Description
The Medical&Pharma company offers a modern antitumor drug Sutent . It is mainly applicable in the treatment of gastric cancer - gastrointestinal stromal tumor (when therapy with imatinib does not give a positive result or is contraindicated). The drug is also used in the treatment of progressive growth of formations in the pancreas. The active antitumor substance of Sutent, Sunitinib malate , is an inhibitor of tyrosine kinase receptors, enzymes involved in tumor growth, the formation of metastases and pathological angiogenesis.
Sutent is also applicable as a drug used in the treatment of renal cell carcinogenesis. Sunitinib was registered and approved for use in 2006. The drug has been registered in Russia since 2007. The growth process of tumor cells largely depends on the activity of receptors that interact with various growth-stimulating factors belonging to the group of tyrosine kinases. The mechanism of action of a substance is characterized by its ability to bind to these receptors, thereby preventing the receptors from binding to substances that stimulate tumor growth.
Modern aspects of the use of Sutent in oncological practice
Sunitinib (SU011248; Sutent) is one of the new oral targeted drugs that are being actively introduced into oncology practice [1]. The targets for targeted drugs are receptors for epidermal growth factors and vascular growth factors; proteins that carry out mitogenic signals from receptor molecules; apoptosis-controlling molecules.
Sunitinib is a multi-targeted tableted tyrosine kinase inhibitor that acts on all known types of receptors for PDGF (platelet-derived growth factor) and VEGF (vascular endothelial growth factor) - VEGFRs, PDGFR-α, PDGFR-β, c-KIT and FLT-3 [2 ], which are involved in the process of tumor growth, pathological angiogenesis and metastasis.
In vitro studies to date have shown that Sutent induces apoptosis of human umbilical vein endothelial cells [3]. A pronounced additive effect is observed in combinations with anthracyclines, taxanes, cisplatin, irinotecan and fluorouracil. Sunitinib also demonstrated its ability to inhibit angiogenesis in other in vivo models: in the C57BL6J mouse model, the drug prevented neovascularization and tumor growth and led to an 83% reduction in the incidence of lung metastasis in the Lewis lung carcinoma model [4]. Tumor regression or growth arrest has been observed with sunitinib in many cell lines and xenografts. In some preclinical studies, sunitinib demonstrated fairly high antitumor activity in models of colon cancer, non-small cell lung cancer, melanoma, renal cell carcinoma, and squamous cell carcinoma [9].
Phase I studies [5] found that the half-life of the drug is 40 hours, and that of its active metabolites is about 80 hours. The drug is metabolized in the liver with the participation of the CYP3A4 enzyme of the cytochrome P450 system. In order to determine the optimal dose of the drug, in one of the studies, patients were divided into several groups, each of which received sunitinib in a dosage gradually increasing in the following order: 25 mg; 37.5 mg; 50 mg respectively. Reception regimen: 4 weeks with a 2-week break. Manifestations of toxicity in this case were hypertension and inhibition of hematopoietic function. It was concluded that the optimal dosage of sunitinib was 50 mg/day for 4 weeks with a 2-week break in monotherapy. In addition, a number of phase I studies have determined the optimal dosage of sunitinib in combination with other drugs (sunitinib and bevacizumab 10 mg/kg, sunitinib and temsirolimus 15 mg weekly) for the treatment of renal cell carcinoma [7, 8].
Phase II studies have documented antitumor efficacy in patients with neuroendocrine tumors, kidney cancer, colon and breast cancer [9]. At the initial stage of phase II studies of sunitinib [6] in forms of renal cell carcinoma with distant metastases refractory to cytokine therapy, an objective response rate of over 40% was obtained. The data obtained served as the basis for the next study.
In 11 US clinics from February to November 2004, the study included 105 patients aged 32 to 79 years with advanced clear cell kidney cancer that had progressed on cytokine therapy. Patients received oral sunitinib at a dose of 50 mg once daily for 4 weeks, followed by a 2-week break, after which treatment continued as usual. If toxic reactions developed, the dose was reduced to 37.5 mg per day. Complete effect was observed in 1 patient (1%) and persisted for 10 months. Partial response was obtained in 45 patients (43%). Thus, the overall response rate was 44% with a median duration of 10 months. Stabilization of the disease (3 months) was observed in 22% (23 patients). Median progression-free survival was 8.3 months. Six-month overall survival rate – 79%.
The most common adverse reactions were asthenia - in 28% of patients (grade II - in 17%, grade III - in 11%), as well as diarrhea - in 20% of patients (grade II - in 17%, grade III - in 3% ). In 8 patients, according to the examination, during therapy there was a decrease in the left ventricular ejection fraction, and in 5 of them - by more than 20% from the initial level. Neutropenia developed in 42% of patients (grade II - in 26%, grade III - in 14%, grade IV - in 2%), there were no cases of febrile neutropenia. An increase in the level of lipase in the blood serum without clinical signs of pancreatitis was detected in 28% of patients (grade II - in 11%, grade III - in 14%, grade IV - in 3%).
