Pazopanib Tablets

Dosage Forms And Strengths

200-mg tablets of VOTRIENT - modified capsule-shaped, gray, film-coated with GS JT debossed on one side. Each tablet contains 216.7 mg of pazopanib hydrochloride equivalent to 200 mg of pazopanib.

Storage And Handling

The 200-mg tablets of VOTRIENT are modified capsule-shaped, gray, film-coated with GS JT debossed on one side and are available in:

Bottles of 120 tablets: NDC 0173-0804-09

Store at room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: May 2016

Included as part of the PRECAUTIONS section.

VOTRIENT®
(VO-tree-ent)
(pazopanib) Tablets

What is the most important information I should know about VOTRIENT?

• VOTRIENT can cause serious liver problems including death. Your healthcare provider will do blood tests to check your liver before you start and while you take VOTRIENT

Tell your healthcare provider right away if you get any of these signs of liver problems during treatment with VOTRIENT:

• yellowing of your skin or the whites of your eyes (jaundice)
• loss of appetite
• pain on the right side of your stomach area
• dark urine (abdomen)
• tiredness
• bruise easily
• nausea or vomiting

Your healthcare provider may need to prescribe a lower dose of VOTRIENT for you or tell you to stop taking VOTRIENT if you develop liver problems during treatment.

What is VOTRIENT?

VOTRIENT is a prescription medicine used to treat people with:

• advanced renal cell cancer (RCC)
• advanced soft tissue sarcoma (STS) who have received chemotherapy in the past

It is not known if VOTRIENT is effective in treating certain soft tissue sarcomas or certain gastrointestinal tumors.

It is not known if VOTRIENT is safe and effective in children under 18 years of age.

What should I tell my healthcare provider before taking VOTRIENT?

Before you take VOTRIENT, tell your healthcare provider if you:

• have or had liver problems. You may need a lower dose of VOTRIENT or your healthcare provider may prescribe a different medicine to treat your advanced renal cell cancer or advanced soft tissue sarcoma.
• have high blood pressure
• have heart problems or an irregular heartbeat including QT prolongation
• have a history of a stroke
• have headaches, seizures, or vision problems
• have coughed up blood in the last 6 months
• had bleeding of your stomach or intestines in the last 6 months
• have a history of a tear (perforation) in your stomach or intestine, or an abnormal connection between two parts of your gastrointestinal tract (fistula)
• have had blood clots in a vein or in the lung
• have thyroid problems
• had recent surgery (within the last 7 days) or are going to have surgery
• have any other medical conditions
• are pregnant or plan to become pregnant. VOTRIENT can harm your unborn baby. You should not become pregnant while you are taking VOTRIENT. You should use effective birth control during treatment with VOTRIENT and for 2 weeks after your last dose of VOTRIENT. Talk to your healthcare provider about types of birth control that may be right for you during this time.
• are breastfeeding or plan to breastfeed. It is not known if VOTRIENT passes into your breast milk. You and your healthcare provider should decide if you will take VOTRIENT or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. VOTRIENT may affect the way other medicines work and other medicines may affect how VOTRIENT works.

Especially, tell your healthcare provider if you:

• take medicines that can affect how your liver enzymes work such as:
• certain antibiotics (used to treat infections) depression
• certain medicines used to treat HIV beats
• certain medicines used to treat
• medicines used to treat irregular heart
• take a medicine that contains simvastatin to treat high cholesterol levels
• take medicines that reduce stomach acid (e.g., esomeprazole)
• drink grapefruit juice

Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take VOTRIENT?

• Take VOTRIENT exactly as your healthcare provider tells you. Your healthcare provider will tell you how much VOTRIENT to take.
• Your healthcare provider may change your dose.
• Take VOTRIENT on an empty stomach, at least 1 hour before or 2 hours after food.
• Do not crush VOTRIENT tablets.
• Do not eat grapefruit or drink grapefruit juice during treatment with VOTRIENT. Grapefruit products may increase the amount of VOTRIENT in your body.
• If you miss a dose, take it as soon as you remember. Do not take it if it is close (within 12 hours) to your next dose. Just take the next dose at your regular time. Do not take more than 1 dose of VOTRIENT at a time.
• Your healthcare provider will test your urine, blood, and heart before you start and while you take VOTRIENT.
• Tell your healthcare provider if you plan to have surgery while taking VOTRIENT. You will need to stop taking VOTRIENT at least 7 days before surgery because VOTRIENT may affect healing after surgery.

