Sutent, 25 mg capsules 28 pcs

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

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

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

Pharmacokinetics

Intake

Sunitinib is well absorbed from the gastrointestinal tract when taken orally. Time to reach C_max is 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 concentration dependence between 100-4000 ng/mL.

The V_d is 2230L, demonstrating tissue distribution.

The metabolism of sunitinib is primarily by the CYP3A4 isoenzyme resulting in the main active metabolite. The proportion of the active metabolite is 23-37% of the AUC.

The C_ss of sunitinib and its main active metabolite are reached after 10-14 days. By day 14, the total plasma concentration of sunitinib and its main active metabolite is 62.9-101 ng/mL. No significant changes in the pharmacokinetics of sunitinib and its main active metabolite have been observed with multiple daily applications or repeated cycles with different dosing regimens.

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

T_1/2 sunitinib and its main active metabolite are 40-60 h and 80-110 h, respectively. With repeated daily use, there is 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, sex, creatinine clearance or ECOG score have no clinically significant effect on the pharmacokinetics of the drug and its active metabolite.

Population pharmacokinetic analysis showed that there was no need to adjust the initial dose of the drug based on body weight and quality of life ECOG score.

The available data indicate that the apparent clearance of sunitinib in women may be 30% lower than in men, but this difference does not require adjustment of the starting dose of sunitinib.

Indications

– gastrointestinal stromal tumors with no effect from imatinib therapy due to resistance or intolerance;

– advanced and/or metastatic renal cell cancer in patients who have not previously received specific treatment;

– advanced and/or metastatic renal cell cancer with no effect from cytokine therapy;

– unresectable or metastatic highly differentiated pancreatic neuroendocrine tumors in adults with disease progression.

Active ingredient

Composition

Solid gelatin capsules, light brownish-orange in color; “Pfizer” is printed in white ink on the cap, “STN 50 mg” on the body; the contents of the capsules are yellow to orange pellets.

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

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

How to take, the dosage

The drug is taken orally with or without food.

Gastrointestinal stromal tumors with no effect of imatinib therapy due to resistance or intolerance: The recommended dose is 50 mg/day orally for 4 weeks followed by a 2-week break (4/2 regimen). A complete therapy cycle is therefore 6 weeks.

Multiple and/or metastatic renal cell cancer in patients who have not previously received specific treatment or in the absence of effect of cytokine therapy: the recommended dose of the drug is 50 mg/day orally for 4 weeks followed by a 2-week break (regimen 4/2). The complete therapy cycle is therefore 6 weeks.

Unresectable or metastatic, highly differentiated neuroendocrine pancreatic tumors in adults with advanced disease: Recommended dose is 37.5 mg daily without interruption.

If medication is missed, do not make up the missed dose. The normal dose of the drug should be taken the next day.

The dose of Sutent may be decreased or increased by 12.5 mg, depending on individual tolerance. The daily dose should be no more than 75 mg but no 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 be no more than 50 mg/day.

In patients with hepatic dysfunction with AST and/or ALT elevations less than 2.5-fold or when these elevations are less than 5-fold due to underlying disease, no dose adjustment is necessary.

Patients with impaired renal function with an increase of serum creatinine less than 2 times the ULN do not require a dose adjustment.

Dose adjustment is not required in elderly patients.

Interaction

Drugs that increase blood plasma concentrations of sunitinib

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

Concomitant use of Sutent with other CYP3A4 inhibitors (including ritonavir, itraconazole, erythromycin, clarithromycin or grapefruit juice) may increase sunitinib concentrations.

The concomitant use of Sutent with CYP3A4 inhibitors should be avoided or an alternative drug with minimal ability to inhibit CYP3A4 should be selected. 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 decrease plasma concentrations of sunitinib

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

Concomitant use of Sutent with other CYP3A4 inducers (including dexamethasone, phenytoin, carbmazepine, rifampin, phenobarbital or St John’s wort) may decrease Sunitinib concentration.

The concomitant use of Sutent with CYP3A4 inducers 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 patient tolerance. The daily dose in this case should not exceed 87.5 mg/day in gastrointestinal stromal tumors and metastatic renal cell cancer and up to 62.5 mg/day in pancreatic neuroendocrine tumors.

