Chemical formula: C₂₂H₂₄BrFN₄O₂ Molecular mass: 475.354 g/mol PubChem compound: 3081361
Vandetanib interacts in the following cases:
Vandetanib is an inhibitor of the organic cation 2 (OCT2) transporter. In healthy subjects with wild type for OCT2, the AUC(0-t) and Cmax for metformin (OCT2 substrate) were increased by 74% and 50%, respectively and CLR of metformin was decreased by 52% when given together with vandetanib. Appropriate clinical and/or laboratory monitoring is recommended for patients receiving concomitant metformin and vandetanib, and such patients may require a lower dose of metformin.
Heart failure has been observed in patients who received vandetanib. Temporary or permanent discontinuation of therapy may be necessary in patients with heart failure. It may not be reversible on stopping vandetanib. Some cases have been fatal.
Vandetanib is not recommended for use in adult and paediatric patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of reference range (ULRR), this criterion does not apply to patients with Gilbert’s Disease and alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) greater than 2.5 times ULRR, or greater than 5.0 times ULRR if judged by the physician to be related to liver metastases), since there is limited data in patients with hepatic impairment, and safety and efficacy have not been established.
Pharmacokinetic data from volunteers, suggests that no change in starting dose is required in patients with mild, moderate or severe hepatic impairment.
A pharmacokinetic study in volunteers with mild, moderate and severe renal impairment shows that exposure to vandetanib after single dose is increased up to 1.5, 1.6 and 2-fold respectively in patients with mild, moderate (creatinine clearance ≥30 to <50 ml/min) and severe (clearance below 30 ml/min) renal impairment at baseline. Clinical data suggest that no change in starting dose is required in patients with mild renal impairment. There is limited data with 300 mg in patients with moderate renal impairment: the dose needed to be lowered to 200 mg in 5 out of 6 patients. The starting dose could be reduced to 200 mg in patients with moderate renal impairment; safety and efficacy have however not been established with 200 mg. Vandetanib is not recommended for use in patients with severe renal impairment since there is limited data in patients with severe renal impairment, and safety and efficacy have not been established.
There is no experience with the use of vandetanib in paediatric patients with renal impairment.
Considering the data available in adult patients with renal impairment:
In healthy subjects, the AUC(0-t) and Cmax for digoxin (P-gp substrate) were increased by 23% and 29% respectively, when given together due to P-gp inhibition by vandetanib. Furthermore, the bradycardiac effect of digoxin may increase the risk of vandetanib QTc interval prolongation and Torsade de Pointes. Therefore, an appropriate clinical (e.g. ECG) and/or laboratory monitoring is recommended for patients receiving concomitant digoxin and vandetanib, and such patients may require a lower dose of digoxin.
As regards other P-gp substrates such as dabigatran, a clinical monitoring is recommended in case of combination with vandetanib.
In healthy male subjects, the exposure to vandetanib was reduced by 40% when given together with the potent CYP3A4 inducer, rifampicin. Administration of vandetanib with potent CYP3A4 inducers should be avoided.
In healthy subjects, the AUC(0-t) and Cmax for digoxin (P-gp substrate) were increased by 23% and 29% respectively, when given together due to P-gp inhibition by vandetanib. Furthermore, the bradycardiac effect of digoxin may increase the risk of vandetanib QTc interval prolongation and Torsade de Pointes. Therefore, an appropriate clinical (e.g. ECG) and/or laboratory monitoring is recommended for patients receiving concomitant digoxin and vandetanib, and such patients may require a lower dose of digoxin.
Vandetanib is an inhibitor of the organic cation 2 (OCT2) transporter. In healthy subjects with wild type for OCT2, the AUC(0-t) and Cmax for metformin (OCT2 substrate) were increased by 74% and 50%, respectively and CLR of metformin was decreased by 52% when given together with vandetanib. Appropriate clinical and/or laboratory monitoring is recommended for patients receiving concomitant metformin and vandetanib, and such patients may require a lower dose of metformin.
In healthy subjects, the Cmax for vandetanib was decreased by 15% while the AUC(0-t) for vandetanib was not affected when given together with omeprazole. Therefore, no change in dose of vandetanib is required when vandetanib is given with omeprazole.
Results of a pharmacodynamic and pharmacokinetic interaction study indicated that co-administration with ondansetron in healthy patients appeared to have little effect on the pharmacokinetics of vandetanib, but had a small additive effect on the prolongation of the QTc interval of approximately 10 ms. Therefore, the concomitant use of ondansetron with vandetanib is not recommended. If ondansetron is administered with vandetanib, closer monitoring of serum electrolytes and ECGs and aggressive management of any abnormalities is required.
Hypertension, including hypertensive crisis, has been observed in patients treated with vandetanib. Patients should be monitored for hypertension and controlled as appropriate. If high blood pressure cannot be controlled with medical management, vandetanib should not be restarted until the blood pressure is controlled medically. Reduction in dose may be necessary.
Interstitial Lung Disease (ILD) has been observed in patients receiving vandetanib and some cases have been fatal. If a patient presents with respiratory symptoms such as dyspnoea, cough and fever, vandetanib treatment should be interrupted and prompt investigation initiated. If ILD is confirmed, vandetanib should be permanently discontinued and the patient treated appropriately.
Rash and other skin reactions including photosensitivity reactions and palmar-plantar erythrodysaesthesia syndrome have been observed in patients who have received vandetanib.
Mild to moderate skin reactions can be managed by symptomatic treatment, or by dose reduction or interruption. For more severe skin reactions (such as Stevens-Johnson syndrome), referral of the patient to seek urgent medical advice is recommended.
