Vandetanib (Vandetanibum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Antineoplastic agents

Antineoplastic agents - inhibitors of protein kinases

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  • Capresa®
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    AstraZeneca UK Ltd     United Kingdom
    • Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

    VED

    АТХ:

    L.01.X.E   Protein kinase inhibitors

    L.01.X.E.12   Vandetanib

    Pharmacodynamics:

    Vandetanib, as a selective tyrosine kinase inhibitor, suppresses the vascular endothelial growth factor receptor (VEGF) receptor tyrosine kinase, stimulated by the vascular endothelial growth factor (VEGF) in endothelial cells. Vandetanib inhibits migration, proliferation, endothelial cell survival, and the formation of new VEGF-stimulated blood vessels in vitro models of angiogenesis. In vivo vandetanib reduced angiogenesis induced by tumor cells, permeability of tumor vessels and density of microvascular tumor network, suppressed tumor growth and metastases on models of human lung cancer heterograft in athymic mice.

    In addition, in tumor cells and endothelial cells vandetanib inhibits tyrosine kinase of the epidermal growth factor (EGF) receptor stimulated by EGF. Vandetanib Suppresses EGFR-dependent proliferation and cell survival in vitro. In vitro The research showed that vandetanib also inhibits the activity of other tyrosine kinases, including those rearranged during transfection (RET) and receptor-3 VEGF receptor (Flt-4) tyrosine kinases.

    In a clinical trial involving 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer, a statistically significant improvement in progression-free survival as well as an advantage in response rates, disease control, biochemical response, and time to worsening pain syndrome in patients receiving vandenanib by compared with placebo.

    The dependence of the efficacy of vandetanib therapy on the status of RET mutation has not been proved.

    Pharmacokinetics:

    The pharmacokinetics of vandetanib in a dose of 300 mg in patients with medullary thyroid cancer is characterized by a clearance of approximately 13.2 l / h, a distribution volume of approximately 7450 liters and a plasma half-life of approximately 19 days.

    Suction

    After oral intake of vandetanib absorption is slow, the maximum concentration in the plasma is usually achieved on average after 6 hours (range 4-10 hours) after administration.With repeated use, an 8-fold cumulation of vandetanib was observed, with the attainment of an equilibrium state after about 2 months.

    Distribution

    Vandetanib binds to albumin and alpha-1-acid glycoprotein of human serum, while in vitro the binding to proteins is approximately 90%. AT ex vivo plasma samples of patients with colorectal cancer at an equilibrium exposure after taking the drug at a dose of 300 mg per day, the binding of the drug to proteins averaged 93.7% (range 92.2-95.7%).

    Metabolism

    After oral administration 14S-Wandetanib unchanged vandetanib and the metabolites of vandetanib-N-oxide and N-desmethyl-vandetanib are found in plasma, urine and feces. The glucuronic acid conjugate was an insignificant metabolite only in the excreta. N-desmethyl-vandetanib is mainly formed by the action of the isoenzyme CYP3A4, and vandetanib-N-oxide - by the action of flavin-containing monooxygenases FM01 and FM03. N-desmethyl-vandetanib and vandetanib-M-oxide circulate in the blood at concentrations of approximately 11% and 1.4%, respectively, of the concentration of vandetanib.

    Excretion

    Within 21 days after a single intake of C-vandetanib, approximately 69% of the drug was excreted (44% with feces and 25% in urine).Removal of the drug was slow, it should be expected that further excretion after 21 days is based on the half-life of plasma.

    Vandetanib was not a substrate for hOCT2 expressed in HEK293 cells. Vandetanib inhibits the uptake of selective substrate OST2 marker 14C-creatinine HEK-OST2 cells, with the average IC50 is about 2.1 μg / ml. This is higher than the plasma concentrations of vandetanib (approximately 0.81 and 0.32 μg / ml) achieved after repeated administration of the drug at doses of 300 mg and 100 mg, respectively. Vandetanib inhibits renal excretion of creatinine, resulting in a concentration of creatinine in the blood plasma of patients taking vandetanib, increases.

    Indications:

    Unresectable locally advanced or metastatic medullary thyroid cancer.

    ICD-10

    II.C73-C75.C73   Malignant neoplasm of thyroid gland

    Contraindications:

    - hypersensitivity to vandetanib or any auxiliary substance;

    - congenital syndrome of prolongation of the QT interval;

    - pregnancy and the period of breastfeeding;

    - Patients with a QTc interval of more than 480 ms;

    - simultaneous use with other drugs that can prolong the QTc interval and / or cause flutter / flicker: arsenic, cisapride, erythromycin (intravenously), toremifene, misolastine, moxifloxacin, antiarrhythmics of IA and III class;

    - children's age till 18 years;

    - severe renal failure (creatinine clearance <30 ml / min);

    - liver failure.

