Capresa® (Caprelsa®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceVandetanibVandetanib
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  • Capresa®
    pills inwards 
    AstraZeneca UK Ltd     United Kingdom
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    One 100 mg tablet contains:

    active substance: vandetanib 100.0 mg;

    Excipients: calcium hydrophosphate dihydrate 105.0 mg, microcrystalline cellulose 25.0 mg, crospovidone 12.5 mg, povidone-K29-32 5.0 mg, magnesium stearate 2.5 mg;

    tablet shell: hypromellose 2910 4.9 mg, macrogol 300 1.0 mg, titanium dioxide 1,6 mg.

    One 300 mg tablet contains:

    active substance: vandetanib 300.0 mg;

    Excipients: calcium hydrophosphate dihydrate 315.0 mg, microcrystalline cellulose 75.0 mg, crospovidone 37.5 mg, povidone-K29-32 15.0 mg, magnesium stearate 7.5 mg;

    tablet shell: hypromellose 2910 14.7 mg, macrogol 300 3.0 mg, titanium dioxide 4.8 mg.

    Description:

    Tablets 100 mg: Round, biconvex tablets, covered with a film shell of white color, with engraving Z100 on one side.

    Tablets 300 mg: Oval, biconvex tablets, covered with a film shell of white color, engraved Z300 on one side.

    Pharmacotherapeutic group:antitumor agent - protein tyrosine kinase inhibitor
    ATX: & nbsp

    L.01.X.E   Protein kinase inhibitors

    L.01.X.E.12   Vandetanib

    Pharmacodynamics:

    Vandetanib, being a selective tyrosine kinase inhibitor, suppresses the receptor-2 receptor-2, vascular endothelial growth factor (VEGF), stimulated by the growth factor of the vascular endothelium (VEGF) in endothelial cells. Vandetanib inhibits migration, proliferation, endothelial cell survival, and the formation of new blood vessels stimulated by VEGF on in vitro models of angiogenesis. In vivo vandetanib reduced angiogenesis induced by tumor cells, tumor receptor permeability and the density of the microvascular tumor network, suppressed tumor growth and metastases on models of the human lung cancer heterograft in athymic mice.

    In addition, in tumor cells and endothelial cells vandetanib inhibits tyrosine kinase of the epidermal growth factor receptor (EGF), stimulated 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 tyrosine kinase receptor-3 VEGF (Flt-4).

    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 the response rate,disease control, biochemical response, and time to worsening pain in patients receiving vandenanib compared with placebo.

    Dependence of vandetanib therapy effectiveness on mutation status RET is not 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 administration, the absorption of vandetanib proceeds slowly, the maximum concentration in the plasma is usually achieved on average through 6 hours (range 4-10 hours) after administration. When repeated use was observed 8-fold cumulation of the vandetanib, with the attainment of an equilibrium state after about 2 month.

    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 / 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 metabolites of vandetanib-Noxide and N-desmethyl-vandetanib 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 an isoenzyme CYP3A4, and vandetanib-N- Oxide - under the influence of flavin-containing monooxygenases FMO1 and FMO3. N-desmethyl-vandetanib and vandetanib-N-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 dose 14C-vandetaniba approximately 69% of the drug was excreted: 44% with feces and 25% with urine. Removal of the drug occurred slowly, and, it should be expected that further excretion after 21 day is based on the half-life of plasma.

    Vandetanib was not a substrate of YUST2 expressed in HEK293 cells. Vandetanib inhibits the uptake of selective substrate OST2 marker 14C-creatinine HEK-OST2 cells, with the mean 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.

    Contraindications:

    - Hypersensitivity to vandenanib or any auxiliary substance;

    - congenital syndrome of lengthening the interval QT;

    - pregnancy and the period of breastfeeding;

    - patients with an interval QTc more than 480 ms;

    - simultaneous use with other drugs capable of lengthening the interval QTc and / or causing flutter / flicker: arsenic, cisapride, erythromycin (intravenously), toremifene, misolastine, moxifloxacin, antiarrhythmic facilities IA and III class;

    - Children under 18 years.

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

    - liver failure.

    Carefully:Renal failure of moderate severity (creatinine clearance ≥ 30 and <50 mL / min).
    Pregnancy and lactation:

    Pregnancy

    Adequate and well-controlled studies of Caprels® with pregnant women were not conducted.According to preclinical studies, taking Caprels® can damage the fetus, because the risk of fetal / fetal pathology 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 Caprels® in women during breastfeeding. Vandetanib was excreted in the milk of rats, and was found in the blood plasma of cubs after administration of the drug to lactating rats. Breastfeeding is contraindicated during the period of treatment with the drug Capresa®.