Care should be taken with sun exposure by wearing protective clothing and/or sunscreen due to the potential risk of phototoxicity reactions associated with vandetanib treatment.
Diarrhoea is a disease related symptom as well as a known undesirable effect of vandetanib. Routine anti-diarrhoeal agents are recommended for the treatment of diarrhoea. QTc and serum electrolytes should be monitored more frequently. If severe diarrhoea (CTCAE grade 3-4) develops, vandetanib should be stopped until diarrhoea improves. Upon improvement, treatment should be resumed at a reduced dose.
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating vandetanib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.
Posterior reversible encephalopathy syndrome (PRES) is a syndrome of subcortical vasogenic oedema diagnosed by a MRI of the brain, has been observed infrequently with vandetanib treatment in combination with chemotherapy. PRES has also been observed in patients receiving vandetanib as monotherapy. This syndrome should be considered in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Brain MRI should be performed in any patient presenting with seizures, confusion or altered mental status.
Caution should be used when administering vandetanib to patients with brain metastases, as intracranial haemorrhage has been reported.
There is a limited amount of data on the use of vandetanib during pregnancy. As expected from its pharmacological actions, vandetanib has shown significant effects on all stages of female reproduction in rats.
If vandetanib is used during pregnancy or if the patient becomes pregnant while receiving vandetanib, she should be apprised of the potential for foetal abnormalities or loss of the pregnancy. Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the foetus.
There are no data on the use of vandetanib in breast-feeding women. Vandetanib and/or its metabolites is excreted into milk in rats and found in plasma of pups following dosing to lactating rats.
Breast-feeding is contraindicated while receiving vandetanib therapy.
Women of childbearing potential must use effective contraception during therapy and for at least four months following the last dose.
In rats, vandetanib had no effect on male fertility but impaired female fertility.
Effects on reproduction in paediatric patients treated with vandetanib are not known.
No studies to establish the effects of vandetanib on ability to drive and use machines have been conducted. However, fatigue and blurred vision have been reported and those patients who experience these symptoms should observe caution when driving or using machines.
The most commonly reported adverse drug reactions have been diarrhoea, rash, nausea, hypertension, and headache.
The following adverse reactions have been identified in clinical studies with patients receiving vandetanib as treatment for MTC. Their frequency is presented below, 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). This section includes only data derived from completed studies where patient exposure is known.
Very common: Nasopharyngitis bronchitis, upper respiratory tract infections, urinary tract infections
Common: Pneumonia, sepsis, influenza, cystitis, sinusitis, laryngitis, folliculitis, furuncle, fungal infection, pyelonephritis
Uncommon: Appendicitis, staphylococcal infection, diverticulitis, cellulitis, abdominal wall abscess
Common: Hypothyroidism
Very common: Appetite decreased, Hypocalcaemia
Common: Hypokalaemia, hypercalcaemia, hyperglycemia, dehydration, hyponatremia
Uncommon: Malnutrition
Very common: Insomnia, Depression
Common: Anxiety
Very common: Headache, paraesthesia, dysaesthesia, dizziness
Common: Tremor, lethargy, loss of consciousness, balance disorders, dysgeusia
Uncommon: Convulsion, clonus, brain oedema
Very common: Vision blurred, corneal structural change (including corneal deposits and corneal opacity)
Common: Visual impairment, halo vision, photopsia, glaucoma, conjunctivitis, dry eye, keratopathy
Uncommon: Cataract, accommodation disorders
Very common: Prolongation of ECG QTc interval,*
Uncommon: Heart failure, acute heart failure, rate and rhythm disorders, cardiac conduction disorders, ventricular arrhythmia and cardiac arrest
Very common: Hypertension
Common: Hypertensive crisis, ischaemic cerebrovascular conditions
Not known: Aneurysms and artery dissections
Common: Epistaxis, haemoptysis, pneumonitis
Uncommon: Respiratory failure, pneumonia aspiration
Very common: Abdominal pain, diarrhoea, nausea, vomiting, dyspepsia
Common: Colitis, dry mouth, stomatitis, dysphagia, constipation, gastritis, gastrointestinal haemorrhage
Uncommon: Pancreatitis, peritonitis, ileus, intestinal perforation, faecal incontinence
Common: Cholelithiasis
Very common: Photosensitivity reaction, rash and other skin rections (including acne, dry skin, dermatitis, pruritus), nail disorders
Common: Palmar-plantar erythrodysaesthiesia syndrome, alopecia
Uncommon: Bullous dermatitis
Very common: Proteinuria, nephrolithiasis
Common: Dysuria, hematuria, renal failure, pollakiuria, micturition urgency
Uncommon: Chromaturia, anuria
Very common: Asthenia, fatigue, pain, oedema
Common: Pyrexia
Uncommon: Impaired healing
Very common: ECG QTc interval prolonged
Common: Increase of serum ALT and AST, weight decreased blood creatinine increased
Uncommon: Increased haemoglobin,serum amylase 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).
Events such as Torsades de pointes, Stevens-Johnson syndrome, erythema multiforme, 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.
Paediatric clinical trial data with vandetanib in MTC obtained during drug development is limited to 16 patients aged 9 years to 17 years with hereditary medullary thyroid carcinoma (Study IRUSZACT0098). Whilst the study size is small owing to the rarity of MTC in children, it is considered representative of the target population. The safety findings in this study are consistent with the safety profile of vandetanib in adult patients with MTC. Long term safety data in paediatric patients are not available.
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