    Carefully:

    Moderate renal failure (creatinine clearance> 30 and <50 mL / min).

    Pregnancy and lactation:

    Pregnancy

    Adequate and well-controlled studies of the drug with pregnant women were not conducted. According to preclinical research, taking the drug can harm the fetus, because the risk of developing embryo / fetal pathologies is high. In accordance with the pharmacological action vandetanib had a significant effect on all stages of reproductive function in female rats.

    The use of the drug during pregnancy is contraindicated.

    Breastfeeding period

    There are no data on the use of the drug in women during breastfeeding. Vandetanib was excreted in the milk of rats, and was found in the blood plasma of the young after administration of the drug to lactating rats. Breastfeeding during drug treatment contraindicated.

    Dosing and Administration:

    Inside, 300 mg once a day (1 tablet 300 mg or 3 tablets 100 mg), regardless of food intake.

    The tablet can also be dispersed in 50 ml of non-carbonated drinking water. Other liquids can not be used. The tablet should be lowered into water without crushing, stirring until complete destruction (for about 10 minutes) and immediately drink the resulting suspension. After washing the walls of the glass, pour another 50 ml of water, and drink the resulting suspension. The drug suspension can also be administered via a nasogastric tube or gastrostomy.

    The drug therapy should be continued until patients with medullary thyroid cancer continue to benefit from the treatment.

    In case the patient missed the next dose, the next daily dose should be taken according to the prescribed treatment regimen.

    Correction of dose

    With the development of toxicity of the 3rd degree of STACEA (General Terminological Criteria for Assessing Adverse Events) or higher, or the prolongation of the QT interval on the ECG,it is necessary to temporarily suspend the therapy until the toxicity is resolved or its severity is reduced to STACEA degree 1, then resuming treatment at a lower dose. The daily dose of 300 mg can be reduced to 200 mg (2 tablets of 100 mg), and then, if necessary, up to 100 mg.

    Special populations of patients

    Children or teenagers

    The drug is not intended for use in children, since safety and efficacy have not been established.

    Elderly patients (over 65 years of age)

    It is not necessary to adjust the initial dose in elderly patients. Clinical data on the use of the drug in patients over the age of 75 years are limited.

    Patients with renal insufficiency

    Data on the use of the drug in patients with moderate renal insufficiency are limited. According to available data, the safety profile in patients with mild renal insufficiency is similar to the safety profile in patients with normal renal function. Correction of the initial dose in patients with mild renal failure is not required. In patients with moderate renal failure (creatinine clearance> 30 and <50 mL / min), the initial dose should be reduced to 200 mg. Vandetanib is contraindicated in patients with severe renal insufficiency (creatinine clearance <30 ml / min), since the experience of using the drug in this population is limited, safety and efficacy have not been established.

    A study of the pharmacokinetics of vandetanib in volunteers with severe renal insufficiency showed that the exposure of vandetanib can be increased up to 2-fold.

    Patients with hepatic insufficiency

    According to the results of pharmacokinetics studies, volunteers do not need to change the initial dose of the drug in patients with mild, moderate or severe hepatic insufficiency. The experience of using the drug in patients with hepatic insufficiency (serum bilirubin concentration above the upper limit of the norm is more than 1.5 times) is limited. The use of the drug in patients with hepatic insufficiency is contraindicated due to a lack of data on the safety and efficacy of the drug in this group of patients.

    Side effects:

    The most frequent undesirable side reactions when using the drug were diarrhea, rash, nausea, hypertension and headache.The undesirable reactions observed in the completed clinical trials involving patients with medullary thyroid cancer who received the drug are described below.

    The frequency of unwanted reactions is presented in the following gradation: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10000 , <1/1000), very rarely (<1/10000), including individual messages.

    From the side of the heart and blood vessels:

    Very often: prolongation of QTc interval on ECG, hypertension.

    Often: ischemic cerebrovascular events, hypertensive crisis.

    Infrequent: heart failure, acute heart failure, rhythm disturbances, cardiac conduction disorder, ventricular arrhythmia and cardiac arrest.

    From the gastrointestinal tract:

    Very often: diarrhea, nausea, vomiting, abdominal pain, indigestion.