    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 60 ml of non-carbonated drinking water. Other liquids can not be used. The tablet should be dipped into water without crushing, stirring for about 10 minutes (the tablet will not dissolve completely) and immediately drink the resulting suspension. Residue mixed with additional 120 ml of water and drink the resulting suspension.A suspension of the Caprels® preparation can also be administered via a nasogastric tube or gastrostomy.

    Therapy with Caprels® 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

    It is necessary to monitor the patient's condition.

    Due to the 19-day half-life, adverse reactions associated with toxicity, including lengthening of the interval QT, may not be resolved quickly.

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

    Special populations of patients

    Children or teenagers

    The preparation Kaprelza® 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 the available data, the safety profile of 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 insufficiency is not required.

    In patients with moderate renal insufficiency (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 not established.The study of the pharmacokinetics of vandetanib in volunteers with renal insufficiency of severe severity showed that the exposure of the 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 Caprels® 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 Caprels® in patients with hepatic insufficiency is contraindicated due to the lack of data on safety and efficacy of the drug in this group of patients.

    Side effects:

    The most frequent adverse reactions with the use of the drug Caprels® were diarrhea, rash, nausea, increased blood pressure and headache. The undesirable reactions observed in the completed clinical trials involving patients with medullary thyroid cancer who received the Capresa® preparation 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:

    Often: interval lengthening QTc on the ECG1,2, increased blood pressure.

    Often: ischemic cerebrovascular phenomena, hypertensive crisis.

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

    From the gastrointestinal tract:

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

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

    General disorders:

    Often: fatigue, asthenia, pain, swelling.

    Often: fever.

    Infrequently: impaired wound healing.

    Laboratory and instrumental data:

    Often: interval lengthening QTc on the ECG.

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

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

    From the side of metabolism and nutrition:

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

    Infrequently: malnutrition (exhaustion).

    From the endocrine system:

    Often: hypothyroidism.

    Disorders of the psyche:

    Often: insomnia.

    Often: depression, anxiety.

    From the side of the kidneys and urinary tract:

    Often: proteinuria, nephrolithiasis, hematuria, dysuria, renal insufficiency, frequent urination, mandatory urges to urinate.

    Infrequently: chromaturia, anuria.

    From the respiratory system:

    Often: nosebleeds, hemoptysis, pneumonitis.

    Infrequently: respiratory insufficiency, 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:

    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, disruption of accommodation.

    From the nervous system:

    Often: headache, paresthesia, dysesthesia, dizziness.

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

    Infrequently: convulsions, clonus, cerebral edema.

    Infectious and parasitic diseases:

    Often: nasopharyngitis, bronchitis, upper respiratory tract infections, urinary tract infections.

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

    Infrequently: appendicitis, staphylococcal infections, diverticulitis, cellulitis, abdominal wall abscess.

    Disorders from the liver and bile ducts:

    Often: cholelithiasis.

    1 In 13.4% of patients in the vandetanib group, the interval QTc (according to Bazett) was> 500 ms compared with 1.0% in the placebo group. Interval lengthening QTcF > 20 ms was observed in more than 91% of patients,> 60 ms in 35% of patients,> 100 ms in 1.7% of patients. In connection with the lengthening of the interval QTc 8% of patients had a reduced dose of the drug.

    2Including 2 deaths (one due to sepsis and one due to heart failure) in patients with a QTc interval of more than 550 ms.

    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 fatal) and reversible leukoencephalopathy syndrome were noted. It is expected that in patients with medullary thyroid cancer receiving vandetanib, these undesirable phenomena will be noted infrequently.

    Visual impairments, such as blurred vision, have often been observed in patients with medullary thyroid cancer who received the Kaprels® 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 in patients with medullary thyroid cancer, the following changes in laboratory parameters were very often noted: protein and blood in the urine (rapid analysis with the help of test strips), increase in the concentration of thyroid-stimulating hormone,hemoglobin and creatinine in the blood serum, increased activity of amylase, increased lipase activity. An increase in the concentration of creatinine of 1-2 degrees of CACAE was noted, which may be due to the inhibition of OCT2 (see the section "Pharmacokinetics").

    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 overdose of the drug Kaprelsa 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. Consider possible lengthening of the interval QT and the development of ventricular arrhythmia of tachysystolic type "pirouette".

    In case of development of undesirable reactions associated with overdose, symptomatic treatment should be performed, in particular, appropriate treatment for severe diarrhea.

    In case of an overdose, stop taking the drug and take appropriate measures to prevent the development of adverse events,for example, perform an ECG for 24 hours to determine the lengthening interval QTc.

