Sutent capsules 25mg, 28pcs

Composition

Capsules are solid gelatin, light brownish-orange in color; “Pfizer” is printed on the lid in white ink, “STN 50 mg” on the body; the contents of the capsules are granules from yellow to orange in color.

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

Capsule shell composition:  gelatin, titanium dioxide, iron oxide red, iron oxide yellow, iron oxide black. The composition of the ink includes:  shellac, povidone, titanium dioxide.

Pharmacological action

Antitumor drug, inhibitor of protein tyrosine kinases. It is able to simultaneously inhibit the receptors of various tyrosine kinases (RTK) involved in the processes of tumor growth, pathological angiogenesis and metastasis formation.

It exhibits inhibitory activity against many kinases (> 80 kinases), is a potent inhibitor of platelet-derived growth factor receptors (PDGFRa and PDGRFb), vascular endothelial growth factor receptors (VEGRF1, VEGRF2, and VEGRF3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT), colony stimulating factor receptor (CSF-IR), and neurotrophic glial factor (RET). The activity of the main metabolite was similar to that of sunitinib.

Sunitinib inhibited phosphorylation of many RTAs (PDGRFb, VEGRF2, and KIT) in tumor xenografts expressing targeted RTAs in vivo and demonstrated tumor growth suppression or regression and/or metastasis suppression in experimental models of various tumors. Sunitinib has demonstrated the ability to inhibit the growth of tumor cells expressing deregulated target RTAs (PDGFR, RET, or KIT) in vitro and PDGRFb-and VEGRF2-dependent angiogenesis in vivo.

Suction

When taken orally, sunitinib is well absorbed from the gastrointestinal tract. The time to reach C_maxis 6-12 hours. Food intake does not affect the bioavailability of sunitinib.

Distribution and metabolism

The binding of sunitinib and its metabolite to plasma proteins is 95% and 90%, respectively, with no apparent dependence on the concentration in the range of 100-4000 ng / ml.

Vd is 2230 L, demonstrating the distribution in tissues.

The metabolism of sunitinib is mainly carried out by the CYP3A4 isoenzyme, resulting in the formation of the main active metabolite. The proportion of the active metabolite is 23-37% of the AUC value.

_csss of sunitinib and its main active metabolite are reached after 10-14 days. By day 14, the total concentration of sunitinib and its main active metabolite in plasma is 62.9-101 ng / ml. No significant changes in the pharmacokinetics of sunitinib and its main active metabolite were detected with repeated daily use or repeated cycles with different dosage regimens.

Deduction

Sunitinib is mainly excreted in the faeces – 61%. Approximately 16% of the dose is excreted by the kidneys as unchanged substance and its metabolites. Total oral clearance reached 34-62 l / h.

The T_1/2 of sunitinib and its main active metabolite is 40-60 h and 80-110 h, respectively. Repeated daily use results in a 3-4-fold accumulation of sunitinib and a 7-10-fold accumulation of its main metabolite.

Pharmacokinetics in special clinical cases

Age, weight, race, gender, creatinine clearance, or ECOG score do not have a clinically significant effect on the pharmacokinetics of the drug and its active metabolite.

Population pharmacokinetic analysis showed that there is no need to adjust the initial dose of the drug depending on body weight and quality of life on the ECOG scale.

Available data indicate that the apparent clearance of sunitinib in women may be 30% lower than in men, but this difference does not require correction of the initial dose of sunitinib.

Indications

— gastrointestinal stromal tumor in the absence of the effect of imatinib treatment due to resistance or intolerance;

— common and/or metastatic renal cell cancer patients who had not previously received specific treatment;

— common and/or metastatic renal cell cancer in the absence of effect of therapy with cytokines;

— vysokomehanizirovannoe unresectable or metastatic neuroendocrine tumors of the pancreas in adults with disease progression.

Contraindications

-pregnancy;

– lactation (breastfeeding);

– childhood (the effectiveness and safety of the drug in children has not been established)—

– hypersensitivity to sunitinib or other components of the drug.

The drug should be used with caution in patients with a history of QT prolongation, in patients taking antiarrhythmic drugs, or in patients with relevant heart diseases, bradycardia or electrolyte disturbances, as well as in patients with renal or hepatic insufficiency.