    Often: stomatitis, dry mouth, colitis, dysphagia, constipation, gastritis, gastrointestinal bleeding.

    Infrequently: pancreatitis, peritonitis, intestinal obstruction, intestinal perforation, fecal incontinence.

    General disorders:

    Very often: fatigue, asthenia, pain, swelling.

    Often: fever.

    Infrequent: a violation of wound healing.

    Laboratory and instrumental data:

    Very often: prolongation of the QTc interval on the ECG.

    Often: weight loss, increased activity alanine aminotransferase and aspartate aminotransferase, an increase in the concentration of creatinine in the blood.

    Infrequent: increased hemoglobin concentration, increased activity of amylase in serum.

    From the side of metabolism and nutrition:

    Very often: decreased appetite, hypocalcemia.

    Often: hypokalemia, hypercalcemia, hyperglycemia, dehydration, hyponatremia.

    Infrequent: eating disorder (exhaustion).

    From the endocrine system:

    Often: hypothyroidism.

    Disorders of the psyche:

    Very often: insomnia.

    Often: depression, anxiety.

    From the side of the kidneys and urinary tract:

    Often: proteinuria, renal stone disease, hematuria, dysuria, renal failure, frequent urination, mandatory urge to urinate.

    Infrequently: chromaturia, anuria.

    From the respiratory system:

    Often: nosebleeds, hemoptysis, pneumonitis.

    Infrequent: respiratory failure, aspiration pneumonia.

    From the skin and subcutaneous tissues:

    Very often: rashes and other skin reactions (including acne, dry skin, dermatitis, pruritus), photosensitivity reactions, nail damage.

    Often: palmar-plantar erythrodysesthesia, alopecia.

    Infrequently: bullous dermatitis.

    From the side of the organ of vision:

    Very often: structural changes in the cornea (including corneal precipitate and corneal opacity).

    Often: blurred vision, conjunctivitis, dry eyes, blurred vision, photopsy, iridescent circles around the light source, glaucoma, keratopathy.

    Infrequently: cataract, violation of accommodation.

    From the nervous system:

    Very often: headache, paresthesia, dysesthesia, dizziness.

    Often: tremor, lethargy, loss of consciousness, imbalance, taste disorders.

    Infrequently: convulsions, clonus, edema of the brain.

    Infectious and parasitic diseases:

    Very often: nasopharyngitis, bronchitis, upper respiratory tract infections, urinary tract infections.

    Often: pneumonia, sepsis, influenza, cystitis, sinusitis, laryngitis, folliculitis, furuncle, fungal infections, pyelonephritis.

    Infrequent: appendicitis, staphylococcal infections, diverticulitis, cellulitis, abscess of the abdominal wall.

    Disorders from the liver and bile ducts:

    Often: cholelithiasis.

    On the background of vandetanib monotherapy, cases of arrhythmia of ventricular tachysystolic type "pirouette", Stevens-Johnson syndrome, erythema multiforme,interstitial lung disease (in some cases, with a fatal outcome) and a syndrome of reversible posterior leukoencephalopathy. It is expected that in patients with medullary thyroid cancer receiving vandetanib, these undesirable phenomena will be noted infrequently.

    Visual impairment, for example, blurred vision, was often observed in patients with medullary thyroid cancer who received the drug. A routine examination with a slit lamp revealed corneal opacity (vorticose keratopathy) in patients, however, regular slit-lamp ophthalmologic examination is not required.

    In a randomized trial, the following changes in laboratory parameters were very often noted in patients with medullary thyroid cancer: protein and blood in the urine (rapid test with test strips), increased serum levels of thyrotropic hormone, hemoglobin and creatinine, increased amylase activity, increased lipase activity. An increase in the concentration of creatinine in the 1-2 degree of CACAE was noted, which may be due to the inhibition of OCT2.

    In patients who took vandetanib, an increase in the concentration of hemoglobin on average by 0.5-1.5 g / dl was noted in comparison with the initial value.

    Overdose:

    Specific treatment for an overdose of the drug does not exist, the possible symptoms of an overdose are not established. An increase in the incidence and severity of some unwanted reactions, such as rash, diarrhea, and hypertension, was noted when taking the drug multiple times at doses of 300 mg or more. It should be considered possible prolongation of the QT interval and the development of arrhythmia of the ventricular tachysystolic type "pirouette".

    In case of development of undesirable reactions associated with overdose, symptomatic treatment should be carried out, in particular, appropriate treatment for severe diarrhea. In case of an overdose, stop taking the drug again, and take appropriate measures to prevent the development of adverse events, for example, performing an ECG for 24 hours to determine the QTc interval elongation.

