Consumer medicine information

Stivarga

Regorafenib

BRAND INFORMATION

Brand name

Stivarga

Active ingredient

Regorafenib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Stivarga.

SUMMARY CMI

STIVARGA®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using STIVARGA?

STIVARGA contains the active ingredient regorafenib. STIVARGA is used for the treatment of colon, rectal or bowel cancer that has spread to other parts of the body, gastrointestinal stromal tumour (GIST) or liver cancer in patients who have been previously treated with other anticancer medicines.

For more information, see Section 1. Why am I using STIVARGA? in the full CMI.

2. What should I know before I use STIVARGA?

Do not use if you have ever had an allergic reaction to STIVARGA or any of the ingredients listed at the end of the CMI.

Tell your doctor if you have conditions affecting your liver, skin, stomach, bowel or heart, if you have bleeding disorders or taking medicines to thin the blood or if you recently had or are going to have a surgical procedure.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use STIVARGA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with STIVARGA and affect how it works.

The most common types of medicines that affect the effectiveness of STIVARGA include antibiotics, antifungals, anti-seizure (antiepileptics), cholesterol lowering medicines, methotrexate and warfarin.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use STIVARGA?

Swallow whole four STIVARGA tablets with a glass of water at the same time each day after a low-fat meal.

More instructions can be found in Section 4. How do I use STIVARGA? in the full CMI.

5. What should I know while using STIVARGA?

Things you should doRemind any doctor, dentist or pharmacist you visit that you are using STIVARGA.
Tell your doctor that you are using STIVARGA before any blood tests or surgical procedures.
Things you should not doDo not stop taking your medicine or change the dosage without checking with your doctor.
Looking after your medicineStore it in a cool dry place away from moisture, heat or sunlight where the temperature stays below 25°C.
Discard medicine 28 days after opening the bottle

For more information, see Section 5. What should I know while using STIVARGA? in the full CMI.

6. Are there any side effects?

Less serious side effects include nausea, diarrhoea, headache, fatigue, decreased appetite, dry mouth, tremor, muscle spasm

Serious side effects that require immediate medical attention includes skin reactions (rash, blisters, pain, swelling, itching or peeling of skin), blood in the stools, urine, coughing or vomiting up blood, frequent nose bleeds, signs of liver damage (yellow discoloration of skin and whites of eyes, dark urine, disorientation), severe stomach pain or signs of infection.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI

WARNING: Liver Problems

STIVARGA can cause liver problems which can be serious and in rare cases lead to death. Your doctor will check your liver function before you start taking STIVARGA and monitor your liver function during treatment. Your doctor may need to change your dose or advise you to stop taking STIVARGA. Please see under section SIDE EFFECTS the possible signs of severe liver injury.



FULL CMI

STIVARGA® (Sti-VAR-gah)

Active ingredient(s): [regorafenib]

Consumer Medicine Information (CMI)

This leaflet provides important information about using STIVARGA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using STIVARGA.

Where to find information in this leaflet:

1. Why am I using STIVARGA?
2. What should I know before I use STIVARGA?
3. What if I am taking other medicines?
4. How do I use STIVARGA?
5. What should I know while using STIVARGA?
6. Are there any side effects?
7. Product details

1. Why am I using STIVARGA?

STIVARGA contains the active ingredient regorafenib. STIVARGA is an antineoplastic (anticancer) agent, it is used to treat cancer by slowing down the growth and spread of cancer cells. It cuts off the blood supply that keeps cancer cells growing

STIVARGA is used to treat:

  • colon, rectal or bowel cancer that has spread to other parts of the body in patients who have previously received other treatments,
  • gastrointestinal stromal tumour (GIST) in patients who have previously received other treatments
  • or liver cancer in patients who have previously been treated with other anticancer medicines.

GIST is a cancer of the stomach and bowel. It is caused by the uncontrolled cells in the wall of the stomach or bowel.