What are the possible side effects of VOTRIENT?

VOTRIENT may cause serious side effects including:

• See “What is the most important information I should know about VOTRIENT?”
• irregular or fast heartbeat or fainting
• heart failure. This is a condition where your heart does not pump as well as it should and may cause you to have shortness of breath.
• heart attack or stroke. Heart attack and stroke can happen with VOTRIENT and may cause death. Symptoms may include: chest pain or pressure, pain in your arms, back, neck or jaw, shortness of breath, numbness or weakness on one side of your body, trouble talking, headache, or dizziness.
• blood clots. Blood clots may form in a vein, especially in your legs (deep vein thrombosis or DVT). Pieces of a blood clot may travel to your lungs (pulmonary embolism). This may be life-threatening and cause death.
  Symptoms may include: new chest pain, trouble breathing or shortness of breath that starts suddenly, leg pain, and swelling of the arms and hands, or legs and feet, a cool or pale arm or leg.
• thrombotic microangiopathy (TMA) including thrombotic thrombocytopenia purpura (TTP) and hemolytic uremic syndrome (HUS). TMA is a condition involving blood clots that can happen while taking VOTRIENT. TMA is accompanied by a decrease in red blood cells and cells that are involved in clotting. TMA may harm organs such as the brain and kidneys.
• bleeding problems . These bleeding problems may be severe and cause death.  Symptoms may include: unusual bleeding, bruising, or wounds that do not heal.
• tear in your stomach or intestinal wall (perforation) or an abnormal connection between two parts of your gastrointestinal tract (fistula).
  Symptoms may include: pain, swelling in your stomach area, vomiting blood, and black sticky stools.
• lung problems . VOTRIENT may cause lung problems that may lead to death. Tell your healthcare provider right away if you get a cough that will not go away or shortness of breath.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS). RPLS is a condition that can happen while taking VOTRIENT that may cause death.
  Symptoms may include: headaches, seizures, lack of energy, confusion, high blood pressure, loss of speech, blindness or changes in vision, and problems thinking.
• high blood pressure. High blood pressure can happen with VOTRIENT, including a sudden and severe rise in blood pressure which may be life-threatening. These blood pressure increases usually happen in the first several months of treatment. Your blood pressure should be well controlled before you start taking VOTRIENT. Your healthcare provider should begin checking your blood pressure within 1 week of you starting VOTRIENT and often during treatment to make sure that your blood pressure is well controlled.
  Have someone call your healthcare provider or get medical help right away for you, if you get symptoms of a severe increase in blood pressure, including: severe chest pain, severe headache, blurred vision, confusion, nausea and vomiting, severe anxiety, shortness of breath, seizures, or you pass out (become unconscious).
• thyroid problems . Your healthcare provider should check you for this during treatment with VOTRIENT.
• protein in your urine. Your healthcare provider will check you for this problem. If there is too much protein in your urine, your healthcare provider may tell you to stop taking VOTRIENT.
• serious infections. Serious infections can happen with VOTRIENT and can cause death. Symptoms of an infection may include: fever, cold symptoms, such as runny nose or sore throat that do not go away, flu symptoms, such as cough, tiredness, and body aches; pain when urinating, cuts, scrapes, or wounds that are red, warm, swollen or painful.
• collapsed lung (pneumothorax). A collapsed lung can happen with VOTRIENT. Air may get trapped in the space between your lung and chest wall. This may cause you to have shortness of breath.

Call your healthcare provider right away if you have any of the symptoms listed above.

The most common side effects in people who take VOTRIENT include:

• diarrhea
• nausea or vomiting
• change in hair color
• loss of appetite

Other common side effects in people with advanced soft tissue sarcoma who take VOTRIENT include:

• feeling tired
• headache
• decreased weight
• taste changes
• tumor pain
• trouble breathing
• muscle or bone pain
• change in skin color

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of VOTRIENT. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I s tore VOTRIENT tablets ?

Store VOTRIENT at room temperature between 68°F and 77°F (20°C to 25°C).

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

General information about the safe and effective use of VOTRIENT.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VOTRIENT for a condition for which it was not prescribed. Do not give VOTRIENT to other people even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about VOTRIENT that is written for healthcare professionals. For more information, go to www.VOTRIENT.com or call 1-888-825-5249.

What are the ingredients in VOTRIENT?

Active ingredient: pazopanib.

