Sunitinib

Sunitinib malate (Sunitinib) 12.5 mg Capsules: Each capsule contains 12.5 mg of Sunitinib (as malate).

Sunitinib malate (Sunitinib) 25 mg Capsules: Each capsule contains 25 mg of Sunitinib (as malate).

Sunitinib malate (Sunitinib) 50 mg Capsules: Each capsule contains 50 mg of Sunitinib (as malate).

Sunitinib malate (Sunitinib), an oral multi-kinase inhibitor targeting several receptor tyrosine kinases (RTK), is the malate salt of Sunitinib. Sunitinib malate is described chemically as Butanedioic acid, hydroxy-, (2S)-, compound with N-[2-(diethylamino) ethyl]-5-[(Z)-(5-fluoro-1, 2-dihydro-2-oxo-3H-indol-3-ylidine) methyl]-2, 4-dimethyl-1H-pyrrole-3-carboxamide (1:1). The molecular formula is C₂₂H₂₇FN₄O₂·C₄H₆O₅ and the molecular weight is 532.6 Daltons.

Sunitinib malate is a yellow to orange powder with a pKa of 8.95. The solubility of Sunitinib malate in aqueous media over the range pH 1.2 to pH 6.8 is in excess of 25 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7 is 5.2.

Excipients/Inactive Ingredients: Mannitol, croscarmellose sodium, povidone and magnesium stearate.

Sunitinib is indicated for the treatment of gastrointestinal stromal tumor (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance.

Sunitinib is indicated for the treatment of treatment-naive advanced and/or metastatic renal cell carcinoma (MRCC).

Sunitinib is indicated for the treatment of unresectable or metastatic; well-differentiated pancreatic neuroendocrine tumors (pNET) with disease progression.

Sunitinib belongs to the group of medicines known as antineoplastics. It is used to treat a gastrointestinal stromal tumor (GIST) after a medicine called imatinib did not work very well. It may also be used when patients are not able to take imatinib. GIST is a group of cancer cells that start growing in the wall of the stomach, intestines, or rectum. Sunitinib is also used to treat advanced (late-stage) kidney cancer.

Sunitinib is also used to treat a type of pancreatic cancer called pancreatic neuroendocrine tumor (pNET), that cannot be surgically removed and is locally advanced or metastatic (cancer that has spread).

Sunitinib interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by Sunitinib, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like hair loss, may not be serious but may cause concern. Some effects may not occur for months or years after the medicine is used.

Before you begin treatment with Sunitinib, you and your doctor should talk about the benefits Sunitinib will do as well as the risks of using it.

Sunitinib is available only with your doctor's prescription.

For GIST and MRCC, the recommended dose of Sunitinib is 50 mg taken orally once daily for 4 consecutive weeks, followed by a 2-week off period (Schedule 4/2) to comprise a complete cycle of 6 weeks.

For pNET, the recommended dose of Sunitinib is 37.5 mg taken orally once daily without a scheduled rest period.

Dose Modifications: For GIST and MRCC, dose modifications in 12.5 mg increments or decrements may be applied based on individual safety and tolerability up to 75 mg or down to 25 mg.

For pNET, dose modification in 12.5 mg increments or decrements may be applied based on individual safety and tolerability. The maximum dose administered in the Phase 3 pNET study was 50 mg daily.

Dose interruptions may be required based on individual safety and tolerability.

CYP3A4 Inhibition/Induction: Co-administration of Sunitinib with strong CYP3A4 inducers, such as rifampin should be avoided. If this is not possible, the dose of Sunitinib may need to be increased in 12.5 mg increments to a maximum of 87.5 mg (GIST and RCC), or 62.5 mg (pNET) daily, based on careful monitoring of tolerability.

Co-administration of Sunitinib with strong CYP3A4 inhibitors, such as ketoconazole, should be avoided. If this is not possible, the dose of Sunitinib may need to be reduced in 12.5 mg decrements to a minimum of 37.5 mg (GIST and RCC), or 25 mg (pNET) daily.

Selection of an alternate concomitant medication with no, or minimal potential to induce or inhibit CYP3A4 is recommended.

Elderly: Dose adjustments are not required in elderly patients. Approximately 34% of the subjects in clinical studies of Sunitinib were 65 years of age or over. No significant differences in safety or efficacy were observed between younger and older patients.

Hepatic Insufficiency: No dose adjustment is necessary when administering Sunitinib to patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Sunitinib was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment.

Renal Insufficiency: No starting dose adjustment is required when administering Sunitinib to patients with renal impairment (mild-severe) or with end-stage renal disease (ESRD) on hemodialysis. Subsequent dose adjustments should be based on individual safety and tolerability.

Administration: Sunitinib may be taken with or without food.

If a dose is missed, the patient should not be given an additional dose. The patient should take the usual prescribed dose on the following day.

See also:
What is the most important information I should know about Sunitinib?

Do not use Sunitinib if you are pregnant. It could harm the unborn baby.

Before using Sunitinib, tell your doctor if you have liver or kidney disease, heart disease, high blood pressure, seizures, a bleeding or blood-clotting disorder, a thyroid or adrenal gland disorder, or if you have ever had a stroke, heart attack, congestive heart failure, a blood clot, or coronary artery disease.

