Sutent^® (Capsules) Instructions for Use

Marketing Authorization Holder

Pfizer, Inc. (USA)

Manufactured By

Pfizer Italia, S.r.L. (Italy)

ATC Code

L01EX01 (Sunitinib)

Active Substance

Sunitinib (Rec.INN registered by WHO)

Dosage Forms

	Sutent®	Capsules 12.5 mg: 28 or 30 pcs.
		Capsules 25 mg: 28 or 30 pcs.
		Capsules 50 mg: 28 or 30 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size 4, opaque, with a reddish-brown cap and body, with white imprints “Pfizer” on the cap and “STN 12.5 mg” on the body; capsule contents – granulated powder from yellow to orange.

Excipients: mannitol, croscarmellose sodium, povidone K-25, magnesium stearate; capsule shell: iron oxide red, titanium dioxide, gelatin.

Ink composition: shellac, propylene glycol, sodium hydroxide, povidone, titanium dioxide.

7 pcs. – blisters (4) – cardboard packs.
30 pcs. – bottles (1) – cardboard packs.

Capsules hard gelatin size 3, opaque, with a brownish-orange cap and a reddish-brown body, with white imprints “Pfizer” on the cap and “STN 25 mg” on the body; capsule contents – granulated powder from yellow to orange.

Excipients: mannitol, croscarmellose sodium, povidone K-25, magnesium stearate; capsule shell: iron oxide black, iron oxide yellow, iron oxide red, titanium dioxide, gelatin.

Ink composition: shellac, propylene glycol, sodium hydroxide, povidone, titanium dioxide.

7 pcs. – blisters (4) – cardboard packs.
30 pcs. – bottles (1) – cardboard packs.

Capsules hard gelatin size 2, opaque, with a cap and body of light brownish-orange color, with white imprints “Pfizer” on the cap and “STN 50 mg” on the body; capsule contents – granulated powder from yellow to orange.

Excipients: mannitol, croscarmellose sodium, povidone K-25, magnesium stearate; capsule shell: iron oxide black, iron oxide yellow, iron oxide red, titanium dioxide, gelatin.

Ink composition: shellac, propylene glycol, sodium hydroxide, povidone, titanium dioxide.

7 pcs. – blisters (4) – cardboard packs.
30 pcs. – bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent, protein tyrosine kinase inhibitor

Pharmacological Action

Antitumor drug, protein tyrosine kinase inhibitor. Capable of simultaneously inhibiting receptors of various tyrosine kinases (RTK) involved in tumor growth, pathological angiogenesis, and metastasis.

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 receptor (FLT), colony-stimulating factor receptor (CSF-IR) and glial cell line-derived neurotrophic factor receptor (RET). The activity of the main metabolite was similar to that of sunitinib.

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

Pharmacokinetics

Absorption

When taken orally, Sunitinib is well absorbed from the gastrointestinal tract. The 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 within the range of 100-4000 ng/ml.

V_d is 2230 L, demonstrating distribution into tissues.

Sunitinib metabolism is primarily 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.

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. With repeated daily administration or repeated cycles with different dosing regimens, no significant changes in the pharmacokinetics of sunitinib and its main active metabolite were found.

Excretion

Sunitinib is excreted mainly in feces – 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.

T_1/2 of sunitinib and its main active metabolite is 40-60 hours and 80-110 hours, respectively. With repeated daily administration, 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, gender, creatinine clearance, or ECOG performance status 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 ECOG performance status.

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

Indications

• Gastrointestinal stromal tumors in case of no effect from imatinib therapy due to resistance or intolerance;
• Advanced and/or metastatic renal cell carcinoma in patients who have not received prior specific treatment;
• Advanced and/or metastatic renal cell carcinoma in case of no effect from cytokine therapy;
• Unresectable or metastatic well-differentiated pancreatic neuroendocrine tumors in adults with disease progression.

ICD codes

Dosage Regimen

The drug is taken orally regardless of meals.

Gastrointestinal stromal tumors in case of no 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 2-week break (4/2 regimen). A full therapy cycle is thus 6 weeks.

Advanced and/or metastatic renal cell carcinoma in patients who have not received prior specific treatment or in case of no effect from cytokine therapy: the recommended dose of the drug is 50 mg/day orally for 4 weeks followed by a 2-week break (4/2 regimen). A full therapy cycle is thus 6 weeks.

Unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors in adults with disease progression: the recommended dose of the drug is 37.5 mg daily without a break.

If a dose of the drug is missed, the missed dose should not be made up. The usual dose of the drug should be taken the next day.

Depending on individual tolerance, the dose of Sutent^® 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 impaired liver function with an increase in AST and/or ALT levels exceeding the upper limit of normal (ULN) by less than 2.5 times, or in case of an increase in these indicators due to the underlying disease by less than 5 times, dose adjustment is not required.