Inactive ingredients :Tablet core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Gray film-coat: Hypromellose, iron oxide black, macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, titanium dioxide.

You should not use this medication if you are allergic to it, or if you have severe liver disease.

To make sure you can safely take pazopanib, tell your doctor if you have any of these other conditions:

• liver disease;
• heart disease, heart rhythm disorder;
• high blood pressure;
• a personal or family history of Long QT syndrome;
• a history of blood clot or stroke;
• a thyroid disorder;
• an ulcer or other stomach disorder;
• headaches, seizures, or vision problems;
• a head injury or bleeding in your brain within the past 6 months;
• stomach or intestinal bleeding within the past 6 months; or
• if you have had surgery within the past 7 days.

FDA pregnancy category D. Do not use pazopanib if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether pazopanib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using pazopanib.

Take the missed dose as soon as you remember. Skip the missed dose if your next dose is less than 12 hours away. Do not take extra medicine to make up the missed dose.

Clinical Trials Experience

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

Potentially serious adverse reactions with VOTRIENT included:

• Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
• QT prolongation and torsades de pointes [see WARNINGS AND PRECAUTIONS]
• Cardiac dysfunction [see WARNINGS AND PRECAUTIONS]
• Hemorrhagic events [see WARNINGS AND PRECAUTIONS]
• Arterial and venous thromboembolic events [see WARNINGS AND PRECAUTIONS]
• Thrombotic microangiopathy [see WARNINGS AND PRECAUTIONS]
• Gastrointestinal perforation and fistula [see WARNINGS AND PRECAUTIONS]
• Interstitial Lung Disease (ILD)/Pneumonitis [see WARNINGS AND PRECAUTIONS]
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see WARNINGS AND PRECAUTIONS]
• Hypertension [see WARNINGS AND PRECAUTIONS]
• Infection [see WARNINGS AND PRECAUTIONS]
• Increased toxicity with other cancer therapies [see WARNINGS AND PRECAUTIONS]

The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range: 0.1 to 27.6), the most commonly observed adverse reactions ( ≥ 20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting.

The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies]. The median duration of treatment was 7.4 months (range: 0 to 23) for patients who received VOTRIENT and 3.8 months (range: 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥ 10% of patients who received VOTRIENT.

Table 1: Adverse Reactions Occurring in ≥ 10% of Patients with RCC Who Received VOTRIENT

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in < 10% (any grade) were alopecia (8% versus < 1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus < 1%), dyspepsia (5% versus < 1%), dysphonia (4% versus < 1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus < 1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below:

Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms.

Table 2 presents the most common laboratory abnormalities occurring in > 10% of patients who received VOTRIENT and more commonly ( ≥ 5%) in patients who received VOTRIENT versus placebo.

Table 2: Selected Laboratory Abnormalities Occurring in > 10% of Patients with RCC Who Received VOTRIENT and More Commonly ( ≥ 5%) in Patients Who Received VOTRIENT versus Placebo

The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range: 0 to 53). The most commonly observed adverse reactions ( ≥ 20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea, and skin hypopigmentation.

The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies]. The median duration of treatment was 4.5 months (range: 0 to 24) for patients who received VOTRIENT and 1.9 months (range: 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 3 presents the most common adverse reactions occurring in ≥ 10% of patients who received VOTRIENT.

Table 3: Adverse Reactions Occurring in ≥ 10% of Patients with STS Who Received VOTRIENT

Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥ 5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus < 1%), chills (5% versus 1%), vision blurred (5% versus 2%), and nail disorder (5% versus 0%).

Table 4 presents the most common laboratory abnormalities occurring in > 10% of patients who received VOTRIENT and more commonly ( ≥ 5%) in patients who received VOTRIENT versus placebo.

Table 4: Selected Laboratory Abnormalities Occurring in > 10% of Patients with STS Who Received VOTRIENT and More Commonly ( ≥ 5%) in Patients Who Received VOTRIENT vers us Placebo

Diarrhea occurred frequently and was predominantly mild to moderate in severity in both the RCC and STS clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in < 1% (4/586) of patients.

Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm.

In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs ( < 60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared with < 1% (1/145) of patients treated with placebo. In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs ( < 60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with VOTRIENT compared with < 1% (1/123) of patients treated with placebo.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Eye Disorders: Retinal detachment/tear.

Gastrointestinal Disorders: Pancreatitis.

Read the entire FDA prescribing information for Votrient (Pazopanib Tablets)