Caprelsa (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi, B.V. (Netherlands)

Manufactured By

Penn Pharmaceutical Services, Limited (United Kingdom)

Packaging and Quality Control Release

EUROAPI UK, Limited (United Kingdom)

Contact Information

SANOFI

ATC Code

L01EX04 (Vandetanib)

Active Substance

Vandetanib (Rec.INN registered by WHO)

Dosage Forms

	Caprelsa	Film-coated tablets, 100 mg: 30 pcs.
		Film-coated tablets, 300 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex, engraved with “Z100” on one side.

Excipients: calcium hydrogen phosphate dihydrate – 105 mg, microcrystalline cellulose PH-101 – 25 mg, crospovidone – 12.5 mg, povidone K29-32 – 5 mg, magnesium stearate – 2.5 mg.

Coating composition: hypromellose 2910* – 4.9 mg, macrogol 300* – 1 mg, titanium dioxide – 1.6 mg.

* a ready-made film coating Opadry white 03B28460 of identical composition may be used.

10 pcs. – blisters (3) – cardboard packs.

Film-coated tablets white, oval, biconvex, engraved with “Z300” on one side.

Excipients: calcium hydrogen phosphate dihydrate – 315 mg, microcrystalline cellulose PH-101 – 75 mg, crospovidone – 37.5 mg, povidone K29-32 – 15 mg, magnesium stearate – 7.5 mg.

Coating composition: hypromellose 2910* – 14.7 mg, macrogol 300* – 3 mg, titanium dioxide – 4.8 mg.

* a ready-made film coating Opadry white 03B28460 of identical composition may be used.

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; other protein kinase inhibitors

Pharmacological Action

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

In addition, in tumor cells and endothelial cells, Vandetanib inhibits epidermal growth factor receptor tyrosine kinase, stimulated by EGF. Vandetanib suppresses EGFR-dependent cell proliferation and survival in vitro. In vitro studies have shown that Vandetanib also inhibits the activity of other tyrosine kinases, including rearranged during transfection and vascular endothelial growth factor receptor-3 tyrosine kinases.

A clinical trial involving 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer showed a statistically significant improvement in progression-free survival, as well as an advantage in response rate, disease control, biochemical response and time to pain worsening in patients taking vandetanib compared with placebo.

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

Pharmacokinetics

The pharmacokinetics of vandetanib at a dose of 300 mg in patients with medullary thyroid cancer is characterized by a clearance of approximately 13.2 L/h, a V_d of approximately 7450 L and a plasma T_1/2 of approximately 19 days.

Absorption

After oral administration, the absorption of vandetanib is slow, C_max in plasma is usually reached on average after 6 hours (range 4-10 hours) after administration. With repeated use, an 8-fold accumulation of vandetanib was observed, with steady state reached after approximately 2 months.

Distribution

Vandetanib binds to human serum albumin and alpha-1-acid glycoprotein, with in vitro protein binding being approximately 90%. In ex vivo plasma samples from patients with colorectal cancer at steady-state exposure after a 300 mg/day dose, vandetanib protein binding averaged 93.7% (range 92.2-95.7%).

Metabolism

After oral administration of ¹⁴C-vandetanib, unchanged Vandetanib and the metabolites Vandetanib-N-oxide and N-desmethyl-Vandetanib were found in plasma, urine and feces. A glucuronic acid conjugate was a minor metabolite only in excreta. N-desmethyl-Vandetanib is mainly formed by the action of the CYP3A4 isoenzyme, and Vandetanib-N-oxide is formed by the action 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 vandetanib concentration.

Excretion

Within 21 days after a single dose of ¹⁴C-vandetanib, approximately 69% of the drug was excreted: via the intestine (44%) and in the urine (25%). Drug excretion was slow, further excretion after 21 days is expected to be based on plasma T_1/2.