A direct comparison of the effectiveness of Sutent and interferon alfa-2 in kidney cancer in phase III trials was presented at ASCO 2006 by RJ Motzer et al. [15]. The study included 750 patients who received interferon alfa-2 at a dose of 9 million units subcutaneously 3 times a week or Sutent 50 mg/day for 4 weeks with a 2-week break. Sutent was superior to interferon alfa-2 in efficacy (24.8% vs. 4.9%, respectively) and time to progression (47.3 vs. 24.9 weeks, respectively). In conclusion, this study confirmed that sunitinib has an effective antitumor effect against metastatic clear cell RCC with a relatively acceptable level of toxicity.
In May 2006, results of the use of sunitinib in patients with gastrointestinal stromal tumors intolerant or resistant to imatinib were published [10]. The course of treatment averaged 16.8 weeks (range 5.2 to 29.6 weeks) with a mean sunitinib dose of 37.5 mg/day. In 1 patient there was a need to increase the dose to 50 mg/day, in 2 patients the dose was reduced to 25 mg/day due to increased fatigue and the occurrence of palmoplantar erythrodysesthesia. The objective response rate in this study was approximately 10%. This suggests that continuous administration of sunitinib was well tolerated and provided equivalent clinical efficacy.
The phase III study included 357 patients with gastrointestinal stromal tumors who received Sutent as usual or placebo. When assessing the effectiveness of the drug, a partial effect was observed in 6.8% of patients, stabilization for more than 22 weeks – in 17.4% (0.0 and 1.9% in the placebo group, respectively). The time to progression was 27.3 weeks with Sutent versus 6.4 weeks with placebo (p
JA Morgan et al. [17] published the results of treatment of 97 patients with Gleevec-resistant gastrointestinal stromal tumors (GIST). Patients took Sutent at a dose of 50 mg/day for 4 weeks with a 2-week break. A partial effect was recorded in 8% of patients, stabilization of the disease from 6 weeks to 6 months – in 32%, more than 6 months – in 37%. The median time to progression was 7.8 months, overall survival was 19.8 months. Based on these studies, Sutent was registered as second-line therapy for disease progression during imatinib therapy for GIST.
Sutent is also effective for other solid tumors. Thus, relatively recently the drug began to be used for breast cancer. Data on the results of phases I and II of the study have now been published. The report by HJ Burstein et al. An attempt to use Sutent in patients with metastatic breast cancer who had previously received anthracycline- and taxane-containing regimens was described. As a result, the objective response rate was 11%; disease stabilization for more than 6 months was observed in 5% of patients. Median time to progression and overall survival were 10 and 38 weeks, respectively [18].
Another study [11] using Sutent in a standard regimen in 38 patients with advanced breast cancer resistant to taxanes and anthracyclines demonstrated the following results. The effectiveness of treatment was 17%. The following side effects were noted: diarrhea (32%), nausea (27%), weakness (23%), arterial hypertension (14%), headache (9%), skin rash (5%), grade III neutropenia (16% ), thrombocytopenia grade III (5.4%), significant increase in ALT and AST levels (2.7%). Thus, we can make a preliminary conclusion about the effectiveness of sunitinib in resistance to taxanes and anthracyclines in patients with metastatic breast cancer with a relatively satisfactory spectrum of toxicity. In this regard, it is worth considering further research in this direction in order to evaluate long-term treatment results. For advanced non-small cell lung cancer after progression on standard first- and second-line chemotherapy, Sutent was studied as usual in 63 patients. A partial effect was recorded in 9.5% of patients, stabilization for more than 6 months – in 19% [12].
Studies conducted at Thomas Jefferson University, Philadelphia, demonstrated the effectiveness of sunitinib in the treatment of metastatic melanoma [13]. The drug was administered orally at an initial dosage of 37.5 mg daily for a 28-day cycle. Manifestations of toxicity in this case were diarrhea, fever, leukopenia, thrombocytopenia, and cardiac arrhythmia. For patients who developed the above phenomena, the dose was reduced to 25 mg/day. At a median follow-up of 5.9 months, median overall survival was not reached. This indicates that sunitinib exhibits clinical efficacy in the treatment of metastatic melanoma.
In advanced colorectal cancer, a phase II study by H. Lenz et al. evaluated 82 patients [16] previously treated with irinotecan, oxaliplatin, and fluoropyrimidines. Another 42 patients had previously received bevacizumab. Sutent was prescribed in a standard manner. When assessing the effectiveness in the group of patients who had previously received bevacizumab, one partial effect and one stabilization lasting more than 5 months were noted. In the group of patients who did not receive bevacizumab, 11 cases of stabilization for more than 5 months were recorded. Overall survival in the groups was 7.1 and 10.2 months, respectively. The final results of this study have not been published to date. Manifestations of grade III–IV toxicity included weakness (15%), diarrhea (11%), thrombocytopenia (9%), arterial hypertension (6%), neutropenia (5%).
The effectiveness of antiangiogenic therapy for metastatic colorectal cancer can also be confirmed by the data of P. Pfeiffer et al. It was shown that the addition of sunitinib or bevacizumab to the treatment of patients with metastatic colorectal cancer in conditions of disease progression against the background of several lines of chemotherapy including fluoropyrimidines, oxaliplatin, irinotecan and cetuximab increased the time to progression from 3.2 to 8.7 months, and overall survival - from 8.7 to 12.1 months. The objective response rate was 8% [19].