    Interaction:

    Effect of vandetanib on the pharmacokinetics of other drugs

    Data in vitro indicate that vandetanib is a moderate isoenzyme inducer CYP3A4. Therefore, care should be taken when using vandetanib with isoenzyme substrates CYP3A4, especially estrogen / progesterone combined preparations, immunosuppressants, such as ciclosporin or tacrolimus, or antitumor drugs like docetaxel and bortezomib.

    When combined with midazolam (substrate isoenzyme CYP3A4) and vandetanib by healthy volunteers, the concentration of midazolam did not change. The use of vandetanib with drugs, the elimination of which occurs with the participation of the transporter P-glycoprotein (P-gp) (for example, 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 (monitoring patients receiving vandetanib, described in the sections "Dosage and Administration" and "Special Instructions"). With the combined use of digoxin and vandetanib, healthy volunteers AUC(0-t) (the area under the concentration-time curve) and CmOh (maximum concentration) of digoxin by 23% and 29%, respectively.

    It should be taken into account the possibility of extending the interval QT, development of ventricular tachyarrhythmia of the "pirouette" type with the combined use of vandetanib and digoxin; a dose adjustment may be required. Vandetanib, being an inhibitor of the organic cation transport (OCT2), can slow down the excretion of metformin and other substrates of OCT2, thereby increasing their concentration. In the joint use of metformin (substrate OST2) and vandetanib in healthy volunteers (wild type OST2), an increase AUC(0-t) and CmOh metformin by 74% and 50%, respectively, and a decrease in renal clearance of metformin by 52%. More careful monitoring of the patient and a reduction in the dose of metformin may be required (monitoring patients receiving vandetanib, described in the sections "Dosage and Administration" and "Special Instructions").

    The effect of other drugs on the pharmacokinetics of vandetanib

    With the combined use of omeprazole and vandetanib, healthy volunteers showed a decrease in CmOh vandetanib by 15%, with the value AUC(0-t) has not changed. In the joint application of ranitidine and vandetanib, the values ​​of CmOh and AUC(0-t) vandetanib did not change. With the combined use of vandetanib and ranitidine or omeprazole, dose adjustment is not required.

    There was no clinically significant interaction between vandetanib and a potent inhibitor of isoenzyme CYP3A4, itraconazole. However, with the combined use of vandetanib and itraconazole, and other potent inhibitors of the isoenzyme CYP3A4 Care should be taken, for example, ketoconazole, ritonavir and clarithromycin.

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

    Medications that can lengthen the interval QTc

    Vandetanib may cause lengthening of the interval QTc, therefore, it should not be taken concomitantly with other drugs capable of lengthening the interval QTc and / or causing flutter / flicker:

    - it is contraindicated with arsenic, cisapride, erythromycin (intravenously), toremifene, misolastine, moxifloxacin, antiarrhythmics IA and III class (see the section "Contraindications");

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

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

    With the combined use of vandetanib and ondansetron, a slight additive effect on the lengthening of the interval QTc (approximately 10 ms), so the combined use of these drugs is not recommended.In the case 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.

    The intake of food does not affect the concentration of vandetanib.

    In view of the possible interaction of vitamin K antagonists and chemotherapeutic agents, more frequent monitoring of the internationally normalized relationship (INR).

    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 the cancer embryonic antigen (CEA), as well as the growth rate of the tumor during dynamic observation, will help identify patients who need this therapy, as well as the optimal time to start it.

    Interval lengthening QTc

    Patients receiving the preparation of Capresa® observed an elongation of the interval QTc on the ECG (see Fig.section "Side effect"). In 8% of patients with medullary thyroid cancer who received the drug at a dose of 300 mg / day, in the phase III study there was a confirmed lengthening of the interval QTc on the ECG. Elongation QTc interval on the ECG is dose dependent, and treatable by appropriate monitoring, suspension of therapy, and dose reduction, if required.

    Infrequent cases of arrhythmia of the ventricular tachysystolic type "pirouette" (Torsades de Pointes) and ventricular tachycardia with the use of the drug Capresa® in a dose of 300 mg.

    Do not start therapy with Caprels® in patients with an adjusted interval QT on the ECG more than 480 ms. You should not prescribe Caprels® to patients with a history of ventricular tachysystolic type "pirouette" in history, unless all the risk factors that contribute to its development have been corrected.

    Studies of the use of Caprels® 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 TSH (thyroid stimulating hormone) should be obtained before the beginning, 2-4 weeks and 8-12 weeks after the beginning of the use of the drug Kaprelsa, 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 lengthening the interval QT (on the ECG). In the absence of alternative therapy, Caprels® can be used with certain drugs that extend the interval QT on the ECG (see "Interaction with Other Drugs and Other Interactions"). If such drugs are prescribed to a patient already taking the drug Caprels®, then it is necessary to perform ECG monitoring of the interval QT in accordance with the pharmacokinetics of the added preparation.