Vandetanib was not a substrate for hOCT2 expressed in HEK293 cells. Vandetanib inhibits the uptake of the OCT2 marker selective substrate ¹⁴C-creatinine by HEK-OCT2 cells, with a mean IC₅₀ value of approximately 2.1 µg/mL. This is higher than the vandetanib plasma concentrations (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 the renal excretion of creatinine, resulting in an increase in plasma creatinine concentration in patients taking Vandetanib.

Indications

• Unresectable locally advanced or metastatic medullary thyroid cancer.

ICD codes

Dosage Regimen

The drug is taken orally at a dose of 300 mg once a day (1 tablet of 300 mg or 3 tablets of 100 mg), regardless of food intake.

The tablet can also be dispersed in half a glass (50 ml) of non-carbonated drinking water. Other liquids must not be used. The tablet should be dropped into the water without crushing, stirred for about 10 minutes (until the tablet is completely dissolved) and the resulting suspension should be drunk immediately. The residue should be mixed with an additional half glass of water and drunk. The Caprelsa^® drug suspension can also be administered via a nasogastric tube or gastrostomy.

Therapy with Caprelsa^® should be continued until patients with medullary thyroid cancer no longer benefit from the treatment.

If a patient misses a dose of the drug, the next daily dose should be taken according to the prescribed treatment regimen.

Dose adjustment

Constant monitoring of the patient’s condition is necessary.

Due to the 19-day T_1/2, adverse reactions associated with toxicity, including QT interval prolongation, may not resolve quickly.

If CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or higher toxicity develops or QT interval prolongation is observed on ECG, therapy should be temporarily suspended until the toxicity resolves or its severity decreases to CTCAE grade 1, then treatment should be resumed 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, to 100 mg.

Caprelsa^® is not intended for use in children, as safety and efficacy have not been established.

No initial dose adjustment is required in elderly patients (over 65 years old). Clinical data on the use of the drug in patients over 75 years of age are limited.

According to available data, the safety profile in patients with mild renal impairment is similar to that in patients with normal renal function. No initial dose adjustment is required in patients with mild renal impairment. Data on the use of the drug in patients with moderate renal impairment are limited. In patients with moderate renal impairment (CrCl ≥30 and <50 mL/min) the initial dose should be reduced to 200 mg. Vandetanib is contraindicated in patients with severe renal impairment (CrCl <30 mL/min), as experience with the drug in this population is limited, and safety and efficacy have not been established. A pharmacokinetic study of vandetanib in volunteers with severe renal impairment showed that vandetanib exposure may increase up to 2-fold.

According to the results of pharmacokinetic studies in volunteers, no initial dose adjustment of the drug is required in patients with mild, moderate or severe hepatic impairment. Experience with Caprelsa^® in patients with hepatic impairment (serum bilirubin concentration more than 1.5 times the ULN) is limited. The use of Caprelsa^® in patients with hepatic impairment is contraindicated due to insufficient data on the safety and efficacy of the drug in this group of patients.

Adverse Reactions

The most common undesirable adverse reactions when using Caprelsa^® were diarrhea, rash, nausea, arterial hypertension and headache. The undesirable reactions observed in completed clinical trials involving patients with medullary thyroid cancer receiving Caprelsa^® are described below.

The frequency of adverse reactions is presented using the following gradation: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), including isolated reports.

Infections and infestations very common – nasopharyngitis, bronchitis, upper respiratory tract infections, urinary tract infections; common – pneumonia, sepsis, influenza, cystitis, sinusitis, laryngitis, folliculitis, furuncle, fungal infections, pyelonephritis; uncommon – appendicitis, staphylococcal infections, diverticulitis, cellulitis, abdominal wall abscess.

Metabolism and nutrition disorders very common – hypocalcemia; common – hypokalemia, hypercalcemia, hyperglycemia, dehydration, hyponatremia; uncommon – nutritional disorder (wasting).

Endocrine disorders common – hypothyroidism.

Psychiatric disorders very common – insomnia; common – depression, anxiety.

Nervous system disorders very common – headache, paresthesia, dysesthesia, dizziness; common – tremor, lethargy, loss of consciousness, balance disorder, taste disorders; uncommon – convulsions, clonus, brain edema.