In conclusion, it should be said that, taking into account a number of studies conducted, it can be noted that sunitinib is quite effective in the treatment of the oncological pathologies listed above. However, despite this, the problems of optimizing the dosage of sunitinib and the possibility of reducing side toxic effects remain unresolved. A large number of studies are devoted to the use of Sutent in the treatment of renal cell cancer, Gleevec-resistant GIST, breast cancer, metastatic colorectal cancer, while there is insufficient data on the use of Sutent in the treatment of non-small cell lung cancer, metastatic melanoma and a number of other tumors. These results suggest that modulation of the VEGF-mediated tumor pathway may be a promising avenue for therapy in patients resistant to standard regimens. Today, a large number of studies are being conducted on the effectiveness of antiangiogenic drugs.
REFERENCE
In vitro studies to date have shown that Sutent induces apoptosis of human umbilical vein endothelial cells. A pronounced additive effect is observed in combinations with anthracyclines, taxanes, cisplatin, irinotecan and fluorouracil.
A large number of studies are devoted to the use of Sutent in the treatment of renal cell cancer, Gleevec-resistant GIST, breast cancer, metastatic colorectal cancer, while there is insufficient data on the use of Sutent in the treatment of non-small cell lung cancer, metastatic melanoma and a number of other tumors. These results suggest that modulation of the VEGF-mediated tumor pathway may be a promising avenue for therapy in patients resistant to standard regimens.
Compound
One capsule 12.5 mg contains
- active substance – sunitinib malate 16.7 mg (corresponding to sunitinib 12.5 mg),
- excipients: mannitol, croscarmellose sodium, magnesium stearate, povidone K-25.
- composition of the capsule shell (body and cap): gelatin, red iron (III) oxide, titanium dioxide..
One 25 mg capsule contains
- active substance – sunitinib malate 33.4 mg (corresponding to sunitinib 25 mg),
- excipients: mannitol, croscarmellose sodium, magnesium stearate, povidone K-25.
- capsule shell composition:
- body: body: gelatin, iron (III) oxide red, titanium dioxide.
- cover: body: gelatin, iron (III) oxide red, titanium dioxide, iron (II, III) oxide black, iron (III) oxide yellow.
One 50 mg capsule contains
- active substance – sunitinib malate 66.8 mg (corresponding to sunitinib 50 mg),
- excipients: mannitol, croscarmellose sodium, magnesium stearate, povidone K-25.
- composition of the capsule shell (body and lid): body: gelatin, iron (III) oxide red, titanium dioxide, iron (II, III) oxide black, iron (III) oxide yellow.
- white ink: shellac, anhydrous ethanol, 2-propanol, butanol, titanium dioxide, propylene glycol, sodium hydroxide, povidone.
Pharmacodynamics
Sunitinib malate is a small molecule that inhibits receptor tyrosine kinases involved in pathological angiogenesis, tumor growth and metastasis. Sunitinib exhibits inhibitory activity against many kinases; is a potent inhibitor of platelet-derived growth factor receptors, vascular endothelial growth factor receptors, stem cell factor receptor, Fms-like tyrosine kinase-3 receptor, neurotrophic glial factor receptor, colony-stimulating factor receptor. The activity of the main metabolite was similar to that of sunitinib.
Biochemical and cellular studies have demonstrated inhibition of tyrosine kinase receptor tyrosine kinase activity by sunitinib. Proliferation tests demonstrated functional suppression of proliferation processes. According to biochemical and cellular experiments, the activity of the main metabolite was similar to sunitinub.
Sunitinib inhibited phosphorylation of many RTKs in tumor xenografts. In experimental models of various tumors, it also demonstrated inhibition of tumor growth or regression and/or suppression of metastases.
Sutent, 25 mg, capsules, 28 pcs.
Treatment with Sutent® should be carried out under the supervision of a physician experienced in working with anticancer drugs.
At the beginning of each cycle of therapy with Sutent®, a complete analysis of hematological parameters should be performed.
Cases of bleeding, sometimes fatal, have been reported, including gastrointestinal bleeding, respiratory tract bleeding, tumor bleeding, urinary tract bleeding, and cerebral 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 hemorrhage. It is periodically necessary to conduct a medical examination and evaluate blood counts to early detect the first signs of bleeding and apply the necessary therapeutic measures. During concomitant therapy with anticoagulants, blood clotting parameters should be monitored.
The relationship between RTK inhibition and cardiac function has not been studied. It is unknown whether patients who have had a history of cardiovascular events in the last 12 months before sunitinib treatment, such as myocardial infarction, severe/unstable angina, coronary/peripheral bypass grafting, symptomatic congestive heart failure, cerebrovascular events, or transient ischemic events disorders, or pulmonary embolism, are at greater risk of developing treatment-related left ventricular dysfunction. When prescribing Sutent® to this category of patients, the risk/benefit ratio should be carefully assessed when prescribing Sutent®.
During therapy with Sutent®, patients should be periodically monitored for clinical signs and symptoms of congestive heart failure (CHF). LVEF is recommended to be assessed before initiation of therapy and periodically during treatment.
