SUTENT

Active material: Sunitinib
When ATH: L01XE04
CCF: Anticancer drug. An inhibitor of protein tyrosine kinase
ICD-10 codes (testimony): C16, C17, C64
When CSF: 22.06
Manufacturer: PFIZER ITALIA S.r.L. (Italy)

Pharmaceutical form, composition and packaging

Capsules hard gelatin, red-brown; printed on the lid “Pfizer”, on the body – “STN 12.5 mg”; contents of capsules – pellets from yellow to orange.

Excipients: mannitol, Croscarmellose sodium, povidone, magnesium stearate.

The composition of the shell capsules: gelatin, Titanium dioxide, iron oxide red.
The structure of the ink includes: shellac, povidone, Titanium dioxide.

30 PC. – bottles of high density polyethylene (1) – packs cardboard.

Capsules hard gelatin, with brownish-orange cap and body of the red-brown color; printed on the lid “Pfizer”, on the body – “STN 25 mg”; contents of capsules – pellets from yellow to orange.

Excipients: mannitol, Croscarmellose sodium, povidone, magnesium stearate.

The composition of the shell capsules: gelatin, Titanium dioxide, iron oxide red, iron oxide yellow, iron oxide black.
The structure of the ink includes: shellac, povidone, Titanium dioxide.

30 PC. – bottles of high density polyethylene (1) – packs cardboard.

Capsules hard gelatin, light brownish-orange color; printed on the lid “Pfizer”, on the body – “STN 50 mg”; contents of capsules – pellets from yellow to orange.

Excipients: mannitol, Croscarmellose sodium, povidone, magnesium stearate.

The composition of the shell capsules: gelatin, Titanium dioxide, iron oxide red, iron oxide yellow, iron oxide black.
The structure of the ink includes: shellac, povidone, Titanium dioxide.

30 PC. – bottles of high density polyethylene (1) – packs cardboard.

Pharmacological action

The antitumor agent, an inhibitor of protein tyrosine kinases. Able to simultaneously inhibit the receptor tyrosine kinases of various (dry), participating in Tumor growth processes, pathological angiogenesis and metastasis.

Exhibits inhibitory activity against many kinases (> 80 kinase), It is a potent inhibitor of platelet derived growth factor receptor (PDGFRα и PDGRFβ), receptors vascular endothelial growth factor (VEGRF1, VEGRF2 and VEGRF3), stem cell factor receptor (KIT), -like tyrosine kinase receptor Fms-3 (FLT), koloniestimuliruyushego factor receptor (CSF-IR) and glial-derived neurotrophic factor receptor (RIGHT). Activity main metabolite was similar to that sunitinib.

Sunitinib inhibited the phosphorylation of many RTC (PDGRFβ, VEGRF2 and KIT) in tumor xenografts, ekspressiruyushih RTK targets in vivo and demonstrated inhibition of tumor growth or regression and / or inhibition of metastasis in experimental models of different tumors. Sunitinib demonstrated the ability to inhibit tumor cell growth, эkspressyruyuschyh derehulyrovannыe Target dry (PDGFR, RET, or KIT) in vitro и PDGRFβ- and VEGRF2-dependent angiogenesis in vivo.

Pharmacokinetics

Absorption

When ingestion of sunitinib is well absorbed from the gastrointestinal tract. The time to reach C_max is 6-12 no. Food intake has no effect on the bioavailability of sunitinib.

Distribution and metabolizm

Binding of sunitinib and its metabolite plasma protein is 95% and 90% respectively, without an explicit dependence on the concentration in the range 100-4000 ng / ml.

V_d is 2230 l, demonstrating the tissue distribution.

Metabolism sunitinib is mainly isoenzyme CYP3A4 thereby forming a main active metabolite. The proportion of active metabolite 23-37% AUC values ​​of.

C_ss Sunitinib and its main active metabolite are achieved through the 10-14 days. K 14 day and the total concentration of sunitinib its main active metabolite in plasma is 62.9-101 ng / ml. Repeated daily application or repeated cycles with different dosing regimen no significant changes in the pharmacokinetics of sunitinib and its main active metabolite not found.

Deduction

sunitinib is displayed mainly in the faeces – 61%. Kidneys in the form of unchanged substance and its metabolites displayed about 16% dose. Total clearance when administered reached 34-62 l /.

T_1/2 sunitinib and its main active metabolite of 40-60 and h 80-110 h, respectively. Repeated daily application comes 3-4-fold accumulation of sunitinib and 7-10-fold accumulation of its main metabolite.

Pharmacokinetics in special clinical situations

Age, the weight, race, flooring, creatinine clearance or ECOG score on the scale does not have a clinically meaningful effect on the pharmacokinetics of the drug and its active metabolite.

Testimony

- gastrointestinal stromal tumors, with no effect on imatinib due to resistance or intolerance;

- common and / or metastatic renal cell carcinoma patients, naïve specific treatment;

- widespread and / or metastatic renal cell carcinoma with no effect on cytokine therapy.

