(sunitinib malate)

Prescribing Information
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12 CLINICAL PHARMACOLOGY

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.

Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo.

12.2 Pharmacodynamics

Exposure-Response Relationship

Based on population pharmacokinetic/pharmacodynamic analyses, there were relationships between changes in different pharmacodynamic endpoints (i.e., safety and efficacy endpoints) over time and sunitinib plasma exposures.

Cardiac Electrophysiology

SUTENT can cause QT interval prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes [see Warnings and Precautions (5.3)].

12.3 Pharmacokinetics

The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in healthy subjects and in patients with solid tumors.

Sunitinib AUC and Cmax increase proportionately over a dose range of 25 mg to 100 mg (0.5 to 2 times the approved RDD of 50 mg). The pharmacokinetics were similar in healthy subjects and in patients with a solid tumor, including patients with GIST and RCC. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 63 to 101 ng/mL.

Absorption

Following oral administration of sunitinib, the time to maximum plasma concentration (Tmax) ranged from 6 to 12 hours.

Effect of Food

The administration of a single dose of SUTENT 50 mg with a high-fat, high-calorie meal (consisting of approximately 150 protein calories and 500 to 600 fat calories) in healthy subjects had no clinically significant effect on SUTENT or active metabolites exposure.

Distribution

The apparent volume of distribution (Vd/F) for sunitinib is 2230 L. Binding of sunitinib and its primary active metabolite to human plasma protein in vitro is 95% and 90%, respectively, with no concentration dependence in the range of 100 to 4000 ng/mL.

Elimination

Following administration of a single oral dose in healthy subjects, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. Sunitinib total oral clearance (CL/F) ranged from 34 to 62 L/h with an interpatient variability of 40%.

Metabolism

Sunitinib is metabolized primarily by CYP3A4 to its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23% to 37% of the total exposure. After a radiolabeled dose, sunitinib and its active metabolite were the major compounds identified in plasma, accounting for 92% of radioactivity.

Excretion

After a radiolabeled dose of sunitinib, approximately 61% of the dose was recovered in feces and 16% in urine.

Sunitinib and its primary active metabolite were the major compounds identified in urine and feces, representing 86% and 74% of radioactivity, respectively.

Specific Populations

No clinically significant differences in the pharmacokinetics of sunitinib or the primary active metabolite were observed based on age (18 to 84 years), body weight (34 to 168 kg), race (White, Black, or Asian), sex, Eastern Cooperative Oncology Group (ECOG) score, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

Patients with Renal Impairment

No clinically significant differences in the pharmacokinetics of sunitinib or its active metabolite were predicted or observed in patients with mild (CLcr 50 to 80 mL/min), moderate (CLcr 30 to <50 mL/min), or severe (CLcr <30 mL/min) renal impairment who are not on dialysis, compared to patients with normal renal function (CLcr >80 mL/min). Although sunitinib was not eliminated through hemodialysis, the sunitinib systemic exposure was 47% lower in patients with end stage renal disease (ESRD) on hemodialysis compared to patients with normal renal function.

Drug Interaction Studies

Clinical Studies

Effect of strong CYP3A4 inhibitors on sunitinib: Co-administration of a single SUTENT dose with ketoconazole (strong CYP3A4 inhibitor) increased the combined sunitinib and its active metabolite Cmax and AUC0–inf by 49% and 51%, respectively, in healthy subjects.

Effect of strong CYP3A4 inducers on sunitinib: Co-administration of a single SUTENT dose with rifampin (strong CYP3A4 inducer) reduced the combined sunitinib and its active metabolite Cmax and AUC0–inf by 23% and 46%, respectively in healthy subjects.

In Vitro Studies

In vitro studies in human hepatocytes and microsomes indicated that sunitinib and the primary active metabolite do not induce CYP1A2, CYP2E1, and CYP3A4/5, or inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 at clinically relevant concentrations.

Medication Guide

MEDICATION GUIDE

This Medication Guide has been approved by the U.S. Food and Drug Administration.     Revised: October 2025

MEDICATION GUIDE
SUTENT® (su TENT)
(sunitinib malate)
capsules

What is the most important information I should know about SUTENT?
SUTENT can cause serious side effects including:

•
Severe liver problems, that can lead to death. Tell your healthcare provider right away if you develop any of the following signs and symptoms of liver problems during treatment with SUTENT:
o
itching
o
yellow eyes or skin
o
dark urine
o
pain or discomfort in the right upper stomach area

Your healthcare provider should do blood tests to check your liver function before you start taking and during treatment with SUTENT. Your healthcare provider may temporarily stop, reduce your dose, or permanently stop treatment with SUTENT if you develop liver problems.
See “What are the possible side effects of SUTENT?” for more information about side effects.

What is SUTENT?
SUTENT is a prescription medicine used to treat:

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a rare cancer of the stomach, bowel, or esophagus called gastrointestinal stromal tumor (GIST) and when:
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you have taken the medicine imatinib mesylate and it did not stop the cancer from growing, or
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you cannot take imatinib mesylate.
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advanced kidney cancer (advanced renal cell carcinoma or RCC).
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adults with kidney cancer that has not spread (localized), and who are at high risk of RCC coming back again after having kidney surgery.
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a type of pancreatic cancer called pancreatic neuroendocrine tumors (pNET), that has progressed and cannot be treated with surgery.