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 require dose adjustment.

Adverse Reactions

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

In patients with metastatic renal cell carcinoma, venous thromboembolisms were 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 receiving Sunitinib, venous thromboembolisms were observed in 7 patients (3%). In 5 out of 7, grade 3 deep vein thrombosis was noted, and in 2 patients – grade 1 or 2.

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

In patients with solid tumors, the most common treatment-related adverse reactions associated with Sutent^® therapy were fatigue, arterial hypertension and neutropenia up to grade 3 severity, increased lipase level up to grade 4.

Treatment-related adverse events noted in clinical studies in at least >5% of patients with solid tumors are listed below and systematized by organ system, frequency and severity. Within each group, adverse reactions are listed in order of decreasing 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 (<1/10,000).

From the hematopoietic system very common – anemia, neutropenia, thrombocytopenia; common – leukopenia.

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

Dermatological reactions very common – skin discoloration, palmar-plantar syndrome (erythrodysesthesia), rash (erythematous, maculopapular, papular, pityriasis-like, generalized, psoriasis-like), blisters, hair color change, dry skin, erythema; common – alopecia, skin peeling, skin itching, exfoliative dermatitis.

From the musculoskeletal system common – limb pain, arthralgia, myalgia.

From the nervous system very common – headache; common – dizziness, paresthesia, insomnia or increased drowsiness, depression.

From the cardiovascular system very common – increased blood pressure; common – decreased left ventricular ejection fraction (LVEF), venous thromboembolisms (pulmonary embolism, deep vein thrombosis); uncommon – heart failure, congestive heart failure, left ventricular dysfunction; rare – QT interval prolongation, torsades de pointes.

From the urinary system common – chromaturia (change in urine color).

From the respiratory system very common – nosebleed; common – dyspnea, laryngopharyngeal pain.

From the endocrine system common – hypothyroidism, increased level of thyroid-stimulating hormone.

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

Post-marketing study results

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

From the hematopoietic organs: rare cases of thrombotic microangiopathy are reported. In such cases, it is recommended to temporarily suspend sunitinib; after resolution of symptoms, the drug may be resumed at the discretion of the attending physician.

From the respiratory organs: cases of pulmonary embolism, sometimes fatal, are reported.

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

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

Infections and infestations: cases of serious infections (with or without neutropenia) are reported, some of which were fatal.

From the musculoskeletal system there are reports of rare cases of myopathy and/or rhabdomyolysis with or without acute renal failure, with rare fatal cases. Most of these patients had baseline risk factors and/or were receiving concomitant therapy with drugs known to have such adverse reactions. There are reports of cases of fistula formation, sometimes associated with necrosis and/or tumor regression, some of which were fatal.

From the nervous system: there are reports of cases of taste disorders, including ageusia.

From the urinary system: there are reports of cases of renal impairment/renal failure, some of which were fatal. Cases of proteinuria and rare cases of nephrotic syndrome are reported.

From the cardiovascular system: cases of cardiomyopathy have been reported, some of which were fatal.

Contraindications

• Pregnancy;
• Lactation period (breastfeeding);
• Childhood (the efficacy and safety of the drug in children have not been established);
• Hypersensitivity to sunitinib or other components of the drug.

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 relevant heart diseases, bradycardia or electrolyte imbalances, as well as in renal or hepatic insufficiency.

Caution is required and the dose of sunitinib should be reduced when used concomitantly with strong inhibitors of CYP3A4 isoenzymes, which may increase the plasma concentration of sunitinib.

Use in Pregnancy and Lactation

Contraindicated use of Sutent^® during pregnancy and lactation (breastfeeding).

During therapy with Sutent^® and for at least three months after its discontinuation, reliable methods of contraception must be used.

Based on the results of preclinical studies, it can be concluded that sunitinib therapy may adversely affect fertility in men and women.

Use in Hepatic Impairment

Use the drug with caution in hepatic insufficiency.

Use in Renal Impairment

Use the drug with caution in renal insufficiency.

Pediatric Use

Contraindication: childhood (the efficacy and safety of the drug in children have not been established).

Geriatric Use

Elderly patients do not require dose adjustment.

Special Precautions

Treatment with Sutent^® should be carried out under the supervision of a physician experienced in working with antitumor drugs.

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

Reports have been received of cases of bleeding, sometimes fatal, including gastrointestinal bleeding, respiratory tract bleeding, tumor bleeding, urinary tract bleeding and cerebral hemorrhage. These events can occur unexpectedly, and in the case of tumor foci in the lungs, they can manifest as severe or life-threatening hemoptysis or pulmonary hemorrhage. Periodic medical examination and blood tests are necessary for early detection of the first signs of bleeding and 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 unknown whether patients who have experienced cardiovascular events within the last 12 months prior to sunitinib therapy initiation (including myocardial infarction, severe/unstable angina, coronary or peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, pulmonary embolism) are at a greater risk of developing left ventricular dysfunction associated with the use of Sutent^®. The risk-benefit ratio should be carefully evaluated when prescribing Sutent^® to this category of patients.