Dosage regimen

The drug is taken orally with or without food.

The recommended dose is 50 mg / day for 4 weeks followed by a break in 2 of the week (mode 4/2). Thus, complete treatment cycle is 6 weeks.

If the drug was omitted, should not make up the missed dose. The usual dose of the drug should be taken on the next day.

B may be reduced depending on individual tolerability Sutent dose or increased by 12.5 mg. The daily dose should not be more than 87.5 mg, but not less than 25 mg.

Patients with impaired liver function with increasing levels of AST and / or ALT, exceeding ULN less than 2.5 times, or in the case of an increase of these parameters due to underlying disease in less than 5 time, dose adjustment is not required.

Patients with impaired renal function with an increase in serum creatinine, less than 2 times the ULN, dose adjustment is not required.

Patients Seniors dose adjustment is not required.

Side effect

The most important serious adverse reactions, associated with Sutent treatment, were the: pulmonary embolism (1%), thrombocytopenia (1%), tumor hemorrhage (0.9%), febrile neutropenia (0.4%) and hypertension (0.4%).

In patients with metastatic renal cell carcinoma in 2% cases were observed venous thromboembolism: pulmonary embolism (4 degrees) – in 2 patients, and deep vein thrombosis (3 degrees) – in 2 patients.

In patients with gastrointestinal stromal tumor, treated with sunitinib, Venous thromboembolic events were observed in 7 patients (3%). In 5 from 7 celebrated deep vein thrombosis 3 degrees, and in 2 patients – 1 or 2 degrees.

The most frequent adverse reactions of all degrees, associated with Sutent treatment (>20%) We were tired, gastrointestinal disorders (incl. diarrhea, nausea, stomatitis, dyspepsia, vomiting, taste disturbance, anorexia), discolouration of the skin.

In patients with solid tumors fatigue, hypertension and neutropenia until 3 severity, increase up to the level of lipase 4 degree were the most common adverse reactions, associated with drug therapy.

Side effects, associated with sunitinib treatment, noted in clinical trials, at least, in >5% Patients with solid tumors, given below and systematized by organ systems, frequency and severity. Within each group are arranged side-reactions in order to reduce the frequency and severity: Often (≥1/10), often (≥ 1/100 to <1/10), sometimes (≥ 1/1000 to <1/100), rarely (≥ 1/10000 to <1/1000), rarely (<1/10000).

Cardio-vascular system: Often – increased blood pressure; often – decrease in left ventricular ejection fraction (LVEF), venous thromboembolism (pulmonary embolism, deep vein thrombosis); sometimes – heart failure, congestive heart failure, left ventricular dysfunction; rarely – QT prolongation, flicker and flutter-type atrial “pirouette”.

From the digestive system: Often – dysgeusia, diarrhea, nausea, vomiting, stomatitis, mucositis, dyspepsia, abdominal pains; often – anorexia, constipation, glossodiniya (neuralgia jazika), flatulence, dry mouth and sore vo, hastroэzofahealnыy reflux; sometimes – pancreatitis; rarely – Gastrointestinal perforation.

CNS: Often – headache; often – dizziness, paresthesia, insomnia or hypersomnia, depression.

The respiratory system: Often – nose bleed; often – breathlessness, laryngopharyngeal pain.

From the urinary system: often – chromaturia (urine discoloration).

On the part of the musculoskeletal system: often – pain in the extremities, arthralgia, myalgia.

On the part of the endocrine system: often – gipotireoz, raising the level of thyroid-stimulating hormone.

From the hematopoietic system: Often – anemia, neutropenia, thrombocytopenia; often – leukopenia.

Dermatological reactions: Often – discolouration of the skin, hand-foot syndrome (эritrodizesteziya), rash (эritematoznaya, Thistle, papular, otrubevidnom, generalized, psoriazopodobnye), Blisters; often – Hair color change, xerosis, эritema, alopecia, peeling of the skin, itching, exfoliative dermatitis.

Other: Often – asthenia, fatigue; often – increase in serum lipase, lacrimation, weight loss, flu, fever, chills, peripheral edema, periorbital edema, dehydration, gipotireoz, increase in serum CK levels and the level of amylase; sometimes – bleeding from the tumor, flu-like symptoms. Patients with brain metastases or reversible leukoencephalopathy syndrome described cases of seizures.

Contraindications

- Pregnancy;

- Lactation (breast-feeding);

- Children's age (the efficacy and safety of the drug has not been established in children);

- Hypersensitivity to sunitinib or other ingredients.

FROM caution should be used on patients with QT interval elongation in the anamnesis, patients, taking antiarrhythmics, or in patients with relevant cardiac disease, bradycardia, or electrolyte imbalance, as well as in renal or hepatic insufficiency.

Requires careful and reduce sunitinib dose while the use of potent inhibitors of CYP3A4, which can increase the concentration of sunitinib plasma.

Pregnancy and lactation

Do not use this Sutent during pregnancy and lactation (breast-feeding).

During therapy and during Sutent, at least, three months after the termination must use reliable methods of contraception.