It is not known if SUTENT is safe and effective in children.

Before taking SUTENT tell your healthcare provider about all of your medical conditions, including if you:

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have any heart problems
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have high blood pressure
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have thyroid problems
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have a history of low blood sugar or diabetes
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have kidney function problems (other than cancer)
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have liver problems
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have any bleeding problem
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plan to have surgery or have had a recent surgery. You should stop taking SUTENT at least 3 weeks before planned surgery. See "What are the possible side effects of SUTENT?"
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have seizures
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have or have had pain in the mouth, teeth or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth
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are pregnant or plan to become pregnant. SUTENT can harm your unborn baby.
Females who are able to become pregnant:
o
Your healthcare provider should do a pregnancy test before you start treatment with SUTENT.
o
You should use effective birth control (contraception) during treatment and for at least 4 weeks after your last dose of SUTENT.
o
Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with SUTENT.
 
Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment and for 7 weeks after your last dose of SUTENT.
SUTENT may cause fertility problems in males and females. Tell your healthcare provider if this is a concern for you.
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are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with SUTENT and for at least 4 weeks (1 month) after the last dose.

Tell all of your healthcare providers and dentists that you are taking SUTENT. They should talk to the healthcare provider who prescribed SUTENT for you, before you have any surgery, or medical or dental procedure.

Tell your healthcare provider about all the medicines you take, including prescription medicines and over-the-counter medicines, vitamins, and herbal supplements. Using SUTENT with certain other medicines can cause serious side effects.

You may have an increased risk of severe jawbone problems (osteonecrosis) if you take SUTENT and a bisphosphonate medicine. Especially tell your healthcare provider if you are taking or have taken an osteoporosis medicine.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take SUTENT?

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Take SUTENT exactly the way your healthcare provider tells you.
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Take SUTENT 1 time each day with or without food.
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If you take SUTENT for GIST or RCC, you will usually take your medicine for 4 weeks (28 days) and then stop for 2 weeks (14 days). This is 1 cycle of treatment. You will repeat this cycle for as long as your healthcare provider tells you to.
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If you take SUTENT for pNET, take it 1 time each day until your healthcare provider tells you to stop.
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Do not drink grapefruit juice or eat grapefruit during your treatment with SUTENT. They may cause you to have too much SUTENT in your body.
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Your healthcare provider may do blood tests before each cycle of treatment to check you for side effects.
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If you miss a dose of SUTENT by less than 12 hours, take the missed dose right away. If you miss a dose of SUTENT by more than 12 hours, just take your next dose at your regular time. Do not make up the missed dose. Tell your healthcare provider about any missed dose.
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Call your healthcare provider right away, if you take too much SUTENT.

What are possible side effects of SUTENT?
SUTENT may cause serious side effects, including:

•
See “What is the most important information I should know about SUTENT?”
•
Heart problems. Heart problems may include heart failure, heart attack and heart muscle problems (cardiomyopathy) that can lead to death. Tell your healthcare provider if you feel very tired, are short of breath, or have swollen feet and ankles.
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Abnormal heart rhythm changes. Changes in the electrical activity of your heart called QT prolongation can cause irregular heart beats that can be life threatening. Your healthcare provider may do electrocardiograms and blood tests (electrolytes) to watch for these problems during your treatment with SUTENT. Tell your healthcare provider right away if you feel dizzy, faint, or have abnormal heartbeats during your treatment with SUTENT
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you feel faint or lightheaded, or you pass out
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dizziness
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feel your heart beat is irregular or fast
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High blood pressure. High blood pressure is common with SUTENT and may sometimes be severe. Follow your healthcare provider’s instructions about having your blood pressure checked regularly. Call your healthcare provider if your blood pressure is high, or if you have any of the following signs or symptoms of high blood pressure:
o
severe headache
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lightheadedness
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dizziness
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change in vision

Your healthcare provider may prescribe medicine for you to treat high blood pressure, if needed.