    Interaction:

    Effect of vandetanib on the pharmacokinetics of other drugs

    Data in vitro indicate that vandetanib is a moderate inducer of the isoenzyme CYP3A4.Therefore, care should be taken when using vandetanib with the substrates of the isoenzyme CYP3A4, especially estrogen / progesterone combined preparations, immunosuppressants, such as ciclosporin or tacrolimus, or antitumor drugs like docetaxel and boardezomibu. The use of vandetanib with drugs, the removal of which occurs with the participation of a P-glycoprotein transporter (P-gp) (eg, dabigatran or digoxin), can lead to an increase in the concentration of these drugs in the plasma and require close clinical and laboratory monitoring of the patient's condition and even a reduction in the dose of these drugs.

    Vandetanib, being an inhibitor of the organic cation transport (OCT2), can slow the excretion of metformin and other OST2 substrates, thereby increasing their exposure. More careful monitoring of the patient and a decrease in the dose of metformin may be required.

    The combined use of vandetanib and proton pump inhibitors can reduce exposure to vandetanib, so the use of this combination of drugs is not recommended.

    The effect of other drugs on the pharmacokinetics of vandetanib

    There was no clinically significant interaction between vandetanib and a potent inhibitor of the isoenzyme CYP3A4, itraconazole. However, with the concomitant use of vandetanib and itraconazole, and other potent inhibitors of the isoenzyme CYP3A4 (eg, ketoconazole, ritonavir and clarithromycin), care should be taken.

    With the combined use of vandetanib and rifampicin, a powerful inducer of the CYP3A4 isoenzyme in men, vandetanib exposure decreased by 40%; therefore, the combined use of vandetanib and the powerful inducers of the CYP3A4 isoenzyme (for example, rifampicin, carbamazepine, phenobarbital and St. John's wort preparations) should be avoided.

    Drugs that can extend the QTc interval

    Vandetanib can cause prolongation of the QTc interval, so it should not be taken concomitantly with other drugs that can prolong the QTc interval and / or cause flutter / flicker:

    - use with arsenic, cisapride, erythromycin (intravenously), toremifene, misolastine, moxifloxacin, antiarrhythmics of IA and III class is contraindicated;

    - use with methadone, haloperidol, amisulpride, chlorpromazine, sulpiride, zuclopentixol, halofantrine, pentamidine and lumefantrine is not recommended.

    In the absence of a suitable alternative therapy, the use of a non-recommended combination of drugs is possible if monitoring of the QTc interval on the ECG, monitoring the concentration of electrolytes, and additional control in the case of occurrence or increase of diarrhea.

    When vandetanib was used together with ondansetron, an insignificant additive effect was observed on the prolongation of the QTc interval (approximately 10 ms), therefore, the concomitant use of these drugs is not recommended. In the case of the appointment of ondansetron with vandetanib, careful monitoring of the concentration of electrolytes in the serum and ECG, as well as intensive therapy of any disorders, is required. Eating does not affect the exposure of the drug.

    Due to the possible interaction of vitamin K antagonists and chemotherapeutic agents, more frequent monitoring of the international normalized relationship is recommended.

    Special instructions:

    Taking into account possible risks,it is very important to prescribe vandetanib therapy only to patients to whom it is objectively shown, namely to patients with symptomatic-aggressive course of the disease. Only the presence of symptoms or only the progression of the disease is not sufficient reason for the appointment of vandetanib.

    The change in concentration of biomarkers, such as calcitonin and / or cancer embryonic antigen (CEA), as well as tumor growth rate during dynamic observation, will help identify patients who need this therapy, as well as the optimal time to start it.

    QTc interval extension

    In patients receiving the drug, prolonged QTc interval on the ECG was observed. In 8% of patients with medullary thyroid cancer who received the drug at a dose of 300 mg per day, in the Phase III study, the QTc interval on the ECG was confirmed to be prolonged. The prolongation of the QTc interval on the ECG is dose dependent, and treatable by appropriate monitoring, suspension of therapy, and dose reduction, if required.

    It was not often reported cases of arrhythmia of the ventricular tachysystolic type "pirouette" and ventricular tachycardia with the use of the drug at a dose of 300 mg.

    Do not start drug therapy in patients with an adjusted QT interval value on an ECG of more than 480 ms. Do not prescribe a drug to patients with ventricular tachycystolic arrhythmia "pirouette" in history, except when all the risk factors that contribute to its development are adjusted.