Eye disorders common – blurred vision, corneal opacity, conjunctivitis, dry eye, visual disturbances, photopsia, halos around lights, glaucoma, keratopathy; uncommon – cataract, accommodation disorder.

Cardiac disorders very common – increased blood pressure; common – QT_c interval prolongation on ECG^1,2, ischemic cerebrovascular conditions, hypertensive crisis; uncommon – heart failure, acute heart failure, arrhythmias, cardiac conduction disorders, ventricular arrhythmia and cardiac arrest.

Respiratory, thoracic and mediastinal disorders common – epistaxis, hemoptysis, pneumonitis; uncommon – respiratory failure, aspiration pneumonia.

Gastrointestinal disorders very common – decreased appetite, diarrhea, nausea, vomiting, abdominal pain, dyspepsia; common – stomatitis, dry mouth, colitis, dysphagia, constipation, gastritis, gastrointestinal bleeding; uncommon – pancreatitis, peritonitis, intestinal obstruction, intestinal perforations, fecal incontinence.

Hepatobiliary disorders common – cholelithiasis.

Renal and urinary disorders common – proteinuria, nephrolithiasis, hematuria, dysuria, renal failure, pollakiuria, urinary urgency; uncommon – chromaturia, anuria.

Skin and subcutaneous tissue disorders very common – rash and other skin reactions (including acne, dry skin, dermatitis, pruritus), photosensitivity reactions; common – palmar-plantar erythrodysesthesia, alopecia, nail lesions; uncommon – bullous dermatitis, Stevens-Johnson syndrome³, toxic epidermal necrolysis³.

General disorders and administration site conditions very common – fatigue, asthenia, pain, edema; common – pyrexia; uncommon – impaired wound healing.

Investigations common – weight loss, increased ALT and AST activity, increased blood creatinine concentration; uncommon – increased hemoglobin concentration, increased plasma amylase activity.

¹ In 13.4% of patients in the vandetanib group, the QT_c interval (by Bazett) was ≥500 ms compared with 1% in the placebo group. QT_cF prolongation of >20 ms was noted in more than 91% of patients, >60 ms in 35% of patients, and >100 ms in 1/7% of patients. Due to QT_c interval prolongation, the drug dose was reduced in 8% of patients.

² Including 2 fatal cases (1 due to sepsis and 1 due to heart failure) in patients with a QT_c interval of more than 550 ms.

³ Frequency is based on the total number of patients (4684) who received Caprelsa^® in clinical trials.

Cases of torsades de pointes ventricular tachyarrhythmia, erythema multiforme, interstitial lung disease (in some cases with fatal outcome) and reversible posterior leukoencephalopathy syndrome have been observed during vandetanib monotherapy. These adverse events are expected to be uncommon in patients with medullary thyroid cancer receiving Vandetanib.

Visual disturbances, such as blurred vision, were frequently observed in patients with medullary thyroid cancer receiving Caprelsa^®. A planned slit-lamp examination revealed corneal opacity (vortex keratopathies) in patients, however, regular ophthalmological examination with a slit lamp is not required.

In a randomized trial in patients with medullary thyroid cancer, the following laboratory changes were very common: protein and blood in urine (dipstick test), increased serum thyrotropin, hemoglobin and creatinine concentrations, increased amylase activity, increased lipase activity. An increase in creatinine concentration of CTCAE grade 1-2 was noted, which may be associated with OCT2 inhibition.

In patients taking Vandetanib, an increase in hemoglobin concentration by an average of 0.5-1.5 g/dL from baseline was observed.

Vandetanib showed no carcinogenic effect in a 6-month carcinogenicity study in rasH2 transgenic mice and in a 2-year bioassay in rats.

Contraindications

• Severe renal impairment (CrCl <30 mL/min);
• Hepatic impairment;
• Congenital long QT syndrome;
• Patients with a QT_c interval greater than 480 ms;
• Concomitant use with other drugs that can prolong the QT_c interval and/or cause torsades de pointes (arsenic, cisapride, erythromycin (IV), toremifene, mizolastine, moxifloxacin, class IA and III antiarrhythmic drugs);
• Pregnancy;
• Lactation (breastfeeding);
• Age under 18 years;
• Hypersensitivity to vandetanib or any excipient.

