Nexavar
Stivarga

STIVARGA INDICATIONS

STIVARGA is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy.

STIVARGA is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.

STIVARGA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

IMPORTANT SAFETY INFORMATION® (regorafenib) tablets

WARNING: HEPATOTOXICITY

  • Severe and sometimes fatal hepatotoxicity has occured in clinical trials.
  • Monitor hepatic function prior to and during treatment.
  • Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients across all clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury. In metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and in 0.4% of patients in the placebo arm. In gastrointestinal stromal tumor (GIST), fatal hepatic failure occurred in 0.8% of patients in the STIVARGA arm. In hepatocellular carcinoma (HCC), there was no increase in the incidence of fatal hepatic failure as compared to placebo.

Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis.

Infections: STIVARGA caused an increased risk of infections. The overall incidence of infection (Grades 1-5) was higher (32% vs 17%) in 1142 STIVARGA-treated patients as compared to the control arm in randomized placebo-controlled trials. The incidence of grade 3 or greater infections in STIVARGA treated patients was 9%. The most common infections were urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) and pneumonia (2.6%). Fatal outcomes caused by infection occurred more often in patients treated with STIVARGA (1.0%) as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% vs 0.2%). Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection.

Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with STIVARGA vs 9.5% with placebo in randomized, placebo-controlled trials. The incidence of grade 3 or greater hemorrhage in patients treated with STIVARGA was 3.0%. The incidence of fatal hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin.

Gastrointestinal Perforation or Fistula: Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials of STIVARGA administered as a single agent; this included eight fatal events. Gastrointestinal fistula occurred in 0.8% of patients treated with STIVARGA and in 0.2% of patients in the placebo arm across randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula.

Dermatological Toxicity: In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients with STIVARGA arm and 25.5% of patients in the placebo arm including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia syndrome (PPES) and severe rash, requiring dose modification. In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treated patients (53% vs 8%) than in the placebo-treated patients. Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% vs <1%), Grade 3 rash (3% vs <1%), serious adverse reactions of erythema multiforme (<0.1% vs 0%), and Stevens-Johnson syndrome (<0.1% vs 0%) were higher in STIVARGA-treated patients. Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3:18%). Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials of STIVARGA administered as a single agent. Withhold STIVARGA, reduce the dose, or permanently discontinue depending on the severity and persistence of dermatologic toxicity.

Hypertension: Hypertensive crisis occurred in 0.2% in STIVARGA-treated patients and in none of the patients in placebo arm across all randomized, placebo-controlled trials. STIVARGA caused an increased incidence of hypertension (30% vs 8% in mCRC, 59% vs 27% in GIST, and 31% vs 6% in HCC). The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in randomized, placebo controlled trials). Do not initiate STIVARGA until blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension.

Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% with STIVARGA vs 0.2% with placebo) in randomized placebo-controlled trials. Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristics finding on MRI, occurred in one of 4800 STIVARGA-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion, or altered mental function. Discontinue STIVARGA in patients who develop RPLS.

Wound Healing Complications: Treatment with STIVARGA should be stopped at least 2 weeks prior to scheduled surgery. Resuming treatment after surgery should be based on clinical judgment of adequate wound healing. STIVARGA should be discontinued in patients with wound dehiscence.

Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose.

Nursing Mothers: Because of the potential for serious adverse reactions in breastfed infants from STIVARGA, do not breastfeed during treatment with STIVARGA and for 2 weeks after the final dose.

Most Frequently Observed Adverse Drug Reactions in mCRC (≥30%): Most Frequently Observed Adverse Drug Reactions in mCRC (=30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), pain (59% vs 48%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%).

Most Frequently Observed Adverse Drug Reactions in GIST (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in GIST, respectively, were: HFSR/PPE (67% vs 12%), pain (60% vs 55%), hypertension (59% vs 27%), asthenia/fatigue (52% vs 39%), diarrhea (47% vs 9%), mucositis (40% vs 8%), dysphonia (39% vs 9%), infection (32% vs 5%), decreased appetite and food intake (31% vs 21%), and rash (30% vs 3%).

Most Frequently Observed Adverse Drug Reactions in HCC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in HCC, respectively, were: pain (55% vs 44%), HFSR/PPE (51% vs 7%), asthenia/fatigue (42% vs 33%), diarrhea (41% vs 15%), hypertension (31% vs 6%), infection (31% vs 18%), decreased appetite and food intake (31% vs 15%).

For Important risk and use information for STIVARGA, including the Boxed Warning, please see the full Prescribing Information.

What is NEXAVAR?

NEXAVAR is a prescription medicine used to treat:

  • a type of liver cancer called hepatocellular carcinoma (HCC) that cannot be removed by surgery
  • a type of kidney cancer called renal cell carcinoma (RCC)
  • a type of thyroid cancer called differentiated thyroid carcinoma (DTC) that can no longer be treated with radioactive iodine and is progressing

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

IMPORTANT SAFETY INFORMATION

Do not take NEXAVAR if you:

  • are allergic to sorafenib or any of the other ingredients in NEXAVAR.
  • have squamous cell lung cancer and receive carboplatin and paclitaxel.