    Studies of the use of the drug in patients with ventricular arrhythmias or recent myocardial infarction have not been conducted.

    The ECG and the results of measurements of serum concentrations of potassium, calcium, magnesium and thyroid-stimulating hormone should be obtained before the beginning, 2-4 weeks and 8-12 weeks after the beginning of the drug application, and then every 3 months throughout the year. ECG and blood tests should also be performed according to clinical indications during this period and subsequently. Serum potassium concentration should be maintained at 4 meq / l or higher, and magnesium and calcium concentrations should be within normal limits to reduce the risk of prolonging the QT interval on the ECG. In the absence of alternative therapy, the drug can be used with some drugs that extend the QT interval on the ECG.If such drugs are prescribed for a patient already taking the drug, then it is necessary to monitor the QT interval in accordance with the pharmacokinetics of the drug added.

    If the QTc interval is more than 500 msec on a single ECG, it is necessary to suspend therapy with the drug. After returning the QTc interval to the original value or less than 450 ms, you can resume taking the drug at a lower dose.

    Skin Reactions

    During the treatment with the drug, the development of rash and other skin reactions (including the photosensitivity reactions and the syndrome of palmar-plantar erythrodysesthesia) was observed in patients.

    Weakly and moderately expressed skin reactions are usually resolved in the course of symptomatic therapy or a decrease in the dose of the drug. In the case of developing more severe skin reactions (such as Stevens-Johnson syndrome), it may be necessary to administer systemic glucocorticosteroids and stop the drug therapy.

    During therapy, the drug should wear clothing that protects from exposure to sunlight, and / or use sunscreen.

    Diarrhea

    Patients taking the drug experienced diarrhea.For the treatment of diarrhea, the use of conventional antidiarrhoeal agents is recommended. Serum concentrations of electrolytes should be closely monitored. With the development of severe diarrhea (3-4 degrees of HTSAE), the drug should be stopped until the condition improves, resuming therapy with a lower dose.

    Bleeding

    Cases of intracranial hemorrhage have been reported, and therefore care should be taken when using the drug in patients with metastases in the brain.

    Arterial hypertension

    Against the background of taking the drug, there was a development of hypertension, including hypertensive crisis. In this connection, it is recommended to observe patients and prescribe appropriate treatment for arterial hypertension. If high blood pressure is not amenable to drug control, taking the drug should not be resumed until the blood pressure normalizes. You may need to reduce the dose of the drug.

    Heart failure

    Patients taking the drug noted the development of heart failure, in some cases irreversible and fatal.With the development of heart failure may require a temporary or complete withdrawal of therapy with the drug.

    Interstitial lung disease

    When using the drug, there was a development of interstitial lung disease, in some cases with a fatal outcome. If such respiratory symptoms such as shortness of breath, cough and fever occur, the drug should be suspended and promptly examined. In case of confirmation of interstitial lung disease, the drug should be discontinued and appropriate treatment should be prescribed.

    Syndrome of reversible posterior leukoencephalopathy

    Patients taking the drug in combination with chemotherapy, or in children with a brain tumor receiving monotherapy with the drug, noted the development of the syndrome of reversible posterior leukoencephalopathy, the syndrome of subcortical vasogenic edema detected on the MRI of the brain. Syndrome of reversible posterior leukoencephalopathy noted in patients taking vandetanib. This syndrome should be suspected when patients develop seizures, headache, visual impairment, confusion, or impaired mental function.

    Renal insufficiency

    In patients with moderate renal failure (creatinine clearance> 30 and <50 mL / min), the initial dose of the drug should be reduced to 200 mg.

    Liver failure

    The experience of using the drug in patients with hepatic insufficiency (serum bilirubin level above the upper limit of the norm is more than 1.5 times) is limited, safety and effectiveness of the drug in this population of patients are not established. The drug is contraindicated in patients with hepatic insufficiency.

    Inductors of the isoenzyme CYP3A4

    Simultaneous application of the drug with powerful inducers of the CYP3A4 isoenzyme should be avoided, such as rifampicin, preparations of St. John's wort perfumed, carbamazepine, phenobarbital.

    Other

    Women of childbearing age should use reliable methods of contraception during treatment with the drug and, at least, within 3 months after the last drug intake.

    Impact on the ability to drive vehicles and manage mechanisms

    There were no studies to study the effect of the drug on the ability to drive vehicles and manage mechanisms.However, during therapy, there may be increased fatigue and blurred vision. In the event of these phenomena, patients should be careful when driving vehicles and other mechanisms.

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