Sutent, 12.5mg capsules 28 pcs

• Gastrointestinal stromal tumors in the absence of effect of imatinib therapy due to resistance or intolerance;
• spread and/or metastatic renal cell cancer in patients who have not previously received specific treatment;
• disseminated 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

Sunitinib

Composition

1 capsule contains:

The active ingredients: sunitinib malate 16.7 mg, which corresponds to sunitinib 12.5 mg.

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

Capsule shell composition: gelatin, titanium dioxide, iron oxide red.

The composition of the ink includes: shellac, povidone, titanium dioxide.

There are 7 capsules in the blister. In the carton 4 blisters.

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: The recommended dose of the drug is 37.5 mg daily without interruption.

If the drug 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 not exceed 50 mg/day.

Patients with impaired liver function when AST and/or ALT levels are less than 2.5 times higher than GGN or when these levels are less than 5 times higher due to underlying disease do not require dose adjustment.

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

Dose adjustment is not required in elderly patients.

Interaction

Drugs that increase plasma concentrations of sunitinib

Concomitant administration of sunitinib in a single dose with the CYP3A4 inhibitor ketoconazole may increase C_max 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 C_max 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 for gastrointestinal stromal tumors and metastatic renal cell cancer and up to 62.5 mg/day for pancreatic neuroendocrine tumors.

Special Instructions

Treatment with Sutent® should be performed under the supervision of a physician experienced in the use of antitumor drugs.

A complete hematologic evaluation 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. In the absence of clinical signs of congestive heart failure, but with a PVLD of 20% compared to baseline (before therapy), the dose of sunitinib should be reduced or discontinued.

At concentrations approximately 2-fold greater than therapeutic, sunitinib promotes prolongation of the QTcF interval (Fridericia 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 does not respond to treatment, temporary discontinuation of therapy with Sutent® is recommended. Therapy should be resumed as soon as it is possible to control the arterial hypertension.

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.

Since nausea and vomiting may occur with 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®. In the presence or appearance of 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 arterial hypertension, headache, lethargy, mental retardation, vision loss, including cortical blindness, should be controlled by standard methods, including BP control. In case 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.

In case of thrombotic microangiopathy, temporary discontinuation of sunitinib 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 ability to drive vehicles and other mechanisms requiring high concentration

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

Contraindications

• Pregnancy;
• lactation period (breastfeeding);
• childhood (efficacy and safety in children has not been established);
• high sensitivity to sunitinib or other drug components.

With caution: the drug should be used 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, and 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 common (≥1/10);
• frequent (≥1/100 to < 1/10);
• infrequent (≥ 1/1000 to < 1/100);
• infrequent (≥ 1/10,000 to < 1/1000);
• very rare ( < 1/10,000).

In the hematopoietic system: very often – anemia, neutropenia, thrombocytopenia; often – 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 – change of 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 thromboembolism (pulmonary embolism, deep vein thrombosis); infrequent – heart failure, congestive heart failure, left ventricular dysfunction; rare – prolongation of QT interval, 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 were 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.

Muscular system disorders: there are reports about 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

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