If you need surgery or a dental procedure, tell the surgeon or dentist ahead of time that you are using Sunitinib. You may need to stop using the medicine for a short time.

To be sure this medication is helping your condition and not causing harmful effects, you will need medical tests at the beginning of each 4-week treatment cycle.

Stop using Sunitinib and call your doctor at once if you have chest pain, severe dizziness or fainting, fast or pounding heartbeats, swelling, feeling short of breath, sudden numbness or weakness, vision or speech problems, easy bruising or bleeding, blood in your urine or stools, coughing up blood, weight changes, tiredness, missed menstrual periods, upper stomach pain, dark urine, or jaundice (yellowing of the skin or eyes).

Tell your doctor about all other medicines you use.

Use Sunitinib as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Sunitinib comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Sunitinib refilled.
• Take Sunitinib by mouth with or without food.
• Swallow Sunitinib whole. Do not open the capsules. Do not break, crush, or chew before swallowing.
• Do not eat grapefruit or drink grapefruit juice while you take Sunitinib.
• If you miss a dose of Sunitinib, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once. Tell your health care provider about any missed dose.

Ask your health care provider any questions you may have about how to use Sunitinib.

Use: Labeled Indications

Gastrointestinal stromal tumor: Treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib

Pancreatic neuroendocrine tumors, advanced: Treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease

Renal cell carcinoma: Adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma (RCC) following nephrectomy; treatment of advanced RCC

Off Label Uses

Thyroid cancer

Data from two phase II studies supports the use of Sunitinib for the treatment of thyroid cancer. Additional studies may be necessary to further define the role of Sunitinib in some subtypes of this condition.

See also:
What other drugs will affect Sunitinib?

CYP3A4 Inhibitors

Strong CYP3A4 inhibitors such as ketoconazole may increase Sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. Concurrent administration of Sunitinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (Sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of Sunitinib in healthy volunteers. Co-administration of Sunitinib with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase Sunitinib concentrations. Grapefruit may also increase plasma concentrations of Sunitinib. A dose reduction for Sunitinib should be considered when it must be co-administered with strong CYP3A4 inhibitors.

CYP3A4 Inducers

CYP3A4 inducers such as rifampin may decrease Sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. Concurrent administration of Sunitinib with the strong CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (Sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of Sunitinib in healthy volunteers. Co-administration of Sunitinib with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's Wort) may decrease Sunitinib concentrations. St. John's Wort may decrease Sunitinib plasma concentrations unpredictably. Patients receiving Sunitinib should not take St. John's Wort concomitantly. A dose increase for Sunitinib should be considered when it must be co-administered with CYP3A4 inducers.

In Vitro Studies Of CYP Inhibition And Induction

In vitro studies indicated that Sunitinib does not induce or inhibit major CYP enzymes. The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that Sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.

See also:
What are the possible side effects of Sunitinib?

The data described below reflect exposure to Sunitinib in 660 patients who participated in the double-blind treatment phase of a placebo-controlled trial (n=202) for the treatment of GIST, an active-controlled trial (n=375) for the treatment of RCC or a placebo-controlled trial (n=83) for the treatment of pNET. The GIST and RCC patients received a starting oral dose of 50 mg daily on Schedule 4/2 in repeated cycles, and the pNET patients received a starting oral dose of 37.5 mg daily without scheduled off-treatment periods.

The most common adverse reactions ( ≥ 20%) in patients with GIST, RCC or pNET are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, and bleeding. The potentially serious adverse reactions of hepatotoxicity, left ventricular dysfunction, QT interval prolongation, hemorrhage, hypertension, thyroid dysfunction, and adrenal function are discussed in WARNINGS AND PRECAUTIONS. Other adverse reactions occurring in GIST, RCC and pNET studies are described below.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions In GIST Study A

Median duration of blinded study treatment was two cycles for patients on Sunitinib (mean 3.0, range 1-9) and one cycle (mean 1.8, range 1-6) for patients on placebo at the time of the interim analysis. Dose reductions occurred in 23 patients (11%) on Sunitinib and none on placebo. Dose interruptions occurred in 59 patients (29%) on Sunitinib and 31 patients (30%) on placebo. The rates of treatment-emergent, non-fatal adverse reactions resulting in permanent discontinuation were 7% and 6% in the Sunitinib and placebo groups, respectively.

Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 56% versus 51% of patients on Sunitinib versus placebo, respectively, in the double-blind treatment phase of the trial. Table 1 compares the incidence of common ( ≥ 10%) treatment-emergent adverse reactions for patients receiving Sunitinib and reported more commonly in patients receiving Sunitinib than in patients receiving placebo.

Table 1: Adverse Reactions Reported in Study A in at Least 10% of GIST Patients who Received Sunitinib in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo*

Venous Thromboembolic Events

Seven patients (3%) on Sunitinib and none on placebo in the double-blind treatment phase of GIST Study A experienced venous thromboembolic events; five of the seven were Grade 3 deep venous thrombosis (DVT), and two were Grade 1 or 2. Four of these seven GIST patients discontinued treatment following first observation of DVT.

Thirteen (3%) patients receiving Sunitinib for treatment-na