With caution moderate renal impairment (CrCl ≥30 and <50 mL/min).

Use in Pregnancy and Lactation

Adequate and well-controlled studies of Caprelsa^® in pregnant women have not been conducted. According to preclinical studies, taking Caprelsa^® may harm the fetus, as there is a high risk of embryo/fetal pathologies. In accordance with its 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.

Women of childbearing potential should use effective methods of contraception during therapy and for at least 3 months after taking the last dose of Caprelsa^®.

There are no data on the use of Caprelsa^® in women during breastfeeding. Vandetanib was excreted in milk in rats and was detected in the plasma of offspring after administration of the drug to lactating rats.

Breastfeeding is contraindicated during treatment with Caprelsa^®.

Use in Hepatic Impairment

The use of the drug is contraindicated in hepatic impairment.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal impairment (CrCl <30 mL/min).

The drug should be prescribed with caution in moderate renal impairment (CrCl ≥30 and <50 mL/min).

Pediatric Use

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

Geriatric Use

No initial dose adjustment is required in elderly patients. Clinical data on the use of the drug in patients over 75 years of age are limited.

Special Precautions

Given the potential risks, it is very important to prescribe vandetanib therapy only to patients for whom it is objectively indicated, namely patients with symptomatic and aggressive disease. The presence of symptoms alone or disease progression alone is not a sufficient basis for prescribing vandetanib.

The indicator of changes in the concentration of biomarkers, such as calcitonin and/or carcinoembryonic antigen (CEA), as well as the tumor growth rate during dynamic observation, will help identify patients requiring this therapy and the optimal time for its initiation.

QT_c interval prolongation

QT_c interval prolongation on ECG was observed in patients treated with Caprelsa^®. In 8% of patients with medullary thyroid cancer receiving the drug at a dose of 300 mg/day in a phase III study, confirmed QT_c interval prolongation on ECG was observed. QT_c interval prolongation on ECG is dose-dependent and manageable with appropriate monitoring, therapy interruption, and dose reduction if required.

Cases of torsade de pointes and ventricular tachycardia were infrequently reported with the use of Caprelsa^® at a dose of 300 mg.

Caprelsa^® therapy should not be initiated in patients with a corrected QT interval on ECG greater than 480 ms. Caprelsa^® should not be prescribed to patients with a history of torsade de pointes unless all risk factors contributing to its development have been corrected.

Studies of Caprelsa^® use in patients with ventricular arrhythmias or recent myocardial infarction have not been conducted.

ECG and measurements of serum potassium, calcium, magnesium, and TSH (thyroid-stimulating hormone) concentrations must be obtained before initiation, 2-4 weeks and 8-12 weeks after starting Caprelsa^®, and then every 3 months for one year. ECG and blood tests should also be performed as clinically indicated 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 the normal range to reduce the risk of QT interval prolongation (on ECG).

In the absence of alternative therapy, Caprelsa^® can be used with some drugs that prolong the QT interval on ECG. If such drugs are prescribed to a patient already taking Caprelsa^®, ECG monitoring of the QT interval should be performed according to the pharmacokinetics of the added drug.

If the QT_c interval on ECG is greater than 500 ms in a single measurement, Caprelsa^® therapy should be interrupted. After the QT_c interval returns to baseline or to less than 450 ms, the drug can be resumed at a lower dose.

Skin reactions

Rash and other skin reactions (including photosensitivity reactions and hand-foot syndrome) were observed in patients during therapy with Caprelsa^®.

Mild and moderate skin reactions usually resolve with symptomatic treatment or reduction of the Caprelsa^® dose. If more severe skin reactions develop (such as Stevens-Johnson syndrome, toxic epidermal necrolysis), the patient is advised to seek emergency medical help. In these cases, systemic corticosteroids may be required and Caprelsa^® therapy should be discontinued.

