoid (hypersensitivity) reaction

Not known: anaphylactic shock

Endocrine disorders

Not known: transient neonatal hypothyroidism

Psychiatric disorders

Very rare: confusional state; agitation; anxiety

Nervous system disorders

Rare: syncope; tremor; vertigo (including dizziness, light-headedness); headache; paraesthesia; dysgeusia

Very rare: loss of consciousness; paralysis; speech disorders; somnolence; stupor; aphasia; dysphasia; hypoaesthesia

Not known: convulsions; dyskinesia; amnesia

Eye disorders

Rare: vision blurred

Very rare: conjunctivitis allergic (including eye irritation, ocular hyperaemia, watery eyes, swelling of conjunctiva, etc.)

Not known: blindness transient

Ear and labyrinth disorders

Very rare: tinnitus

Cardiac disorders

Rare: tachycardia

Very rare: heart block; arrhythmia; angina; ECG abnormal; bradycardia; atrial fibrillation

Not known: cardiac arrest; ventricular fibrillation; coronary artery spasm; cyanosis; extrasystole; palpitations

Vascular disorders

Rare: hypotension; flushing

Very rare: cerebrovascular disorder; phlebitis; hypertension; vasodilation

Unknown: Shock; thrombosis; vasospasm

Respiratory, thoracic and mediastinal disorders

Rare: laryngeal spasm, oedema and obstruction (incl. throat tightness, stridor, etc.); dyspnoea; rhinitis (incl. sneezing, nasal congestion); throat irritation; cough

Very rare: pulmonary oedema; pharyngitis; hypoxia

Not known: respiratory arrest; asthma; bronchospasm; dysphonia

Gastrointestinal disorders

Uncommon: nausea

Rare: vomiting; dry mouth

Very rare: sialoadenitis; abdominal pain; tongue oedema; dysphagia; hypersalivation

Not known: diarrhoea

Skin and subcutaneous tissue disorders

Uncommon: urticaria

Rare: erythema; pruritus; rash

Very rare: angioedema; hyperhidrosis (incl. cold sweat)

Not known: toxic epidermal necrolysis; drug reaction with eosinophilia and systemic symptoms (DRESS); acute generalized erythematous pustulosis; erythema multiforme, pallor

Musculoskeletal, connective tissue and bone disorders

Very rare: muscle cramps

Renal and urinary disorders

Rare: micturition urgency

Very rare: acute renal failure; abnormal renal function; incontinence; haematuria; decreased creatinine clearance; BUN (blood urea nitrogen) increased

Not known: anuria; dysuria

General disorders and administration site conditions

Very common: feeling hot

Common: pain

Rare: face oedema (incl. eye swelling, periorbital oedema, etc.); pharyngeal oedema; chills (incl. shaking chills, feeling cold);

Very rare: oedema; injection site reactions (incl. pain, erythema, and haemorrhage up to necrosis especially after extravasation); chest pain; asthenic conditions (incl. malaise, tiredness, sluggishness, etc.); feeling abnormal

Not known: pyrexia

c. Description of selected adverse reactions

Adverse reactions may be classified as follows:

a. Hypersensitivity or anaphylactoid reactions are mostly mild to moderate with symptoms like rash, pruritus, urticaria and rhinitis.

However, serious reactions may occur. Serious anaphylactic reactions generally affect the cardiovascular and respiratory system. These may be life-threatening and include anaphylactic shock, cardiac and respiratory arrest, or pulmonary oedema. Fatal cases were reported.

Patients with a history of allergic reactions are at increased risk of developing a hypersensitivity reaction. Other type 1 (immediate) reactions include symptoms like nausea and vomiting, skin rashes, dyspnoea, rhinitis, paraesthesia or hypotension.

b. Vasovagal reactions e.g. dizziness or syncope which may be caused either by the contrast medium, or by the procedure.

c. Cardiologic side effects during cardiac catheterisation e.g. angina pectoris, ECG changes, cardiac arrhythmias, conductivity disorders, as well as coronary spasm and thrombosis. Such reactions are very rare and may be caused by the contrast medium or by the procedure.

d. Nephrotoxic reactions in patients with pre-existing renal damage or renal vasopathy, e.g. decrease in renal function with creatinine elevation. These adverse effects are transient in the majority of cases. In single cases, acute renal failure has been observed.

e. Neurotoxic reactions after intra-arterial injection of the contrast medium e.g. visual disorders, disorientation, paralysis, convulsions, or fits. These symptoms are generally transient and abate spontaneously within several hours or days. Patients with pre-existing damage of the blood-brain barrier are at increased risk of developing neurotoxic reactions.

f. Local reactions at the injection site may occur in very rare cases and include rashes, swelling, inflammation and oedema. Such reactions occur probably in most cases due to extravasation of the contrast agent. Extended paravasation may necessitate surgical treatment.

g. Extravasation can cause serious tissue reactions including blistering and skin exfoliation, the extent of which is dependent on the amount and strength of the contrast solution in the tissues.