Adverse reactions : תופעות לוואי

4.8 Undesirable effects

The use of iodinated contrast media may cause untoward side effects.
Side effects are usually mild to moderate and transient in nature; however, rare severe and life- threatening reactions, sometimes leading to death, have been reported.

Following intravascular administration, in most cases reactions occur within minutes of dosage.
However, delayed reactions, usually involving skin, may occur, mostly within 2-3 days, more rarely within 7 days, after the administration of the contrast medium.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalized exanthematous pustulosis (AGEP) have been reported in association with Iopamiro administration (see section 4.4).

After intrathecal administration, most side effects occur with a delay of some hours due to the slow absorption from the site of administration and distribution to the whole body. Reactions usually occur within 24 hours after injection.

More severe reactions affecting the cardiovascular system, such as marked hypotension, tachycardia, dyspnoea, agitation, cyanosis and loss of consciousness, may require emergency measures.

The adverse reactions reported in clinical trials among 3,008 adult subjects and 35 paediatric patients, and from post marketing surveillance are presented in the tables below by frequency and classified by MedDRA system organ classes.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Intravascular administration
Adult subjects
Adult patients involved in clinical trials with intravascular administration of Iopamidol were 2,919, of whom 1,681 with intra-arterial and 1,238 with intravenous administration.



                      Adverse Reactions
Clinical Trials                                       Post-marketing
Surveillance
System Organ Class Common            Uncommon            Rare               Frequency (≥1/100 to <1/10) (≥1/1,000 to        (≥1/10,000 to      unknown* <1/100)             <1/1,000)

Blood and lymphatic                                                         Thrombocytopenia system disorders
Metabolism and                                                              Acidosis, Anorexia nutrition disorders
Immune system                                                               Anaphylaxis, disorders                                                                   Anaphylactoid reactions
Psychiatric disorders                                    Confusional state Nervous system        Headache        Dizziness,         Paraesthesia      Coma, disorders                             Taste alteration                     Transient ischaemic attack,
Syncope,
Depressed level of consciousness or loss of consciousness,
Convulsion, Amnesia,
Paralysis, Sleepiness,
Tremors, Hemiplegia,
Contrast induced encephalopathy***
Eye disorders                                                              Transient blindness, Visual disturbance,
Conjunctivitis,
Photophobia, Ocular itching, Increased tear secretion
Ear and labyrinth                                                          Auditory deficit disorders
Cardiac disorders                     Cardiac              Bradycardia      Cardiopulmonary dysarrhythmias                        arrest, Myocardial such as                               ischemia or infarction,
extrasystoles,                        Heart failure, Angina
Atrial fibrillation,                  pectoris, Cyanosis,
Ventricular                           Tachycardia, Kounis tachycardia and                       syndrome ventricular fibrillation**
Vascular disorders                    Hypotension,                          Circulatory Hypertension,                         collapse or shock,
Redness                               Thromboembolismus,
Arterial thrombosis,
Venous thrombosis


Thrombophlebitis,
Pallor
Respiratory, thoracic                                 Pulmonary       Respiratory arrest, and mediastinal                                       oedema,         Apnoea, disorders                                             Asthma,         Respiratory failure, Bronchospasm    Acute respiratory distress syndrome,
Laryngeal oedema,
Dyspnoea, Coughing,
Rhinitis, Sneezing
Gastrointestinal        Nausea      Vomiting,                         Salivary gland disorders                           Diarrhea,                         enlargement, Salivary Abdominal pain,                   hypersecretion
Dry mouth
Skin and                            Rash,                             Stevens-Johnson subcutaneous                        Urticaria,                        syndrome, Toxic tissue disorders                    Pruritus,                         epidermal necrolysis, Erythema,                         Erythema multiforme,
Hyperhidrosis                     skin necrosis****,
Facial oedema,
Periorbital oedema,
Acute generalised exanthematous pustulosis (AGEP)
Musculoskeletal and                 Back pain         Muscle spasms    Compartment connective tissue                                                      syndrome****, disorders                                                              Musculoskeletal pain, Muscular weakness
Renal and urinary                   Acute renal                       Anuria, Urinary disorders                           failure                           retention, Renal failure (including acute renal failure and renal damage), Oliguria,
Hematuria, Urinary incontinence
General disorders and Feeling hot   Chest tightness Swelling at        Rigors, administration site                 pain,            injection site    Pain, Malaise conditions                          Injection site                     Inflammation at pain, Pyrexia,                     injection site****
Feeling cold
Investigations                      Blood creatinine                  Electrocardiogram increased                         change (including ST segment depression,
increased T-wave amplitude, prolonged
QT), Decreased systolic blood pressure,
Electrolyte imbalances

*
Frequency cannot be estimated from the available data.
**
Cardiac dysarrhythmias may occur mostly after cardiac angiographic and coronary catheterization procedures.
***
Contrast induced encephalopathy may manifest with symptoms and signs described in section 4.4.
****
In rare occasions, extravasation of contrast medium causes inflammation (manifested locally by erythema, oedema and vesicles), skin necrosis and compartment syndrome.

The most appropriate MedDRA term is used to describe a certain reaction, its symptoms and related conditions.

Coronary thrombosis has been reported as a complication of coronary catheterization procedures.

Accidents during the procedure could lead to pseudoaneurysm and/or peripheral embolism or cause bruising at the site of administration.

Brachial plexus injury can occur due to axillary artery injection.