During therapy with Caprelsa^®, it is necessary to wear clothing that protects from sun exposure and/or use sunscreen.

Diarrhea

Diarrhea developed in patients taking Caprelsa^®. The use of conventional antidiarrheal agents is recommended for the treatment of diarrhea. Serum electrolyte concentrations should be carefully monitored. If severe diarrhea (CTCAE grade 3-4) develops, the drug should be interrupted until improvement, resuming therapy at a lower dose.

Bleeding

Cases of intracranial hemorrhage have been reported, therefore caution should be exercised when using Caprelsa^® in patients with brain metastases.

Arterial hypertension

Arterial hypertension, including hypertensive crisis, has been noted during treatment with Caprelsa^®. Therefore, patient monitoring and appropriate treatment of arterial hypertension are recommended. If high blood pressure is not controlled with medication, Caprelsa^® should not be resumed until blood pressure normalizes. A dose reduction of the drug may be required.

Heart failure

Heart failure was noted in patients taking Caprelsa^®, in some cases irreversible and fatal. If heart failure develops, temporary or permanent discontinuation of Caprelsa^® therapy may be required.

Increased ALT activity

Increased ALT activity was frequently noted during treatment with Caprelsa^®. Most cases resolved with continued therapy, others after treatment interruption for 1-2 weeks. Periodic assessment of ALT activity is recommended during the use of Caprelsa^®.

Interstitial lung disease

Interstitial lung disease was observed with the use of Caprelsa^®, in some cases fatal. If respiratory symptoms such as dyspnea, cough, and fever occur, the use of Caprelsa^® should be interrupted and immediate examination performed. If interstitial lung disease is confirmed, Caprelsa^® should be discontinued and appropriate treatment initiated.

Reversible posterior leukoencephalopathy syndrome (RPLS)

Reversible posterior leukoencephalopathy syndrome, a syndrome of subcortical vasogenic edema detected on brain MRI, was noted in patients taking Caprelsa^® in combination with chemotherapy, or in children with brain tumors receiving Caprelsa^® monotherapy. RPLS has been noted in patients taking Vandetanib. This syndrome should be suspected if patients develop seizures, headache, visual disturbances, confusion, or impaired mental function.

Renal failure

In patients with moderate renal impairment (CrCl ≥30 and <50 ml/min), the initial dose of the drug should be reduced to 200 mg.

Hepatic failure

Experience with Caprelsa^® in patients with hepatic impairment (serum bilirubin level more than 1.5 times the ULN) is limited; the safety and efficacy of the drug in this patient population have not been established. Caprelsa^® is contraindicated in patients with hepatic impairment.

CYP3A4 isoenzyme inducers

Concomitant use of Caprelsa^® with potent inducers of the CYP3A4 isoenzyme, such as rifampicin, St. John’s wort preparations, carbamazepine, phenobarbital, should be avoided.

Other

The benefit of vandetanib therapy in patients with a calcitonin concentration of less than 500 pg/ml has not been studied in clinical trials, therefore such patients may require careful monitoring of calcitonin concentration to reduce the risk of vandetanib therapy.

Effect on ability to drive vehicles and operate machinery

No studies have been conducted on the effect of Caprelsa^® on the ability to drive vehicles and operate machinery. However, increased fatigue and blurred vision may occur during therapy. If these phenomena occur, patients should exercise caution when driving vehicles and operating other machinery.

Overdose

Possible symptoms of overdose have not been established. An increase in the frequency and severity of some adverse reactions, such as rash, diarrhea, and arterial hypertension, was noted with repeated administration of the drug at doses of 300 mg and higher. Possible QT interval prolongation and development of torsade de pointes should be considered.

Treatment There is no specific treatment for overdose with Caprelsa^®. In case of adverse reactions associated with overdose, symptomatic treatment should be provided, in particular, appropriate treatment for severe diarrhea. In case of overdose, further administration of the drug should be discontinued, and appropriate measures should be taken to prevent the development of adverse events, for example, perform ECG for 24 hours to determine QT_c prolongation.