If clinical signs of CHF develop, treatment with sunitinib should be discontinued. In the absence of clinical signs of CHF, but with LVEF less than 50% or a decrease in this indicator by more than 20% compared to the initial one (before the start of therapy), it is recommended to reduce the dose of sunitinib or stop taking the drug. At concentrations approximately 2 times higher than therapeutic levels, sunitinib promotes prolongation of the QTcF interval (Frederick 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 prolongation, in patients taking antiarrhythmic drugs, or in patients with underlying cardiac disease, bradycardia, or electrolyte disturbances. Caution is required and the dose of sunitinib should be reduced when concomitantly taking strong inhibitors of the CYP3A4 isoenzyme, which may increase the plasma concentration of sunitinib. Before starting therapy and during treatment with Sutent®, ECG monitoring is recommended. Patients should be monitored for the occurrence of hypertension using standard blood pressure monitoring methods. In patients with severe arterial hypertension that is unresponsive to treatment, temporary cessation of therapy with Sutent® is recommended. Therapy is resumed as soon as arterial hypertension is controlled.
Background testing of laboratory parameters of thyroid function is recommended in patients with hypothyroidism or hyperthyroidism. Patients with hypothyroidism are treated according to standard medical practice before initiating sunitinib therapy. Monitoring of all patients during sunitinib therapy for the development of thyroid dysfunction is recommended. Patients with signs and/or symptoms of thyroid dysfunction should undergo laboratory monitoring.
Patients should be warned that during treatment with Sutent®, a change in skin color may occur due to the presence of a dye (yellow) in the drug. Hair or skin discoloration may also occur. Since nausea and vomiting may occur when using Sutent®, prophylactic administration of antiemetic drugs should be considered. If diarrhea occurs, antidiarrheals are prescribed.
During treatment with Sutent®, it is necessary to periodically check the activity of lipase and amylase in the blood serum. If symptoms of pancreatitis are present or appear, regular medical monitoring is necessary.
Patients with brain metastases, a history of seizures, and/or symptoms of reversible posterior leukoencephalopathy, such as hypertension, headache, lethargy, cognitive impairment, visual loss, including cortical blindness, should be monitored with standard methods, including blood pressure control. If these symptoms appear during therapy, it is recommended to temporarily stop taking Sutent®. After the symptoms disappear, treatment can be resumed at the discretion 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.
A baseline study of renal function prior to initiation of treatment is recommended, as is monitoring of renal function parameters during sunitinib therapy. The safety of sunitinib in patients with moderate or severe proteinuria has not been assessed. In patients with nephrotic syndrome, treatment with sunitinib should be discontinued.
During and for at least 3 months after discontinuation of therapy with Sutent®, reliable methods of contraception must be used.
Fertility.
Based on the results of preclinical studies, it can be concluded that sunitinib therapy may adversely affect the fertility of men and women.
Influence on driving vehicles and working with machinery.
Patients should be warned about the possibility of dizziness and other side effects during treatment with Sutent®, which may affect the ability to drive a car and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
Pharmacokinetics
Suction
Sunitinib is administered orally in the form of malate, in gelatin capsules, regardless of food intake. After taking the drug, the maximum concentration of sunitinib in the blood plasma is reached approximately 6-12 hours after administration; Food intake does not affect the bioavailability of sunitinib. / When taken orally, sunitinib is well absorbed from the gastrointestinal tract. The time to reach Cmax is 6-12 hours. Food intake does not affect the bioavailability of sunitinib.
Distribution
Equilibrium concentrations of sunitinib and its main metabolite in blood plasma are achieved 10-14 days after starting the drug. The binding of sunitinib and its metabolite to plasma proteins is 95 and 90%, respectively.
The mean volume of distribution is 2230 L, demonstrating tissue distribution. The apparent volume of distribution of sunitinib was significant at 2230 L, indicating its tissue distribution. In the dose range of 25–100 mg, the area under the curve (AUC) of time and plasma concentrations and Cmax increased proportionally to the dose.
Metabolism
Metabolism of sunitinib occurs mainly in the liver - due to oxidation mediated by the CYP3A4 isoenzyme, resulting in the formation of the main active metabolite (which is further metabolized by the same CYP3A4 isoenzyme). The activity of the main metabolite is similar to the activity of sunitinib itself. The proportion of active metabolite circulating in plasma is 23-37% of the area under the concentration-time curve.
In vitro clinical data indicate that sunitinib does not inhibit or induce major CYP enzymes, including CYP3A4. The biotransformation of sunitinib is carried out mainly 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. By day 14, the total plasma concentration of sunitinib and its main active metabolite is 62.9-101 ng/ml. With repeated daily use or repeated cycles with different dosing regimens, no significant changes in the pharmacokinetics of sunitinib and its main active metabolite were observed.
Removal
Sunitinib is excreted mainly in feces – 61%. Approximately 16% of the dose is excreted by the kidneys in the form of unchanged substance and its metabolites. The total clearance when taken orally reached 34-62 l/h. The half-life of sunitinib and its main active metabolite is 40-60 hours and 80-110 hours, 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 situations
Liver failure
Sunitinib and its main active metabolite are metabolized primarily in the liver. Systemic exposure following a single dose of sunitinib was similar in patients with mild to moderate hepatic impairment compared with healthy patients. Sunitinib has not been studied in patients with severe hepatic impairment.
Kidney failure
According to a population pharmacokinetic analysis, it was shown that in patients with a recorded creatinine clearance in the range of 42–347 ml/min, the pharmacokinetics of sunitinib did not change. Systemic exposure after a single dose of Sutenta was similar in patients with severe renal impairment (CLcr <30 ml/min) compared to patients with normal renal function (CLcr >80 ml/min). Although sunitinib and its primary active metabolite are not eliminated by hemodialysis in patients with end-stage renal disease, total systemic exposures were lower by 47% for sunitinib and 31% for its primary metabolite compared with patients with normal renal function.
