Adverse reactions : תופעות לוואי

4.8   Undesirable effects
Summary of the safety profile
The most commonly reported adverse drug reactions have been diarrhoea, rash, nausea, hypertension, and headache.

Tabulated list of adverse reactions
The following adverse reactions have been identified in clinical studies with patients receiving vandetanib as treatment for MTC and in post-marketing setting. Their frequency is presented in Table 1, adverse reactions using Council for International Organizations of Medical Sciences (CIOMS III), listed by MedDRA System Organ Class (SOC) and at the preferred term level and then by frequency classification. Frequencies of occurrence of undesirable effects are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Table 1 Adverse reactions and system organ class

System            Very common          Common                 Uncommon         Not known Organ Class
Infection and   Nasopharyngitis       Pneumonia, sepsis,       Appendicitis, infestation     bronchitis, upper     influenza, cystitis,     staphylococca disorders       respiratory tract     sinusitis, laryngitis,   l infection, infections, urinary   folliculitis,            diverticulitis,
tract infections      furuncle, fungal         cellulitis,
infection,               abdominal pyelonephritis           wall abscess

Endocrine                             Hypothyroidism disorders

Metabolism      Appetite              Hypokalaemia,            Malnutrition and nutrition   decreased,            hypercalcaemia,
disorders       Hypocalcaemia         hyperglycemia,
dehydration,
hyponatremia

Psychiatric     Insomnia,             Anxiety disorders       Depression

Nervous         Headache,             Tremor, lethargy,        Convulsion, system          paraesthesia,         loss of                  clonus, brain disorders       dysaesthesia,         consciousness,           oedema dizziness             balance disorders,
dysgeusia

Eye disorders   Vision blurred,       Visual impairment, Cataract,
corneal structural    halo vision,        accommodati change (including     photopsia,          on disorders corneal deposits      glaucoma,
and corneal           conjunctivitis, dry opacity)              eye, keratopathy

Cardiac         Prolongation of                                Heart failure, disorders       ECG QTc                                        acute heart interval(*) (**)                               failure, rate and rhythm disorders,
cardiac conduction disorders,
ventricular arrhythmia and cardiac arrest
Vascular         Hypertension         Hypertensive crisis,                   Aneurysms disorders                             ischaemic                              and artery cerebrovascular                        dissections conditions

Respiratory,                          Epistaxis,             Respiratory thoracic and                          haemoptysis,           failure, mediastinal                           pneumonitis            pneumonia disorders                                                    aspiration 
Gastrointestin Abdominal pain,        Colitis, dry mouth,    Pancreatitis, al disorders   diarrhoea, nausea,     stomatitis,            peritonitis, vomiting,              dysphagia,             ileus,
dyspepsia              constipation,          intestinal gastritis,             perforation,
gastrointestinal       faecal haemorrhage            incontinence

Hepatobiliary                         Cholelithiasis disorders

Skin and         Photosensitivity     Palmar-plantar      Bullous            Stevens- subcutaneous     reaction, rash and   erythrodysaesthiesi dermatitis         Johnson tissue           other skin           a syndrome,                            syndrome / disorders        reactions            alopecia                               Toxic (including acne,                                            epidermal dry skin,                                                   necrolysis dermatitis,                                                 (***),
pruritus), nail                                             erythema disorders                                                   multiforme 
Renal and        Proteinuria,         Dysuria, hematuria, Chromaturia, urinary          nephrolithiasis      renal failure,      anuria disorders                             pollakiuria,
micturition urgency

General         Asthenia, fatigue,    Pyrexia                Impaired disorders and pain, oedema                                   healing administration site conditions

Investigations   ECG QTc interval Increase of serum          Increased prolonged        ALT and AST,               haemoglobin,
weight decreased           serum blood creatinine           amylase increased                  increased
* 13.4% vandetanib patients had QTc (Bazett's) ≥ 500 ms compared with 1.0% placebo patients. QTcF prolongation was > 20 ms in over 91% of patients, > 60 ms in 35%, > 100 ms in 1.7%. Eight percent of patients had a dose reduction due to QTc prolongation.
** including two deaths in patients with QTc > 550 ms (one due to sepsis and one due to heart failure) *** See section 4.4


Description of selected adverse reactions
Events such as Torsades de pointes, interstitial lung disease (sometimes fatal) and PRES (RPLS) have occurred in patients treated with vandetanib monotherapy. It is expected that these would be uncommon adverse reactions in patients receiving vandetanib for MTC.

Ocular events such as blurred vision are common in patients who received vandetanib for MTC.
Scheduled slit lamp examinations have revealed corneal opacities (vortex keratopathies) in treated patients; however, routine slit lamp examinations are not required for patients receiving vandetanib.

At various exposure durations, median haemoglobin levels in patients treated with vandetanib were increased by 0.5-1.5 g/dl compared to baseline.

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 at https://sideeffects.health.gov.il