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

  • have heart problems including a condition called “congenital long QT syndrome”
  • have chest pain
  • have abnormal magnesium, potassium, or calcium blood levels
  • have bleeding problems
  • have high blood pressure
  • plan to have any surgical procedures or have had recent surgery
  • are pregnant or plan to become pregnant. NEXAVAR may harm your unborn baby. Tell your healthcare provider right away if you become pregnant during treat- ment with NEXAVAR.

For females who are able to become pregnant:

  • Your healthcare provider should do a pregnancy test before you start treatment with NEXAVAR
  • Use effective birth control (contraception) during your treatment with NEXAVAR and for 6 months after the last dose of NEXAVAR.

For males with female partners who are able to become pregnant:

  • Use effective birth control (contraception) during your treatment with NEXAVAR and for 3 months after the last dose of NEXAVAR.
  • NEXAVAR may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you.
  • are breastfeeding or plan to breastfeed. It is not known if NEXAVAR passes into your breast milk. Do not breastfeed during treatment with NEXAVAR and for 2 weeks after receiving the last dose of NEXAVAR.

Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take the medicine warfarin.

What are the possible side effects of NEXAVAR?

NEXAVAR may cause serious side effects, including:

  • decreased blood flow to the heart, heart attack and heart failure. Get emergency help right away if you get symptoms such as chest pain, shortness of breath, racing heartbeat, swelling in lower legs, feet and abdomen, feel lightheaded or faint, tiredness, nausea, vomiting, or sweat a lot.
  • increased risk of bleeding. Bleeding is a common side effect of NEXAVAR that can be serious and can lead to death. Tell your healthcare provider right away if you have any signs of bleeding during treatment with NEXAVAR:
    • vomiting blood or if your vomit looks like coffeegrounds
    • pink or brown urine
    • red or black (looks like tar) stools
    • coughing up blood or blood clots
    • heavier than normal menstrual cycle
    • unusual vaginal bleeding
    • frequent nose bleeds
    • bruising
  • high blood pressure. High blood pressure is a common side effect of NEXAVAR and can be serious. Your blood pressure should be checked every week during the first 6 weeks of starting NEXAVAR. Your blood pressure should be checked regularly and any high blood pressure should be treated during treatment with NEXAVAR.
  • skin problems. A condition called hand-foot skin reactions and skin rash are common with NEXAVAR treatment and can be severe. NEXAVAR may also cause severe skin and mouth reactions that can be life threatening. Tell your healthcare provider if you have any of the following symptoms:
    • skin rash
    • pain or swelling
    • blistering and peeling of your skin
    • blistering and peeling on the inside of your mouth
    • blisters on the palms of your hand or soles of your feet
  • an opening in the wall of your stomach or intestines (gastrointestinal perforation). Tell your healthcare provider right away if you get fever, nausea, vomiting or severe stomach (abdominal) pain.
  • possible wound healing problems. If you need to have a surgical procedure, tell your healthcare provider that you are taking NEXAVAR. NEXAVAR may need to be stopped until your wound heals after some types of surgery
  • changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life threatening. Your health- care provider may do tests during your treatment with NEXAVAR to check the levels of potassium, magnesium, and calcium in your blood, and check the elec- trical activity of your heart with an electrocardiogram (ECG). Tell your healthcare provider right away if you feel faint, lightheaded, dizzy or feel your heart beating irregularly or fast during your treatment with NEXAVAR.
  • liver problems (drug-induced hepatitis). NEXAVAR may cause liver problems that may lead to liver failure and death. Your healthcare provider will do blood tests to check your liver function regularly during your treatment with NEXAVAR. Tell your healthcare provider right away if you develop any of the following symptoms:
    • yellowing of your skin or the whites of your eyes
    • dark “tea-colored” urine
    • light-colored bowel movements (stools)
    • worsening nausea or vomiting
    • pain on the right side of your stomach area
    • bleeding or bruising more easily than normal
    • loss of appetite
  • change in thyroid hormone levels. If you have differentiated thyroid cancer, you can have changes in your thyroid hormone levels during treatment with NEXAVAR. Your healthcare provider may need to change your dose of thyroid medicine during treatment with NEXAVAR. Your healthcare provider should check your thyroid hormone levels every month during treatment with NEXAVAR.

The most common side effects of NEXAVAR include:

  • diarrhea (frequent or loose bowel movements)
  • tiredness
  • infection
  • hair thinning or patchy hair loss
  • rash
  • weight loss
  • loss of appetite
  • nausea
  • stomach-area (abdomen) pain
  • low blood calcium levels in people with differentiated thyroid cancer

These are not all of the possible side effects of NEXAVAR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

For Important risk and use information for NEXAVAR, please see the full Prescribing Information.