Caution is required to reduce the dose of sunitinib when used concomitantly with strong inhibitors of CYP3A4 isoenzymes, which may increase the concentration of sunitinib in blood plasma.

Side effects

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

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

In patients with gastrointestinal stromal tumors treated with sunitinib, venous thromboembolism was observed in 7 patients (3%).5 out of 7 patients had grade 3 deep vein thrombosis, and 2 patients had grade 1 or 2 thrombosis.

The most frequent adverse reactions of all degrees associated with treatment with Sutent® (>20% of cases) were fatigue, gastrointestinal disorders (including diarrhea, nausea, stomatitis, dyspepsia, vomiting, taste disorders, anorexia), skin pigmentation disorders, rash, palmar-plantar erythrodysesthesia syndrome, dry skin, hair discoloration, inflammation of the mucous membranes, asthenia.

In patients with solid tumors, the most common adverse reactions associated with Sutent® therapy were fatigue, arterial hypertension and neutropenia up to 3 degrees of severity, increased lipase levels up to 4 degrees.

Adverse events associated with sunitinib treatment reported in clinical trials in at least >5% of patients with solid tumors are listed below and categorized by organ system, frequency, and severity. Within each group, adverse reactions are arranged in decreasing order of frequency and severity: very common (≥1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000), very rare (

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

From the digestive system:  very often-taste distortion, diarrhea, nausea, vomiting, stomatitis, mucositis, dyspepsia, abdominal pain, anorexia, constipation, glossodynia (tongue neuralgia), flatulence, dry mouth; often-mouth pain, gastroesophageal reflux; infrequently-pancreatitis; rarely-gastrointestinal perforations.

Dermatological reactions:  very often – skin discoloration, palmar-plantar syndrome (erythrodysesthesia), rash (erythematous, spotty, papular, pityriasis, generalized, psoriasis-like), blisters, hair discoloration, dry skin, erythema; often-alopecia, skin peeling, pruritus, exfoliative dermatitis.

Musculoskeletal disorders:  often-pain in the extremities, arthralgia, myalgia.

Nervous system disorders:  very often-headache; often-dizziness, paresthesia, insomnia or increased drowsiness, depression.

From the cardiovascular system:  very often-an increase in blood pressure; often-a decrease in the left ventricular ejection fraction( LVEF), venous thromboembolism (pulmonary embolism, deep vein thrombosis); infrequently – heart failure, congestive heart failure, left ventricular dysfunction; rarely – prolongation of the QT interval, atrial fibrillation and flutter of the “pirouette”type.

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

Respiratory system disorders:  very often – nosebleeds; often-shortness of breath, laryngopharyngeal pain.

From the endocrine system:  often – hypothyroidism, an increase in the level of thyroid-stimulating hormone.

Other services:  very often – asthenia, increased fatigue, increased serum lipase activity; often-lacrimation, weight loss, flu, fever, chills, peripheral edema, periorbital edema, dehydration, increased serum CPK activity and amylase activity; infrequently – bleeding from tumors, flu-like syndrome. Seizures have been reported in patients with brain metastases or reversible leukoencephalopathy.

Results of post-marketing research

During the use of sunitinib after its registration, the following adverse events were recorded.

From the side of hematopoietic organs: Rare cases of thrombotic microangiopathy have been reported. In such cases, it is recommended to temporarily suspend taking sunitinib; after the symptoms resolve, the drug can be resumed at the discretion of the attending physician.

Respiratory system disorders: cases of pulmonary embolism, sometimes fatal, have been reported.

From the endocrine system: in clinical studies and during post-marketing use of the drug, rare cases of hyperthyroidism with a transition to hypothyroidism were recorded.

From the immune system: hypersensitivity reactions, including angioedema, have been reported.

Infections and infestations: cases of serious infections (with or without neutropenia) have been reported, some of which have resulted in death.

Musculoskeletal disorders: rare cases of myopathy and/or rhabdomyolysis, with or without acute renal failure, with rare cases of death, have been reported. Most of these patients had baseline risk factors and / or received concomitant therapy with drugs that are characterized by adverse reactions of this kind. There have been reports of fistula formation, sometimes associated with necrosis and / or tumor regression, some of which have resulted in death.