Cautions

Sutent treatment should be under the supervision of a physician, with experience in anti-cancer drugs.

At the beginning of each cycle of therapy Sutent should conduct a full analysis hematological. Since the therapy Sutent can be observed bleeding from the tumor, periodically necessary to carry out a medical examination and evaluate blood parameters for early detection of the first signs of bleeding, and the use of the necessary therapeutic measures.

The connection between the receptor tyrosine kinase inhibition and cardiac function has not been studied. Unknown, whether patients are exposed, in which cases of cardiovascular disease over the past were recorded 12 months prior to the appointment of treatment with sunitinib (incl. myocardial infarction, severe / unstable angina, coronary or peripheral bypass surgery, symptomatic congestive heart failure, cerebrovascular complications, transient ischemic attack, pulmonary embolism), greater risk for left ventricular dysfunction, associated with the use of Sutent. Sutent in the appointment of these patients should carefully weigh the risk / benefit.

During therapy Sutent patients should be periodically evaluated for the detection of clinical signs and symptoms of congestive heart failure. LVEF should be assessed prior to initiating therapy, and periodically during treatment.

When the manifestation of clinical signs of congestive heart failure, treatment should cease sunitinib. In the absence of clinical signs of congestive heart failure, but with indicators LVEF <50% or decrease of this index >20% compared with the original (to shake her therapy), the dose of sunitinib is recommended to reduce or stop taking the drug.

At concentrations, about 2 times higher than therapeutic, sunitinib promotes elongation QTcF interval (Fridericia correction). The clinical significance of this effect is uncertain and depends on the risk factors and the susceptibility of the individual patient. Sunitinib should be used with caution in patients with prolongation of the QT interval in history, taking antiarrhythmics, or patients with relevant cardiac disease, ʙradikardiej, electrolyte imbalance.

Requires careful dose and reduce Sutent while applying strong CYP3A4 inhibitors, which may increase sunitinib plasma concentration.

Prior to initiation of therapy and during treatment with Sutent is recommended that ECG monitoring.

Patients should be evaluated for the occurrence of hypertension, Using standard blood pressure monitoring methods. In patients with severe form of hypertension, not treatable, It recommends suspension termination of Sutent therapy to relief hypertension.

Patients with symptoms of hypothyroidism is necessary to conduct laboratory examination of the thyroid gland. Treatment of such patients is conducted in accordance with standard medical practice.

Patients should be warned, that during treatment with Sutent may experience changes in skin color due to the presence of the dye formulation (yellow). It may also be the hair or skin discoloration.

Since the application Sutent may be nausea and vomiting, should provide prophylactic antiemetics. If you experience diarrhea prescribe antidiarrheal.

During treatment with Sutent should be checked periodically, and the level of lipase Serum amylase. In the presence or occurrence of symptoms of pancreatitis requires regular medical control.

Patients with brain metastases, a history of seizures and / or symptoms of reversible posterior leukoencephalopathy (incl. arterial hypertension, headache, lethargy, infringement of intellectual activity, loss of sight, including cortical blindness) should be monitored by standard methods, including blood pressure control. In case of these symptoms during treatment it is recommended to suspend the use of Sutent. After the disappearance of the symptoms, treatment may be resumed by a decision of a doctor.

Use in Pediatrics

Efficacy and safety of Sutent in children has not been established.

Effects on ability to drive vehicles and management mechanisms

Patients should be warned of the possibility of occurrence during treatment with Sutent dizziness, which may affect the ability to control the car and busy with other potentially hazardous activities, require high concentration and speed of psychomotor reactions.

Overdose

Treatment: symptomatic; if necessary, induce vomiting, to gastric lavage. There is no specific antidote.

Drug Interactions

Preparations, increase the concentration of sunitinib plasma

With the simultaneous application of a single dose of sunitinib malate CYP3A4 inhibitor – ketoconazole may increase C_max and AUC complex sunitinib and its primary active metabolite in healthy volunteers 49% and 51% respectively.

When applied simultaneously with Sutent other inhibitors of CYP3A4 (incl. ritonavirom, itraconazole, Erythromycin, clarithromycin or grapefruit juice) may increase concentration of sunitinib.

Sutent simultaneous use should be avoided with CYP3A4 inhibitors or choose an alternative drug with minimal ability to inhibit CYP3A4. If this is not possible, Sutent dose should be reduced.

Preparations, lowering the concentration of sunitinib plasma

With the simultaneous application of a single dose of sunitinib with CYP3A4 inducer, rifampin lowers C_max and AUC y healthy volunteers 23% and 46% respectively.

When applied simultaneously with other Sutent CYP3A4 inducers (incl. deksametazonom, phenytoin, karbmazepinom, rifampicin, phenobarbital or St. John's wort) may decrease the concentration of sunitinib.

Avoid the simultaneous application with inductors SYR3A4 Sutent or choose an alternative drug with minimal ability to induce CYP3A4. If this is not possible, the dose of sunitinib should be increased.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at or above 25 ° C. Shelf life – 2 year.