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Bleeding problems. Bleeding is common with SUTENT, but SUTENT can also cause severe bleeding problems that can lead to death. Your healthcare provider will monitor you for bleeding and may do blood tests if needed. Call your healthcare provider right away if you have any of these symptoms or a serious bleeding problem during treatment with SUTENT, including:
o
painful, swollen stomach (abdomen)
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vomiting blood
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coughing up blood
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black, sticky stools
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bloody urine
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headache
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change in your mental status
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Serious stomach and intestinal problems, that can sometimes lead to death. Some people have had tears in their stomach or intestine (perforation), or have developed an abnormal opening between the stomach and intestine (fistula). Get medical help right away if you get stomach-area (abdominal) pain that does not go away or is severe during treatment with SUTENT.
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Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells and may lead to death. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS.
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Abnormal changes in the brain (Reversible Posterior Leukoencephalopathy Syndrome [RPLS]). RPLS can cause a collection of symptoms including headache, confusion, and vision loss. Some people who have taken SUTENT have developed RPLS that can lead to death.
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Thrombotic microangiopathy (TMA) including thrombotic thrombocytopenia purpura (TTP) and hemolytic uremic syndrome (HUS). TMA is a condition that involves injury to the smallest blood vessels, and blood clots that can happen while taking SUTENT. TMA is accompanied by a decrease in red cells and cells that are involved with clotting. TMA may harm your body’s organs such as the brain and kidneys, and can sometimes lead to death.
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Protein in your urine. Some people who have taken SUTENT have developed protein in their urine, and in some cases, kidney problems that can lead to death. Your healthcare provider will check you for this problem.
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Serious skin and mouth reactions. Treatment with SUTENT has caused severe skin reactions that can lead to death, including:
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severe rash with blisters or peeling of the skin.
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painful sores or ulcers on the skin, lips or inside the mouth.
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tissue damage (necrotizing fasciitis).
 
If you have any signs or symptoms of severe skin reactions, stop taking SUTENT and call your healthcare provider or get medical help right away.
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Thyroid problems. Your healthcare provider may do tests to check your thyroid function during SUTENT treatment. Tell your healthcare provider if you have any of the following signs and symptoms during your treatment with SUTENT:
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tiredness that gets worse and does not go away
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loss of appetite
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problems with heat
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feeling nervous or agitated, tremors
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sweating
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nausea or vomiting
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diarrhea
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fast heat rate
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weight gain or weight loss
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feeling depressed
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irregular menstrual periods or no menstrual periods
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headache
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hair loss
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Low blood sugar (hypoglycemia). Low blood sugar can happen with SUTENT, and may cause you to become unconscious, or you may need to be hospitalized. Low blood sugar with SUTENT may be worse in people who have diabetes and take antidiabetic medicines. Your healthcare provider should check your blood sugar levels regularly during treatment with SUTENT and may need to adjust the dose of your antidiabetic medicines. Call your healthcare provider right away if you have any of the following signs or symptoms of low blood sugar during your treatment with SUTENT:
o
headache
o
drowsiness
o
weakness
o
dizziness
o
confusion
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irritability
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hunger
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fast heart beat
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sweating
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feeling jittery
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Jawbone problems (osteonecrosis). Severe jawbone problems have happened in some people who take SUTENT. Certain risk factors such as taking a bisphosphonate medicine or having dental disease may increase your risk of getting osteonecrosis. Your healthcare provider may tell you to see your dentist before you start taking SUTENT. Your healthcare provider may tell you to avoid dental procedures, if possible, during your treatment with SUTENT, especially if you are receiving a bisphosphonate medicine into a vein (intravenous). Tell your healthcare provider if you plan to have any dental procedures before or during treatment with SUTENT.
o
You should stop taking SUTENT at least 3 weeks before planned dental procedures.
o
Your healthcare provider should tell you when you may start taking SUTENT again after dental procedures.
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Wound healing problems. Wound healing problems have happened in some people who take SUTENT. Tell your healthcare provider if you plan to have any surgery before or during treatment with SUTENT.
o
You should stop taking SUTENT at least 3 weeks before planned surgery.
o
Your healthcare provider should tell you when you may start taking SUTENT again after surgery.

Your healthcare provider may temporarily stop, reduce your dose, or permanently stop treatment with SUTENT if you develop serious side effects.

Common side effects of SUTENT include:

•
tiredness
•
weakness
•
diarrhea
•
pain, swelling or sores inside of your mouth
•
nausea
•
loss of appetite
•
indigestion
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vomiting
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stomach-area (abdominal) pain
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blisters or rash on the palms of your hands and soles of your feet
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high blood pressure
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taste changes
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low platelet counts

The medicine in SUTENT is yellow, and it may make your skin look yellow. Your skin and hair may get lighter in color. SUTENT may also cause other skin problems including: dryness, thickness or cracking of the skin.

These are not all of the possible side effects of SUTENT.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store SUTENT?

•
Store SUTENT at room temperature, between 68°F to 77°F (20°C to 25°C).

Keep SUTENT and all medicines out of the reach of children.

General information about the safe and effective use of SUTENT.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SUTENT for a condition for which it was not prescribed. Do not give SUTENT to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about SUTENT that is written for health professionals.

What are the ingredients in SUTENT?
Active ingredient: sunitinib malate
Inactive ingredients: mannitol, croscarmellose sodium, povidone (K-25), and magnesium stearate.
Orange gelatin capsule shells: titanium dioxide, and red iron oxide.
Caramel gelatin capsule shells: titanium dioxide, red iron oxide, yellow iron oxide, and black iron oxide.
Yellow gelatin capsule shells: titanium dioxide and yellow iron oxide.
White printing ink: shellac, propylene glycol, sodium hydroxide, povidone, and titanium dioxide.
Black printing ink: shellac, propylene glycol, potassium hydroxide and black iron oxide.

Logo

LAB-0361-13.0
For more information go to www.SUTENT.com or call 1-877-5-SUTENT.

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