Population pharmacokinetics
Pharmacokinetic population analysis of demographic data shows that there is no clinically significant dependence on age, body weight, creatinine clearance, race, gender of the patient and do not have a clinically important effect on the pharmacokinetics of the drug and its active metabolite.
Floor
Available data suggest that the estimated clearance of sunitinib may be 30% lower in women than in men; this difference does not require adjustment of the starting dose.
Sutent®
Treatment with Sutent® should be carried out under the supervision of a physician experienced in working with anticancer drugs.
At the beginning of each cycle of therapy with Sutent®, a complete analysis of hematological parameters should be performed.
Bleeding
Cases of bleeding, sometimes fatal, have been reported, including gastrointestinal bleeding, respiratory tract bleeding, tumor bleeding, urinary tract bleeding, and cerebral 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 hemorrhage.
There have been reports of pulmonary hemorrhage (in some cases fatal) in patients taking sunitinib for renal cell carcinoma, gastrointestinal tumors, or non-small cell lung cancer. Important: Sunitinib is not approved for the treatment of non-small cell lung cancer. It is periodically necessary to conduct a medical examination and evaluate blood counts to early detect the first signs of bleeding and apply the necessary therapeutic measures. During concomitant therapy with anticoagulants, blood clotting parameters should be monitored.
Epistaxis associated with sunitinib therapy was the most common type of bleeding in patients with solid tumors, occurring in 8% of cases. It was observed in half of the cases in patients with hemorrhagic complications.
The cardiovascular system
The relationship between receptor tyrosine kinase (RTK) inhibition and cardiac function has not been studied. It is unknown whether patients who have had a history of cardiovascular events in the last 12 months prior to sunitinib treatment, such as myocardial infarction (including severe/unstable angina), coronary/peripheral bypass grafting, symptomatic congestive heart failure, cerebrovascular events, or transient ischemic events, or pulmonary embolism, are at greater risk of developing treatment-related left ventricular dysfunction. When prescribing Sutent® to this category of patients, the risk/benefit ratio should be carefully assessed.
During therapy with Sutent®, patients should be periodically monitored for clinical signs and symptoms of chronic heart failure (CHF). LVEF is recommended to be assessed before initiation of therapy and periodically during treatment.
If clinical signs of CHF appear, treatment with sunitinib should be discontinued. In the absence of clinical signs of CHF, but with LVEF less than 50% or a decrease in this indicator by more than 20% compared to the initial one (before the start of therapy), it is recommended to reduce the dose of sunitinib or stop taking the drug.
In the post-marketing period, cases of cardiac dysfunction (sometimes fatal), such as heart failure, cardiomyopathy, myocardial ischemia and myocardial infarction, have been reported. Sunitinib should be used with caution in patients at risk of developing these disorders. Based on this information, it is suggested that the use of sunitinib may increase the risk of developing cardiomyopathy. Patients treated with sunitinib had no risk factors for developing cardiomyopathy other than the drug itself.
Vascular disorders
There have been reports of cases of arterial thromboembolism (in some cases fatal) in patients taking Sutent®.
The most common were: cerebrovascular accident, transient ischemic attack and stroke.
Risk factors, in addition to the underlying disease and the patient's age over 65 years, are: arterial hypertension, diabetes mellitus, history of thromboembolic complications.
In clinical studies, the development of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, was noted. With the development of pulmonary embolism, in one case, Sutent® was discontinued, and in several cases a dose reduction or temporary cessation of therapy was required. After resumption of therapy, no further cases of pulmonary embolism were observed in these patients.
Taste disorders
In clinical studies, dysgeusia was observed in 28% of patients receiving therapy with Sutent®.
Prolongation of the QT interval
At concentrations approximately 2 times higher than therapeutic levels, sunitinib promotes prolongation of the QTcF interval (Frederick 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 prolongation, in patients taking antiarrhythmic drugs, or in patients with underlying cardiac disease, bradycardia, or electrolyte disturbances. Caution is required and the dose of sunitinib should be reduced when concomitantly taking strong inhibitors of the CYP3A4 isoenzyme, which may increase the plasma concentration of sunitinib. Before starting therapy and during treatment with Sutent®, ECG monitoring is recommended.
Increased blood pressure
An increase in blood pressure is very often observed in patients receiving therapy with Sutent®.
Patients should be monitored for increased blood pressure using standard monitoring methods. In patients with severe arterial hypertension that is unresponsive to treatment, temporary cessation of therapy with Sutent® is recommended. Therapy is resumed as soon as arterial hypertension is controlled.
Respiratory system disorders
Patients with pulmonary embolism events recorded within 12 months before the start of sunitinib therapy were excluded from clinical studies.
Cases of respiratory dysfunction (eg, dyspnea, pleural effusion, pulmonary embolism, or pulmonary edema) were reported in patients receiving sunitinib in phase 3 registration studies. Approximately 22.2% of patients with solid tumors who received sunitinib therapy experienced pulmonary dysfunction.