Patients should be periodically examined for clinical signs and symptoms of congestive heart failure during therapy with Sutent^®. It is recommended to assess LVEF before the initiation of therapy and periodically during treatment.

If clinical signs of congestive heart failure manifest, sunitinib treatment should be discontinued. In the absence of clinical signs of congestive heart failure, but with LVEF values <50% or a decrease of this indicator >20% compared to baseline (prior to therapy initiation), it is recommended to reduce the sunitinib dose or discontinue the drug.

At concentrations approximately twice the therapeutic levels, Sunitinib contributes to the prolongation of the QTcF interval (Fridericia’s correction). The clinical significance of this effect is unclear and depends on the specific patient’s risk factors and susceptibility. Sunitinib should be used with caution in patients with a history of QT interval prolongation, those taking antiarrhythmic drugs, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte imbalances. Caution is required and the dose of Sutent^® should be reduced when used concomitantly with strong CYP3A4 inhibitors, which may increase plasma sunitinib concentrations. ECG monitoring is recommended before starting therapy and during treatment with Sutent^®.

Patients should be examined for the occurrence of arterial hypertension using standard blood pressure monitoring methods. In patients with severe arterial hypertension that is not amenable to treatment, temporary discontinuation of Sutent^® therapy is recommended. Therapy is resumed once arterial hypertension is controlled.

Baseline laboratory testing of thyroid function is recommended in patients with hypothyroidism or hyperthyroidism. Treatment of patients with hypothyroidism should be conducted in accordance with standard medical practice before initiating 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 undergo laboratory monitoring.

Patients should be warned that a change in skin coloration may be observed during treatment with Sutent^® due to the presence of a dye (yellow) in the drug. Discoloration of hair or skin may also occur.

Since nausea and vomiting may occur with the use of Sutent^®, prophylactic administration of antiemetic drugs should be considered. Antidiarrheal agents should be prescribed if diarrhea occurs.

During treatment with Sutent^®, serum lipase and amylase activity should be checked periodically. Regular medical supervision is necessary if symptoms of pancreatitis are present or appear.

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 using standard methods, including blood pressure control. If these symptoms appear during therapy, temporary discontinuation of Sutent^® is recommended. After the symptoms resolve, treatment may be resumed at the discretion of the treating physician.

If thrombotic microangiopathy occurs, temporary discontinuation of sunitinib treatment is recommended. After the symptoms resolve, treatment may be resumed as recommended by the treating physician.

Baseline assessment of renal function is recommended before starting treatment, along with monitoring of renal function parameters during sunitinib therapy. The safety of sunitinib intake in patients with moderate or severe proteinuria has not been evaluated. Treatment with sunitinib should be discontinued in patients with nephrotic syndrome.

Use in pediatrics

The efficacy and safety of Sutent^® use in children have not been established.

Effect on the ability to drive vehicles and operate machinery

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 hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

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

Drug Interactions

Drugs that increase the plasma concentration of sunitinib

With the simultaneous use of a single dose of sunitinib with the CYP3A4 inhibitor ketoconazole, an increase in C_max and AUC of the sunitinib complex and its main active metabolite in healthy volunteers by 49% and 51%, respectively, is possible.

With the simultaneous use of Sutent^® with other CYP3A4 inhibitors (including ritonavir, itraconazole, erythromycin, clarithromycin, or grapefruit juice), an increase in sunitinib concentration is possible.

Concomitant use of Sutent^® with CYP3A4 inhibitors should be avoided, or an alternative drug with minimal CYP3A4 inhibitory potential 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 no less than 37.5 mg.

Drugs that decrease the plasma concentration of sunitinib

With the simultaneous use of a single dose of sunitinib with the CYP3A4 inducer rifampin, C_max and AUC in healthy volunteers decrease by 23% and 46%, respectively.

With the simultaneous use of Sutent^® with other CYP3A4 inducers (including dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital, or St. John’s wort), a decrease in sunitinib concentration is possible.

Concomitant use of Sutent^® with CYP3A4 inducers should be avoided, or an alternative drug with minimal CYP3A4 induction potential should be selected. If this is not possible, the sunitinib dose should be increased by 12.5 mg, monitoring the patient’s tolerance of the drug. In this case, the daily dose should not exceed 87.5 mg/day for gastrointestinal stromal tumors and metastatic renal cell carcinoma and up to 62.5 mg/day for pancreatic neuroendocrine tumors.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.