Special Instructions

The treatment with Sutent® should be supervised by a physician experienced in the use of antitumor drugs.

A complete hematology work-up should be performed at the beginning of each cycle of therapy with Sutent.

There have been reports of bleeding, sometimes fatal, including gastrointestinal bleeding, respiratory bleeding, tumors, urinary tract bleeding, and cerebral hemorrhage. These events can occur unexpectedly and, in the case of tumor foci in the lungs, can manifest as severe or life-threatening hemoptysis or pulmonary hemorrhage. Periodic examinations and blood counts should be performed to detect early signs of bleeding and to apply the necessary therapeutic measures. If there is concomitant therapy with anticoagulants, 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 events within the past 12 months prior to treatment with sunitinib (including myocardial infarction, severe/unstable angina, coronary or peripheral bypass, symptomatic congestive heart failure, cerebrovascular complications, transient ischemic disturbances, pulmonary embolism) are at greater risk for Sutent-related left ventricular dysfunction. The risk/benefit ratio should be carefully evaluated when prescribing Sutent to this patient population.

Patients should be periodically evaluated for clinical signs and symptoms of congestive heart failure during therapy with Sutent. RVF is recommended to be evaluated before therapy and periodically during treatment.

In case of clinical signs of congestive heart failure, sunitinib treatment should be discontinued. If there are no clinical signs of congestive heart failure, but with a PVL of <50% or a decrease of >20% from baseline (before therapy), sunitinib dose should be reduced or discontinued.

At concentrations approximately 2-fold greater than therapeutic, sunitinib contributes to prolongation of the QTcF interval (Friedericia correction). 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 interval prolongation, taking antiarrhythmic drugs or in patients with associated heart disease, bradycardia, electrolyte imbalance. Caution should be exercised and the dose of Sutent should be reduced with concomitant use of strong CYP3A4 inhibitors that may increase the plasma concentration of sunitinib. ECG monitoring is recommended before and during therapy with Sutent.

Patients should be evaluated for arterial hypertension using standard methods of BP control. In patients with severe arterial hypertension that is not curable, temporary discontinuation of therapy with Sutent® is recommended. Therapy should be resumed as soon as the arterial hypertension has resolved.

Background investigation of laboratory parameters of thyroid function in patients with hypothyroidism or hyperthyroidism is recommended. Patients with hypothyroidism are treated according to standard medical practice prior to initiation of sunitinib therapy. It is recommended that all patients be monitored during sunitinib therapy for the development of thyroid dysfunction. Patients with signs and/or symptoms of thyroid dysfunction should undergo laboratory monitoring.

Patients should be cautioned that during treatment with Sutent® there may be changes in skin coloration due to the dye (yellow) in the drug. Discoloration of the hair or skin may also occur.

Because nausea and vomiting may occur when using Sutent®, anti-emetic drugs should be considered for prophylactic administration. In case of diarrhea anti-diarrheal agents are prescribed.

Serum lipase and amylase activity should be monitored periodically during treatment with Sutent®. If symptoms of pancreatitis are present or appear, regular medical monitoring is necessary.

Patients with brain metastases, a history of seizures and/or signs/symptoms of reversible posterior leukoencephalopathy, such as arterial hypertension, headache, lethargy, mental retardation, vision loss, including cortical blindness, should be controlled with standard methods, including BP control. If these symptoms occur during therapy, it is recommended to temporarily discontinue the use of Sutent®. Once the symptoms disappear, treatment may be resumed at the discretion of the attending physician.

If thrombotic microangiopathy occurs, temporary discontinuation of sunitinib therapy is recommended. Once symptoms disappear, treatment may be resumed at the recommendation of the treating physician.

Pre-treatment baseline renal function tests are recommended, as well as monitoring of renal function parameters during sunitinib therapy. The safety of sunitinib administration in patients with moderate to severe proteinuria has not been evaluated. In patients with nephrotic syndrome, treatment with sunitinib should be discontinued.

Pediatric use

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

Impact on driving and operating ability

Patients should be cautioned about the possibility of dizziness during treatment with Sutent® dizziness which may affect the ability to drive and to engage in other potentially dangerous activities requiring increased concentration and rapid psychomotor reaction.