2. What should I know before I use STIVARGA?

Warnings

Do not use STIVARGA if:

  • you are allergic to regorafenib, the active ingredient in STIVARGA or any of the ingredients listed at the end of this leaflet.
  • you are pregnant or think you might be pregnant

Check with your doctor if you:

  • Have liver problems including Gilbert's syndrome.
    Treatment with STIVARGA may lead to a higher risk of liver problems and will require blood tests to monitor how your liver is working.
  • Have or get an infection with signs such as high fever, severe cough, severe sore throat, shortness of breath, burning / pain when urinating, unusual vaginal discharge or irritation, redness, swelling and/or pain in any part of the body. Your doctor may temporarily stop your treatment.
  • Have any bleeding problems and you are taking warfarin or another medicine that thins the blood to prevent blood clots. Treatment with STIVARGA may lead to a higher risk of bleeding. Your doctor may conduct blood tests before starting you on STIVARGA
  • Have chest pain or any heart problems. Increased heart problems are reported more often in patients over 75 years old. Before starting STIVARGA and during treatment your doctor will check how well your heart is working.
  • Have or had a history of high blood pressure and / or aneurysm. STIVARGA can increase your blood pressure. Your doctor will monitor your blood pressure before and during treatment.
  • Develop a severe and persistent headache, visual disturbances, seizures or altered mental status.
  • Are going to or recently had surgery. STIVARGA might affect the way your wounds heal. Your doctor may stop STIVARGA temporarily before surgery and until your wound has healed.
  • Have severe stomach and bowel problems. Your doctor may decide to discontinue treatment.
  • Have skin problems. STIVARGA can cause redness, pain, swelling or blisters on the palms of your hands or soles of the feet which may require treatment with creams and shoe cushions. Your doctor may change the dose or stop STIVARGA until your condition improves

Before you use STIVARGA tell your doctor if any of these conditions apply to you. You may need treatment for them, or extra tests may be done.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

  • Avoid becoming pregnant while taking STIVARGA, as this may harm your unborn baby. You doctor will advise about using contraception during treatment and for at least eight weeks after treatment if you are of childbearing age.
  • Tell your doctor immediately if you are pregnant or intend to become pregnant during treatment with STIGVARGA.
  • STIGVARGA should not be used during pregnancy unless necessary. Your doctor will discuss the potential risk of taking STIVARGA during pregnancy.
  • STIVARGA may reduce fertility in both men and women. Your doctor will advise you of your options prior to starting treatment.
  • Do not breast-feed while taking STIVARGA. Talk to your doctor if you are breastfeeding or intend to breastfeed. This medicine may interfere with the growth and development of your baby

Children and Adolescents

Do not give this medicine to children and adolescents. Safety and effectiveness in children and adolescents have not been established.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and STIVARGA may interfere with each other. These include:

AntibioticsRifampicin, neomycin
AntifungalsKetoconazole, itraconazole, Posaconazole, voriconazole
Anti-seizure medicines
(Anti-epileptics)		carbamazepine, primidone, phenytoin, phenobarbitone
Cholesterol lowering medicationRosuvastatin, atorvastatin, Fluvastatin
Other medicationsWarfarin, Methotrexate, St John's Wort

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect STIVARGA.

4. How do I use STIVARGA?

How much to take

Always take STIVARGA exactly as your doctor has told you to. Check with your doctor or pharmacist if you are not sure

  • The recommended daily dose of STIVARGA is four (40 mg tablets) daily. This is equivalent to 160 mg total daily dose.
  • Your doctor will usually prescribe STIVARGA for three weeks and then stop for one week. This three week on, one week off treatment period is one cycle of treatment.
  • Your doctor may change your dose. Take the dose of STIVARGA that your doctor prescribes for you.
  • Follow the instructions provided and use STIVARGA until your doctor tells you to stop.

How to take

  • Take four STIVARGA tablets at the same time each day after a low-fat meal (ideally at breakfast).
    A low-fat meal contains less than 30% fat. Example of a low-fat meal can include one cup of cereal, 250 mL or one glass of skimmed milk, one slice of toast with jam, apple juice and one cup of coffee or tea.

Swallow the tablets whole with a glass of water.

Do not drink grapefruit juice while taking STIVARGA.

If you forget to use STIVARGA

If you miss a dose, take it as soon as you remember.

Do not take two doses of STIVARGA on the same day to make up for a missed dose from the previous day.

Tell your doctor about any missed dose.

If you use too much STIVARGA

If you think that you have used too much STIVARGA you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

If you take too much STIVARGA it may make the side effects more severe, especially skin reactions (rash, blisters, redness, pain, swelling, itching or peeling of your skin), dysphonia (voice changes or hoarseness), diarrhoea (frequent or loose bowel movements), mucosal inflammation (mouth sores), dry mouth, decreased appetite, hypertension (high blood pressure) and fatigue (excessive tiredness).