Other cardiac reactions which may occur as a consequence of the procedural hazard include coronary artery dissection.

Anaphylaxis (anaphylactoid reactions/hypersensitivity) may manifest with: localized or diffuse angioneurotic oedema, tongue oedema, laryngospasm or laryngeal oedema, dysphagia, pharyngitis and throat tightness, pharyngolaryngeal pain, cough, conjunctivitis, rhinitis, sneezing, feeling hot, sweating increased, asthenia, dizziness, pallor, dyspnoea, wheezing, bronchospasm, and moderate hypotension.
Skin reactions may occur in the form of various types of rash, redness, diffuse blisters, urticaria, and pruritus. These reactions, which occur irrespective of the dose administered and the route of administration, may represent the first signs of incipient state of shock. Administration of the contrast medium must be discontinued immediately and – if necessary – specific treatment initiated via a venous access.
More severe reactions involving the cardiovascular system such as redness with severe hypotension, tachycardia, dyspnoea, agitation, cyanosis and loss of consciousness (syncope) may result in respiratory and/or cardiac arrest. These reactions may occur rapidly and require emergency treatment.
A cardiovascular collapse can occur as the only and/or initial presentation without respiratory symptoms or without other signs or symptoms.

Injection site pain and swelling may occur. On very rare occasions extravasation of contrast medium led to inflammation, skin necrosis and compartment syndrome.

Severe skin diseases
As with other contrast media, very rare cases of mucocutaneous syndromes, including Stevens- Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome) and erythema multiforme, have been reported following the administration of Iopamidol.

Paediatric patients
The iopamidol safety profile is similar in children and adults.

Cases of transient neonatal hypothyroidism have been reported with Iopamidol in very low birth weight infants.

Intrathecal administration

Adult subjects
Adult patients involved in clinical trials with intrathecal administration of Iopamidol were 132.
Adverse Reactions
Clinical Trials                                                   Post-marketing Surveillance
System Organ Very common                   Common               Uncommon            Frequency Class             (≥ 1/10)                 (≥1/100 to <1/10) (≥1/1,000 to           unknown* <1/100)

Infections and                                                                   Meningitis infestations                                                                     aseptic, Meningitis bacterial as consequence of the procedural hazard
Metabolism and                                                                   Acidosis nutrition disorders
Immune system                                                                    Anaphylaxis, disorders                                                                        Anaphylactoid reactions
Psychiatric                                                                      Hallucinations, disorders                                                                        Confusion, Disorientation,
Depression,
Agitation,
Anxiety,
Irritability
Nervous system Headache                                                          Coma, Syncope, disorders                                                                        Depressed level of consciousness or loss of consciousness,
Seizures,
Paralysis,
Myelitis,
Meningism,
Vertigo,
Paraesthesia,
Hypoaesthesia
Dizziness,
Radicular pain,
Drowsiness,
Tremors, Muscle

spasms,
Contrast induced encephalopathy**
Eye disorders                                                                Transient blindness,
Conjunctivitis,
Photophobia,
Increased tear secretion, Itchy eyes
Ear and                                                                      Auditory deficit, labyrinth                                                                    Tinnitus disorders
Cardiac                                                                      Arrhythmia, disorders                                                                    Tachycardia, Cyanosis
Vascular                              Redness                                Hypertension disorders
Respiratory,                                                                 Respiratory arrest, thoracic                                                                     Apnoea, and mediastinal                                                              Respiratory disorders                                                                    Failure, Dyspnoea Gastrointestinal                      Nausea,
disorders                             Vomiting
Skin and                                                  Rash,
subcutaneous                                              Hyperhidrosis tissue disorders
Musculoskeletal                       Back pain,                            Muscular and                                   Neck pain,                            weakness connective                            Pain in extremity tissue disorders
Renal and                                                                   Renal failure urinary                                                                     (including acute disorders                                                                   renal failure), Urinary retention,
Hematuria,
Urinary incontinence
General                               Sensation of                           Pyrexia, Malaise, disorders and                         heaviness                              Rigor administration site conditions
*
Frequency cannot be estimated from the available data.
**
Contrast induced encephalopathy may manifest with symptoms and signs described in section 4.4.

The most appropriate MedDRA term is used to describe a certain reaction, its symptoms and related conditions.



Anaphylaxis (anaphylactoid reactions/hypersensitivity) may occur.
Anaphylactoid reactions with circulatory disturbances such as severe blood pressure decrease leading to syncope or cardiac arrest and life threatening shock are much less common after intrathecal administration than after intravascular administration. Also less common than after intravascular administration are the respiratory (dyspnoea or respiratory distress in the form of bronchospasm) and mucocutaneous reactions (urticaria, angioneurotic oedema and other skin reactions such as rash).

Urography
Side effects that may arise in connection with intravenous urography are as described at the beginning of the paragraph.

Paediatric patients
The iopamidol safety profile is similar in children and adults.
Cases of transient neonatal hypothyroidism have been reported with Iopamidol in very low birth weight infants.

Use in body cavities
The majority of the reactions occur some hours after the contrast administration due to the slow absorption from the area of administration and distribution in the whole organism.

Very rare cases of pancreatitis have been described.

The reactions reported in cases of arthrography and fistulography usually represent irritative manifestations superimposed on existing tissue inflammation.

Systemic hypersensitivity is rare, generally mild and in the form of skin reactions. However, the possibility of severe anaphylactoid reactions cannot be excluded.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il