Cases of pulmonary embolism were observed in approximately 3.1% of patients with gastrointestinal stromal tumors and in 1.2% of patients with advanced and/or metastatic renal cell carcinoma who received sunitinib therapy in phase 3 clinical trials. No cases of pulmonary embolism were observed in patients with unresectable or metastatic high-grade pancreatic neuroendocrine tumors who received sunitinib in phase 3 clinical trials. Rare cases of death have been observed during post-marketing studies.
Aneurysm and arterial dissection
The use of vascular endothelial growth factor (VEGF) inhibitors in patients with or without hypertension may lead to aneurysm formation and/or arterial dissection. Before initiating therapy with sunitinib, the possible risks should be carefully assessed in patients with risk factors such as hypertension or a history of aneurysm.
Thyroid dysfunction
Monitoring of all patients during sunitinib therapy for the development of thyroid dysfunction is recommended. Patients with signs and/or symptoms of thyroid dysfunction should undergo laboratory monitoring. Baseline laboratory testing of thyroid function is also recommended in patients with hypothyroidism or hyperthyroidism. Patients with hypothyroidism are treated according to standard medical practice before initiating sunitinib therapy.
In post-registration clinical studies, cases of hyperthyroidism were noted, in some cases with subsequent development of hypothyroidism.
Skin and subcutaneous tissues
Patients should be warned that during treatment with Sutent®, a change in skin color may occur due to the presence of a dye (yellow) in the drug. Hair or skin discoloration may also occur. Other possible side effects with sunitinib include dry, thinning or cracking of the skin, blisters, or a local rash on the palms and soles of the hands.
These effects do not tend to spread, are usually reversible and in most cases did not lead to the need to discontinue therapy.
Rare cases of severe skin lesions, such as erythema multiforme, Stevens-Johnson syndrome-like skin lesions, some of which have been fatal, have been reported. Therapy with Sutent should be discontinued if symptoms of Stevens-Johnson syndrome or erythema multiforme develop (for example, progressive skin rash, usually with blistering and damage to the mucous membranes). If the diagnosis of Stevens-Johnson syndrome is confirmed, therapy is not resumed. In some cases, patients with suspected erythema multiforme tolerated resumption of therapy at lower doses after resolution of skin symptoms; some of these patients were simultaneously receiving therapy with glucocorticosteroids or antihistamines.
Lesions of the gastrointestinal tract
In patients with intra-abdominal tumors receiving therapy with Sutent®, serious complications (including gastrointestinal perforation), in some cases with death, were observed.
Nausea, diarrhea, dyspepsia, stomatitis and vomiting may occur when using Sutent®. In such cases, the use of antiemetic or antidiarrheal drugs should be considered as maintenance therapy.
Pancreatitis
In clinical studies with the use of the drug Sutent®, cases of pancreatitis were noted. In patients with various solid tumors receiving therapy with Sutent®, an increase in lipase and amylase activity in the blood plasma was observed. Increases in lipase activity were transient and were generally not accompanied by symptoms of pancreatitis. During treatment with Sutent®, it is necessary to periodically check the activity of lipase and amylase in the blood serum. If symptoms of pancreatitis are present or appear, treatment with Sutent should be discontinued and appropriate therapy administered.
Convulsions
Seizures (sometimes fatal) have been reported in patients with radiological evidence of brain metastases or posterior reversible leukoencephalopathy syndrome.
Patients with brain metastases, a history of seizures, and/or signs/symptoms of reversible posterior leukoencephalopathy, such as increased blood pressure, headache, lethargy, cognitive impairment, visual loss, including cortical blindness, should be monitored with standard methods, including blood pressure monitoring. pressure. If these symptoms appear during therapy, it is recommended to temporarily stop taking Sutent®. After the symptoms disappear, treatment can be resumed at the discretion of the attending physician.
Thrombotic microangiopathy
Cases of TMA, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or death, have been reported in clinical trials and post-marketing use of sunitinib alone and in combination with bevacizumab. If a patient develops TMA, sunitinib should be discontinued. After cessation of treatment, the symptoms of TMA disappeared.
Proteinuria
There are reports of the development of proteinuria or nephrotic syndrome during therapy with sunitinib.
A baseline study of renal function prior to initiation of treatment is recommended, as is monitoring of renal function parameters during sunitinib therapy. The safety of sunitinib in patients with moderate to severe proteinuria has not been assessed. In patients with nephrotic syndrome, treatment with sunitinib should be discontinued.
Hypoglycemia
During sunitinib therapy, some patients experienced a decrease in blood glucose concentrations. In some cases, such changes were accompanied by clinical symptoms. Blood glucose concentrations in patients with diabetes mellitus should be regularly monitored and, if necessary, the dose of hypoglycemic drugs should be adjusted.
Hepatotoxicity
Cases of liver failure, sometimes fatal, have been reported during sunitinib therapy. Liver enzymes (alanine aminotransferase, aspartate aminotransferase, bilirubin concentration) should be monitored before initiating sunitinib therapy, during each cycle of therapy, and when clinically indicated. If grade 3 or 4 side effects on liver function develop, you should stop taking the drug. If symptoms of hepatotoxicity do not resolve, the drug should be discontinued.
Hematological disorders
There are reports of a decrease in the number of neutrophils and platelets during the use of sunitinib. The listed cases are not cumulative; they were usually reversible and did not lead to discontinuation of therapy. In some cases, fatal bleeding was observed in combination with thrombocytopenia.