5. What should I know while using STIVARGA?

Things you should do

  • Tell all doctors, dentists and pharmacists who treat you that you are taking STIVARGA.
  • Tell your doctor immediately if you become pregnant during treatment with STIVARGA, or plan to become pregnant.
  • Tell your doctor if you are breast-feeding while being treated with STIVARGA.
  • If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.
  • Tell your doctor if you are planning to have surgery or you have a wound that is not healing properly.

Things you should not do

  • Do not stop taking your medicine or change the dosage without checking with your doctor
  • Do not take STIVARGA to treat any other conditions, unless your doctor tells you to
  • Do not give your medicine to anyone else

Driving or using machines

Be careful before you drive or use any machines or tools until you know how STIVARGA affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Keep your tablets in the bottle until it is time to take them. If you take the tablets out of the bottle they may not keep well. Do not remove the desiccant from the bottle.

Store it in a cool dry place away from moisture, heat or sunlight where the temperature says below 25°C

Do NOT store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

Once the bottle is opened the medicine is to be discarded after 28 days

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal System Related
  • diarrhoea
  • painful or dry mouth, painful tongue, mouth sores
  • decreased appetite and food intake
  • nausea, vomiting
  • heartburn
  • stomach pain
  • infection or irritation of the stomach and intestine
  • changes in your voice or hoarseness
  • weight loss
  • changes in taste
Hair, Skin and Nails
  • hand-foot skin reactions (redness, pain, blisters and swelling of the palms of the hands or soles of the feet)
  • dry skin
  • hair loss (alopecia)
  • changes to the nail such as ridges and/or splitting
  • rash or rash with flaking or peeling of skin
Muscle related
  • muscle spasm
Nervous system related
  • loss of balance
  • tremor (shaking)
  • headache
  • impaired ability to feel
  • dizziness
Bleeding related
  • bruise easily
  • bleeding e.g. nosebleed
General
  • weakness, lack of strength and energy, excessive tiredness and unusual sleepiness
  • infection
  • ringing in your ears
  • pain
  • fever
Speak to your doctor if you have any of these less serious side effects and they worry you.
These are the more common side effects, other side effects not listed may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

These test results include:What to do
Blood Test Abnormalities
  • high blood pressure
  • hyperbilirubinemia (an increase in bilirubin, a substance produced by the liver)
  • decreased activity of the thyroid gland
  • anaemia (tiredness, pale skin)
Your doctor will tell you if there are any changes in your blood test that might need treatment.

Serious side effects

Serious side effectsWhat to do
Decreased blood flow to the heart or heart attack
  • Chest pain or discomfort which may spread beyond your chest to your shoulders, arms, back, neck, teeth, jaw or stomach and may come and go
  • Shortness of breath
  • Sudden outbreak of a cold sweat with clammy skin
  • Lightheaded or feeling faint
  • Nausea or vomiting
  • Heartburn.
Condition affecting brain function (posterior reversible encephalopathy syndrome)
  • Headache, confusion, seizures, loss of orientation and visual loss associated with or without high blood pressure
Severely elevated blood pressure (hypertensive crisis)
  • Severely elevated blood pressure causing headache, confusion, blurry vision, nausea, vomiting and fits
Liver injury
  • yellowish discoloration of the skin and the whites of the eyes
  • dark urine
  • excessive tiredness and unusual sleepiness
  • nausea or vomiting or loss of appetite
  • confusion and/or disorientation
  • bruise easily
  • pain on the right side of your stomach.
Call your doctor straight away, or go straight to the >Emergency Department at your nearest hospital if you notice any of these serious side effects.
Serious side effectsWhat to do
Bleeding from the digestive system
  • Passing blood in the stools or passing black stools
  • Passing blood in the urine
  • Stomach pain
  • Coughing / vomiting up blood.
Bowel perforation or fistula (severe stomach problems)
  • Diarrhoea
  • Dehydration
  • Severe pain in your stomach
  • Red or black stools
  • Fever
  • Chills
  • Nausea or vomiting
Severe skin reactions
  • Painful blisters and fever including detachment of the skin.
  • Multiple skin eruptions
  • Certain skin cancers.
Infection
  • High fever
  • Severe cough with or without an increase in mucus (sputum) production,
  • Severe sore throat
  • Shortness of breath
  • Burning / pain when urinating,
  • Unusual vaginal discharge or irritation
  • Redness, swelling and/or pain in any part of the body
Inflammation of the pancreas
  • pain in the stomach, nausea, vomiting and fever
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What STIVARGA contains