Nervous system disorders: cases of taste disorders, including ageusia, have been reported.

From the urinary system: cases of impaired renal function/renal failure have been reported, some of which have resulted in death. Cases of proteinuria and rare cases of nephrotic syndrome have been reported.

From the cardiovascular system: cases of cardiomyopathy have been reported, some of which have resulted in death.

Interaction

Drugs that increase the concentration of sunitinib in blood plasma

Concomitant use of sunitinib in a single dose with the CYP3A4 inhibitor ketoconazole may increase the_cmax and AUC of the sunitinib complex and its main active metabolite in healthy volunteers by 49% and 51%, respectively.

When Sutent is co-administered with other CYP3A4 inhibitors (including ritonavir, itraconazole, erythromycin, clarithromycin or grapefruit juice), the concentration of sunitinib may increase.

Concomitant use of Sutent with CYP3A4 inhibitors should be avoided or an alternative drug with minimal ability to inhibit CYP3A4 should be chosen. If this is not possible, the daily dose of sunitinib should be reduced by 12.5 mg. In this case, the daily dose should be at least 37.5 mg.

Drugs that lower the concentration of sunitinib in blood plasma

Concomitant use of sunitinib in a single dose with the CYP3A4 inducer rifampin decreased_cmax and AUC y in healthy volunteers by 23% and 46%, respectively.

When Sutent is co-administered with other CYP3A4 inducers (including dexamethasone, phenytoin, carbazepine, rifampin, phenobarbital or St. John’s wort), the concentration of sunitinib may decrease.

Concomitant use of Sutent with inducers of 3 and 4 SUR should be avoided, or an alternative drug with minimal ability to induce CYP3A4 should be chosen. If this is not possible, the dose of sunitinib should be increased by 12.5 mg, monitoring the patient’s tolerance to the drug. The daily dose in this case should not exceed 87.5 mg / day for gastrointestinal stromal tumors and metastatic renal cell carcinoma and up to 62.5 mg / day for neuroendocrine pancreatic tumors.

How to take, course of use and dosage

The drug is taken orally regardless of food intake.

Gastrointestinal stromal tumors in the absence of an effect from imatinib therapy due to resistance or intolerance: the recommended dose of the drug is 50 mg/day orally for 4 weeks, followed by a break of 2 weeks (regimen 4/2). The full cycle of therapy is thus 6 weeks.

Advanced and / or metastatic renal cell carcinoma in patients who have not previously received specific treatment or in the absence of an effect from cytokine therapy: the recommended dose of the drug is 50 mg/day orally for 4 weeks, followed by a break of 2 weeks (regimen 4/2). The full cycle of therapy is thus 6 weeks.

Unresectable or metastatic, highly differentiated neuroendocrine tumors of the pancreas in adults with disease progression: the recommended dose of the drug is 37.5 mg daily without interruption.

If you missed taking the drug, you should not make up for the missed dose. The usual dose of the drug should be taken the next day.

Depending on individual tolerance, the Sutent dose may be reduced or increased by 12.5 mg. The daily dose should not exceed 75 mg, but not less than 25 mg in patients with gastrointestinal and renal cell tumors. For patients with unresectable or metastatic pancreatic neuroendocrine tumors, the dose of Sutent®should not exceed 50 mg / day.

Patients with hepatic impairment who have elevated AST and/or ALT levels that exceed the ULN by less than 2.5 times, or who have increased these levels by less than 5 times due to the underlying disease, do not need to adjust the dose.

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

Elderly patients do not need to adjust the dose.

Overdose

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

Special instructions

Treatment with Sutent® should be carried out under the supervision of a doctor who has experience with antitumor drugs.

At the beginning of each Sutent therapy cycle, a complete analysis of hematological parameters should be performed.

Cases of bleeding, sometimes fatal, have been reported, including gastrointestinal bleeding, respiratory bleeding, tumors, urinary tract bleeding, and brain hemorrhage. These phenomena can occur unexpectedly, and in the case of tumor foci in the lungs, manifest in the form of severe or life-threatening hemoptysis or pulmonary bleeding. Periodically, it is necessary to conduct a medical examination and evaluate blood parameters for early detection of the first signs of bleeding and the application of necessary therapeutic measures. With concomitant anticoagulant therapy, blood clotting parameters should be monitored.