In patients receiving treatment with Sutent®, a complete blood count should be performed before each cycle of therapy.
Tumor lysis syndrome
Patients with large tumor burdens (before initiating treatment with sunitinib) should be closely monitored as they are at greatest risk of developing tumor lysis syndrome.
Infections and infestations
Cases of serious infections (including those due to neutropenia), some of which were fatal, have been reported. Infections that develop during the use of sunitinib are common in cancer patients, for example, respiratory infections (pneumonia, bronchitis), urinary tract infections, skin infections (for example, inflammation of the subcutaneous fat), sepsis. Often infections can be bacterial, viral or fungal in nature.
Necrotizing fasciitis
There are reports of rare cases of necrotizing fasciitis, including the perineum, in some cases with a fatal outcome. If this adverse event occurs, sunitinib should be discontinued and appropriate treatment should be prescribed.
Surgical interventions
Cases of delayed wound healing have been reported with the use of Sutent®. If extensive surgery is necessary, a temporary suspension of the drug is recommended. There are limited data on the time after surgery after which therapy can be resumed. Therefore, the decision to restart therapy should be based on an assessment of the wound after surgery.
Osteonecrosis of the jaw
Cases of osteonecrosis of the jaw have been reported with the use of sunitinib. Most of the cases were observed in patients receiving intravenous bisphosphonates, the use of which is a risk factor for the development of osteonecrosis of the jaw. Caution should be exercised when using sunitinib and intravenous bisphosphonates simultaneously.
In addition, invasive procedures for oral diseases are also risk factors for the development of osteonecrosis of the jaw. A dental examination of the patient should be performed before initiating sunitinib therapy.
In patients taking sunitinib who have previously received intravenous bisphosphonate therapy, invasive oral procedures should be avoided if possible.
Pharmaceutical characteristics
Hard gelatin capsules with dosage:
- Capsule 12.5 mg. (has a red-brown body, with engravings “Pfizer”, “STN 12.5 mg”).
- Capsule 25 mg. (has a brownish-orange body, with a red-brown base, with “Pfizer”, “STN 25 mg” engravings on the body).
- Capsule 50 mg. (has a light brownish-orange body, with “Pfizer”, “STN 50 mg” engraved on the body).
Capsule contents: yellow to orange granules.
Packaging, expiration date, storage conditions
Capsules of 12.5 mg, 25 mg or 50 mg. 30 capsules are packed in a polyethylene bottle with a polypropylene cap. One bottle along with instructions is placed in a cardboard box.
Store at a temperature not exceeding 25°C. Keep out of the reach of children.
Shelf life 3 years.
Our company operates both in Kazakhstan and delivers to neighboring countries. Contact us for advice by contact numbers.
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Sunitinib-nativ
Treatment with Sunitinib-native should be carried out under the supervision of a physician experienced in working with anticancer drugs.
At the beginning of each cycle of therapy with Sunitinib-native, a complete analysis of hematological parameters should be performed.
Hemorrhages, tumor bleeding
There have been reports of bleeding, sometimes fatal, including gastrointestinal bleeding, respiratory tract bleeding, tumor bleeding, urinary tract bleeding and cerebral 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 hemorrhage. There have been reports of pulmonary hemorrhage (in some cases fatal) in patients taking sunitinib for renal cell carcinoma, gastrointestinal tumors, or non-small cell lung cancer.
Important: Sunitinib is not intended for the treatment of non-small cell lung cancer.
It is periodically necessary to conduct a medical examination and evaluate blood counts to early detect the first signs of bleeding and apply the necessary therapeutic measures. During concomitant therapy with anticoagulants, blood clotting parameters should be monitored. Epistaxis associated with sunitinib therapy was the most common type of bleeding in patients with solid tumors, occurring in 8% of cases. It was observed in half of the cases in patients with hemorrhagic complications.
Heart dysfunction
The relationship between receptor tyrosine kinase (RTK) inhibition and cardiac function has not been studied. It is unknown whether patients who have had a history of cardiovascular events in the last 12 months prior to treatment with sunitinib, such as myocardial infarction (including severe/unstable angina), coronary/peripheral bypass grafting, symptomatic congestive heart failure, cerebrovascular events, or transient ischemic events, or pulmonary embolism, are at greater risk of treatment-related left ventricular dysfunction. When prescribing Sunitinib-native to this category of patients, the risk/benefit ratio should be carefully assessed.
During therapy with Sunitinib-native, patients should be periodically monitored for clinical signs and symptoms of chronic heart failure (CHF). LVEF is recommended to be assessed before initiation of therapy and periodically during treatment. If clinical signs of CHF appear, treatment with sunitinib should be discontinued. In the absence of clinical signs of CHF, but with LVEF less than 50% or a decrease in this indicator by more than 20% compared to the initial one (before starting therapy), it is recommended to reduce the dose of Sunitinib-native or stop taking the drug.
QT prolongation
At concentrations approximately 2 times higher than therapeutic levels, sunitinib promotes prolongation of the QTcF interval (Frederick 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 prolongation, in patients taking antiarrhythmic drugs, or in patients with underlying cardiac disease, bradycardia, or electrolyte disturbances. Caution is required and the dose of sunitinib should be reduced when concomitantly taking strong inhibitors of the CYP3A4 isoenzyme, which may increase the plasma concentration of sunitinib. ECG monitoring is recommended before starting therapy and during treatment with sunitinib.