Drug Interactions

Effect of vandetanib on the pharmacokinetics of other drugs

In vitro data indicate that Vandetanib is a moderate inducer of the CYP3A4 isoenzyme. Therefore, caution should be exercised when using vandetanib with substrates of the CYP3A4 isoenzyme, especially combination drugs containing estrogen/progesterone, immunosuppressants such as cyclosporine or tacrolimus, or antitumor drugs such as docetaxel and bortezomib. When midazolam (a CYP3A4 isoenzyme substrate) and vandetanib were co-administered to healthy volunteers, the concentration of midazolam did not change.

Use of vandetanib with drugs whose elimination involves the P-glycoprotein (Pgp) transporter (e.g., dabigatran or digoxin) may lead to an increase in the plasma concentration of these drugs and require close clinical and laboratory monitoring of the patient’s condition and even a dose reduction of these drugs. When digoxin and vandetanib were co-administered to healthy volunteers, an increase in the AUC_(0-t) and C_max of digoxin by 23% and 29%, respectively, was noted. The possibility of QT interval prolongation and development of torsade de pointes should be considered when vandetanib and digoxin are used concomitantly; dose adjustment may be required.

Vandetanib, being an inhibitor of the organic cation transporter (OCT2), may slow the elimination of metformin and other OCT2 substrates, thereby increasing their concentration. When metformin (an OCT2 substrate) and vandetanib were co-administered to healthy volunteers (wild-type OCT2), an increase in the AUC_(0-t) and C_max of metformin by 74% and 50%, respectively, was noted, as well as a 52% decrease in the renal clearance of metformin. More careful patient monitoring and a reduction in the metformin dose may be required.

Effect of other drugs on the pharmacokinetics of vandetanib

When omeprazole and vandetanib were co-administered to healthy volunteers, a 15% decrease in the C_max of vandetanib was noted, while the AUC_(0-t) value did not change. When ranitidine and vandetanib were co-administered, the C_max and AUC_(0-t) values of vandetanib did not change. When vandetanib is used concomitantly with ranitidine or omeprazole, no dose adjustment is required.

No clinically significant interaction was observed between vandetanib and the potent CYP3A4 isoenzyme inhibitor itraconazole. However, caution should be exercised when vandetanib is used concomitantly with itraconazole and other potent CYP3A4 isoenzyme inhibitors (e.g., ketoconazole, ritonavir, and clarithromycin).

When vandetanib and rifampicin, a potent CYP3A4 isoenzyme inducer, were co-administered to men, the concentration of vandetanib decreased by 40%, therefore concomitant use of vandetanib and potent inducers of the CYP3A4 isoenzyme (e.g., rifampicin, carbamazepine, phenobarbital, and St. John’s wort preparations) should be avoided.

Drugs that can prolong the QT_c interval

Vandetanib can cause QT_c interval prolongation, therefore it should not be taken concurrently with other medicinal products that can prolong the QT_c interval and/or cause torsade de pointes

• Contraindicated for use with arsenic, cisapride, erythromycin (IV), toremifene, mizolastine, moxifloxacin, class IA and III antiarrhythmic agents;
• Not recommended for use with methadone, haloperidol, amisulpride, chlorpromazine, sulpiride, zuclopenthixol, halofantrine, pentamidine, and lumefantrine.

In the absence of a suitable alternative therapy, the use of a non-recommended drug combination is possible if ECG monitoring of the QT_c interval, control of electrolyte concentrations, and additional control in case of occurrence or worsening of diarrhea are ensured.

When vandetanib was used concomitantly with ondansetron, a slight additive effect on QT_c interval prolongation (approximately 10 ms) was observed, therefore concomitant use of these drugs is not recommended. If ondansetron is prescribed concomitantly with vandetanib, careful monitoring of serum electrolyte concentrations and ECG, as well as intensive therapy for any abnormalities, is required.

Food intake does not affect the concentration of vandetanib.

Due to the possible interaction of vitamin K antagonists and chemotherapeutic drugs, more frequent monitoring of INR is recommended.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.