The relationship between tyrosine kinase receptor inhibition and cardiac function has not been studied. It is not known whether patients who have had a history of cardiovascular disease in the last 12 months prior to sunitinib treatment (including myocardial infarction, severe/unstable angina, coronary or peripheral bypass surgery, symptomatic congestive heart failure, cerebrovascular complications, transient ischemic disorders, pulmonary embolism) are at greater risk of developing left ventricular dysfunction associated with Sutent use. When prescribing Sutent to this category of patients, the risk/benefit ratio should be carefully evaluated.

During Sutent therapy, patients should be periodically evaluated for clinical signs and symptoms of congestive heart failure. LVEF is recommended to be evaluated before starting therapy, as well as periodically during treatment.

If there are clinical signs of congestive heart failure, treatment with sunitinib should be discontinued. In the absence of clinical signs of congestive heart failure, but with LVEF <50% or a decrease in this indicator >20% compared to the initial one (before starting therapy), the dose of sunitinib is recommended to be reduced or discontinued.

At concentrations approximately 2 times higher than therapeutic, sunitinib promotes prolongation of the QTcF interval (Friederich adjustment). The clinical significance of this effect is unclear and depends on the risk factors and susceptibility of the individual patient. Sunitinib should be used with caution in patients with a history of QT prolongation, taking antiarrhythmic medications, or in patients with associated heart disease, bradycardia, or electrolyte disturbances. Caution is required to reduce the dose of Sutent when concomitantly using strong CYP3A4 inhibitors, which may increase the concentration of sunitinib in plasma. ECG monitoring is recommended before starting therapy and during Sutent treatment.

Patients should be evaluated for hypertension using standard blood pressure monitoring methods. In patients with severe hypertension that cannot be treated, temporary discontinuation of Sutent®therapy is recommended. Therapy is resumed as soon as it is possible to stop arterial hypertension.

Background testing of laboratory thyroid function parameters in patients with hypothyroidism or hyperthyroidism is recommended. Patients with hypothyroidism are treated in accordance with standard medical practice before starting sunitinib therapy. It is recommended to monitor all patients during sunitinib therapy for the development of thyroid dysfunction. Patients with signs and / or symptoms of thyroid dysfunction should be monitored in the laboratory.

Patients should be warned that skin discoloration may occur during treatment with Sutent® due to the presence of a dye (yellow) in the preparation. Hair or skin discoloration may also occur.

Since nausea and vomiting may occur during the use of Sutent®, preventive use of antiemetic drugs should be considered. If diarrhea occurs, antidiarrheal drugs are prescribed.

During treatment with Sutent®, it is necessary to periodically check the activity of lipase and amylase in the blood serum. If there are or appear symptoms of pancreatitis, regular medical monitoring is necessary.

Patients with brain metastases, a history of seizures, and/or signs / symptoms of reversible posterior leukoencephalopathy, such as hypertension, headache, lethargy, impaired mental activity, vision loss, including cortical blindness, should be monitored by standard methods, including blood pressure monitoring. If these symptoms occur during therapy, it is recommended to temporarily discontinue the use of Sutent®. After the symptoms disappear, treatment can be resumed by the decision of the attending physician.

If thrombotic microangiopathy occurs, temporary discontinuation of sunitinib treatment is recommended. After the symptoms disappear, treatment can be resumed on the recommendation of the attending physician.

Background testing of renal function prior to treatment is recommended, as well as monitoring of renal function during sunitinib therapy. The safety of sunitinib in patients with moderate or severe proteinuria has not been evaluated. In patients with nephrotic syndrome, sunitinib treatment should be discontinued.

Use in pediatrics

The efficacy and safety of Sutent® in children has not been established.

Influence on the ability to drive motor vehicles and manage mechanisms

Patients should be warned about the possibility of dizziness during treatment with Sutent®, which may affect the ability to drive a car and engage in other potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Sunitinib

Conditions of release from pharmacies

By prescription

Dosage form

Capsules

Purpose

For adults as directed by your doctor

Indications

Cancer