Arterial hypertension
Patients should be monitored for increased blood pressure using standard monitoring methods. In patients with severe unresponsive hypertension, temporary discontinuation of sunitinib therapy is recommended. Therapy is resumed as soon as arterial hypertension is controlled.
Thyroid dysfunction
Monitoring of all patients during sunitinib therapy for the development of thyroid dysfunction is recommended. Patients with signs and/or symptoms of thyroid dysfunction should undergo laboratory monitoring. Baseline laboratory testing of thyroid function is also recommended in patients with hypothyroidism or hyperthyroidism. Patients with hypothyroidism are treated according to standard medical practice before initiating sunitinib therapy.
Skin and subcutaneous tissue disorders
Patients should be warned that skin discoloration may occur during treatment with sunitinib due to the presence of a dye (yellow) in the drug. Hair or skin discoloration may also occur.
Gastrointestinal disorders
Since nausea and vomiting may occur with sunitinib, prophylactic antiemetics should be considered. If diarrhea occurs, antidiarrheals are prescribed.
Pancreatic dysfunction
During treatment with Sunititnib-native, it is necessary to periodically check the activity of lipase and amylase in the blood serum. If symptoms of pancreatitis are present or appear, regular medical monitoring is necessary.
Symptoms of reversible posterior leukoencephalopathy
Patients with brain metastases, a history of seizures, and/or signs/symptoms of reversible posterior leukoencephalopathy, such as increased blood pressure, headache, lethargy, cognitive impairment, visual loss, including cortical blindness, should be monitored with standard methods, including blood pressure monitoring. pressure. If these symptoms appear during therapy, it is recommended to temporarily stop taking Sunitinib-native. After the symptoms disappear, treatment can be resumed at the discretion of the attending physician.
Thrombotic microangiopathy
If thrombotic microangiopathy occurs, temporary discontinuation of sunitinib treatment is recommended. After the symptoms disappear, treatment can be resumed at the discretion of the attending physician.
Renal dysfunction
A baseline study of renal function prior to initiation of treatment is recommended, as is monitoring of renal function parameters during sunitinib therapy. The safety of sunitinib in patients with moderate to severe proteinuria has not been assessed. In patients with nephrotic syndrome, treatment with sunitinib should be discontinued.
Liver dysfunction
Cases of liver failure, sometimes fatal, have been reported during sunitinib therapy. Liver function tests (alanine aminotransferase, aspartate aminotransferase, bilirubin concentration) should be monitored before initiating sunitinib therapy, during each treatment cycle, and as clinically indicated. If grade 3 or 4 side effects on liver function develop, you should stop taking the drug. If symptoms of hepatotoxicity do not resolve, the drug should be discontinued.
Hematological disorders
There are reports of a decrease in the number of neutrophils of grades 3 and 4 (in 13.1% and 0.9% of cases, respectively). A decrease in platelet counts of grade 3 and 4 was noted in 4% and 0.5% of cases, respectively. The listed cases were not cumulative, were usually reversible and did not lead to discontinuation of therapy. In some cases, fatal bleeding was observed in combination with thrombocytopenia.
Tumor lysis syndrome
Patients with large tumor burdens (before initiating treatment with sunitinib) should be closely monitored as they are at greatest risk of developing tumor lysis syndrome.
Delayed wound healing
Cases of delayed wound healing have been reported with the use of sunitinib. If extensive surgery is necessary, a temporary suspension of the drug is recommended. There are limited data on the time after surgery after which therapy can be resumed. Therefore, the decision to restart therapy should be based on an assessment of the wound after surgery.
Osteonecrosis of the jaw
Cases of osteonecrosis of the jaw have been reported with the use of sunitinib. Most of the cases were observed in patients receiving intravenous bisphosphonates, the use of which is a risk factor for the development of osteonecrosis of the jaw. Caution should be exercised when using sunitinib and intravenous bisphosphonates simultaneously.
In addition, invasive procedures for oral diseases are also risk factors for the development of osteonecrosis of the jaw. A dental examination of the patient should be performed before initiating sunitinib therapy. In patients taking sunitinib who have previously received intravenous bisphosphonate therapy, invasive oral procedures should be avoided if possible.
Hypersensitivity reactions and angioedema
If angioedema develops as a result of a hypersensitivity reaction, sunitinib therapy should be discontinued and standard treatment instituted.
Fistula formation
If fistulas occur, sunitinib therapy should be discontinued. There are limited data on the use of sunitinib after fistula formation.
Cardiomyopathy
In post-marketing studies of sunitinib, cases of cardiac dysfunction (sometimes fatal), such as heart failure, cardiomyopathy, and myocardial dysfunction, have been reported. Based on this information, it is suggested that the use of suntinib may increase the risk of developing cardiomyopathy. Patients treated with sunitinib had no risk factors for cardiomyopathy other than exposure to sunitinib itself.
Effect on fertility
Based on the results of preclinical studies with sunitinib, it appears that sunitinib therapy may adversely affect fertility in both men and women. Reliable contraception must be used during and for at least three months after discontinuation of sunitinib therapy.