    With the value of the interval QTc on an ECG of more than 500 ms with a single measurement, it is necessary to suspend therapy with Caprels®. After the interval is returned QTc to the initial value or less than 450 ms, you can resume taking the drug at a lower dose.

    Skin Reactions

    During the therapy with the drug Capresa®, the development of rash and other skin reactions (including photosensitivity reactions and palmar-plantar erythrodysesthesia syndrome) was observed in patients.Slightly and moderately expressed skin reactions are usually resolved with symptomatic therapy or a reduction in the dose of Caprels®. In the case of developing more severe skin reactions (such as Stevens-Johnson syndrome), it may be necessary to administer systemic glucocorticosteroids and discontinue therapy with Caprels®.

    During therapy with Capresa®, you must wear sun protection clothing and / or use sunscreen.

    Diarrhea

    Patients taking the drug Capresa®, there was a development of 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 (see sections on "Method of administration and dose" "Side effect").

    Bleeding

    There have been reports of intracranial hemorrhage, and caution should be exercised when using Caprels® in patients with metastases to the brain.

    Arterial hypertension

    Against the background of taking the drug Caprels®, the development of hypertension, including hypertensive crisis, was noted. 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 Caprels® should not be resumed until blood pressure normalization (see "Side-Effects" section). You may need to reduce the dose of the drug.

    Heart failure

    Patients taking the drug Kaprelsa, noted the development of heart failure, in some cases, irreversible and fatal. With the development of heart failure, it may be necessary to temporarily or completely discontinue therapy with the drug Capresa®.

    Increased ALT activity

    Against the background of taking the drug Capresa®, ALT activity was often noted to increase. Most cases were resolved with the continuation of therapy, others - after the suspension of treatment for 1-2 weeks. When using the drug Caprels® it is recommended to periodically evaluate the activity of ALT.

    Interstitial lung disease

    With the use of the drug Capresa ®, interstitial lung disease, in some cases with a fatal outcome, was observed. If such respiratory symptoms such as shortness of breath, cough and fever occur, the use of the Caprels® drug should be suspended and an immediate examination performed. In case of confirmation of interstitial lung disease, taking Caprels® should be stopped and appropriate treatment prescribed.

    Syndrome of reversible posterior leukoencephalopathy (COPD)

    In patients who took the drug Caprels® in combination with chemotherapy, or in children with brain tumors who received monotherapy with Caprels®, they noted the development of the syndrome of reversible posterior leukoencephalopathy, the syndrome of subcortical vasogenic edema detected on the MRI of the brain.

    COPD was 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 insufficiency (creatinine clearance ≥ 30 and <50 mL / min), the initial dose of the drugshould be reduced to 200 mg (see section "Method of administration and dose").

    Liver failure

    Experience with the use of the drug Caprels® 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 Kaprelsa® is contraindicated in patients with hepatic impairment (see section "Contraindications").

    Inductors of isoenzyme CYP3A4

    It is necessary to avoid simultaneous application of the preparation Capresa® with moniinductors of the isoenzyme CYP3A4, such as rifampicin, preparations of St. John's wort perfumed, carbamazepine, phenobarbital (see section "Interaction with Other Drugs and Other Interactions").

    Other

    Women of childbearing age should use reliable contraceptive methods during treatment with Caprels® and for at least 3 months after the last dose of the drug.

    Dependence of vandetanib therapy effectiveness on mutation status RET is not proved.

    The advantage of therapy with vandetanib in patients with a calcitonin concentration of less than 500 pg / ml has not been studied in clinical studies,so these patients may need careful monitoring of the concentration of calcitonin to reduce the risk of therapy with vandenanib.
    Effect on the ability to drive transp. cf. and fur:

    No studies have been conducted to study the effect of the Capresa® preparation on the ability to drive vehicles and control 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.

    Form release / dosage:

    Film-coated tablets are 100 mg and 300 mg.

    Packaging:

    For 10 tablets in a blister formed from an unplasticized polyvinyl chloride (PVC) film with polyvinylidene chloride (PVDC), sealed aluminum foil of high hardness, coated with thermo lacquer; 3 blisters with instructions for use in a cardboard box with the control of the first opening.

    Storage conditions:

    Store at a temperature not exceeding 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002238
    Date of registration:19.09.2013
    Date of cancellation:2018-09-19
    The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom
    Manufacturer: & nbsp
    ASTRAZENECA UK, Ltd. United Kingdom
    Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.
    Information update date: & nbsp11.12.2015
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