Contraindications

– pregnancy;

– period of lactation (breast-feeding);

– childhood (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 interval prolongation, in patients taking antiarrhythmic drugs, or in patients with associated heart disease, bradycardia or electrolyte disturbances, or in cases of renal or hepatic impairment.

Cautions are required to reduce the dose of sunitinib when used concomitantly with strong CYP3A4 isoenzyme inhibitors that may increase plasma concentrations of sunitinib.

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 occurred 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 receiving sunitinib, venous thromboembolisms were observed in 7 patients (3%). Five of the 7 had grade 3 deep vein thrombosis and 2 patients had grade 1 or 2.

The most common adverse reactions of all grades associated with treatment with Sutent® (>20% of cases) were fatigue, gastrointestinal disturbances (including diarrhea, nausea, stomatitis, dyspepsia, vomiting, taste disorders, anorexia), skin pigmentation disorders, rash, palmar erythrodysesthesia syndrome, dry skin, hair color changes, mucosal inflammation, asthenia.

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

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

Hematopoietic system: very common – anemia, neutropenia, thrombocytopenia; common – leukopenia.

Digestive system disorders: very common – perversion of taste, diarrhea, nausea, vomiting, stomatitis, mucositis, dyspepsia, abdominal pain, anorexia, constipation, glossodynia (tongue neuralgia), flatulence, dry mouth; common – pain in the mouth, gastroesophageal reflux; infrequent – pancreatitis; rare – gastrointestinal perforations.

Dermatological reactions: very common – changes in skin color, palm-treated syndrome (erythrodysesthesia), rash (erythematous, patchy, papular, pelt-like, generalized, psoriasis-like), blisters, hair color changes, dry skin, erythema; common – alopecia, skin flaking, itching, exfoliative dermatitis.

Muscular system disorders: often – pain in the extremities, arthralgia, myalgia.

Nervous system disorders: very often – headache; often – dizziness, paresthesia, insomnia or hypersomnia, depression.

Cardiovascular system disorders: very common – increased BP; common – decreased left ventricular ejection fraction (LVEF), venous thromboemboli (pulmonary embolism, deep vein thrombosis); infrequent – heart failure, congestive heart failure, impaired left ventricular function; rare – QT interval prolongation, atrial fibrillation and flutter type “pirouette”.

Urinary system disorders: often – chromaturia (change in color of urine).

Respiratory system disorders: very common – nasal bleeding; common – shortness of breath, laryngeal-pharyngeal pain.

Endocrine system: often – hypothyroidism, increased thyroid hormone levels.

Others: very common – asthenia, increased fatigability, increased serum lipase activity; common – lacrimation, weight loss, flu, fever, chills, peripheral edema, periorbital edema, dehydration, increased serum CPK activity and amylase activity; infrequent – bleeding from tumors, flu-like syndrome. In patients with brain metastases or with reversible leukoencephalopathy syndrome, cases of seizures have been described.

Post-marketing study results

The following adverse events have been reported during sunitinib use after its registration.

Hematopoietic disorders: rare cases of thrombotic microangiopathy have been reported. In these cases, it is recommended to temporarily suspend sunitinib; after resolution of symptoms, the drug may be resumed at the discretion of the attending physician.

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

Endocrine system disorders: rare cases of hyperthyroidism with conversion to hypothyroidism have been reported in clinical studies and during post-marketing use of the drug.

Immune system disorders: 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.

Muscular system disorders: there are reports of rare cases of myopathy and/or rhabdomyolysis with or without combination with acute renal failure, with rare cases of lethal outcome. Most of these patients had underlying risk factors and/or received concomitant therapy with drugs characterized by adverse reactions of this type. There have been reports of fistulas, sometimes associated with tumor necrosis and/or regression, some of which have been fatal.

Nervous system disorders: there have been reports of cases of taste sensitivity disorders, including aguesia.

Uses of the urinary system: there have been reports of cases of renal dysfunction/renal failure, some of which have resulted in death. Cases of proteinuria and rare cases of nephrotic syndrome have been reported.

Cardiovascular system disorders: cases of cardiomyopathy have been reported, some of which have resulted in death.

Overdose