Active ingredient
(main ingredient)		40 mg regorafenib (as monohydrate)
Other ingredients
(inactive ingredients)		microcrystalline cellulose
croscarmellose sodium magnesium stearate povidone
silica colloidal anhydrous
iron oxide red iron oxide yellow lecithin
macrogol 3350
polyvinyl alcohol purified talc titanium dioxide.

Do not take this medicine if you are allergic to any of these ingredients.

What STIVARGA looks like

STIVARGA is available in 28, 28 (starter pack) or 3 x 28 tablet bottles.

The tablets are light pink, oval embossed with ‘BAYER’ on one side and ‘40’ on the other side.

(AUST R 200553)

Who distributes STIVARGA?

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

® Registered Trademark of Bayer group, Germany.
© Bayer Australia Ltd
All rights reserved.

This leaflet was prepared in 04 July 2023

Published by MIMS September 2023

BRAND INFORMATION

Brand name

Stivarga

Active ingredient

Regorafenib

Schedule

S4

 

1 Name of Medicine

Regorafenib.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 40 mg regorafenib (as 41.49 mg regorafenib monohydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Light pink, oval tablets marked with 'BAYER' on one side and '40' on the other side.

4 Clinical Particulars

4.1 Therapeutic 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 unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib.
Stivarga is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

4.2 Dose and Method of Administration

Method of administration.

For oral use.

Dosage regimen.

Take four Stivarga (40 mg) tablets daily at the same time each day for three weeks on therapy (21 days) followed by one week off therapy (7 days) to comprise a cycle of four weeks (28 days) (see Section 5.2 Pharmacokinetic Properties, Absorption). The tablets should be swallowed whole with water after a low fat meal (ideally at breakfast) that contains less than 30% fat. Example of a low fat meal include one cup of cereal, 250 mL or one glass of skimmed milk, one slice of toast with jam, apple juice and one cup of coffee or tea (520 calories, 2 g fat, 17 g protein, 93 g of carbohydrate).
The recommended daily dose is 160 mg and contains 2.427 mmol (equivalent to 55.8 mg) of sodium per daily dose.
If a dose of Stivarga is missed, then it should be taken on the same day as soon as the patient remembers. The patient should not take two doses on the same day to make up for a missed dose.
Treatment should continue as long as benefit is observed or until unacceptable toxicity occurs (see Section 4.4 Special Warnings and Precautions for Use).

Dose modification/ discontinuations.

Dose interruptions and/or dose reductions or dose discontinuations may be required based on individual safety and tolerability. Dose modifications are to be applied in 40 mg (one tablet) steps. The lowest recommended daily dose is 80 mg. The maximum daily dose is 160 mg.

Discontinue Stivarga permanently for (see Section 4.4 Special Warnings and Precautions for Use).

Severe and persistent hepatotoxicity; severe or life threatening haemorrhage; severe and persistent HFSR; hypertensive crisis; RPLS; gastrointestinal perforation or fistula; development of new or acute onset cardiac ischaemia and/or infarction if not resolved after interruption; wound dehiscence; significant biochemical and metabolic abnormalities; failure to tolerate 80 mg dose; for any grade 4 adverse reaction, only resume if the potential benefit outweighs the risks.

Interrupt Stivarga for the following.

Symptomatic grade 2 hypertension; any grade 3 or 4 adverse reaction; surgical procedures; development of new or acute onset cardiac ischaemia and/or infarction.

Reduce the dose of Stivarga to 120 mg.

After recovery of any grade 3 or 4 adverse reaction.

Reduce the dose of Stivarga to 80 mg.

After recovery of any grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity).
For recommended dose modifications and measures in case of hand foot skin reaction (HFSR/ palmar plantar erythrodysesthesia syndrome (PPE)), see Table 1.
For recommended measures and dose modifications in case of worsening of liver function tests considered related to treatment with Stivarga, see Table 2 (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric use.

The safety and efficacy of Stivarga in children and adolescents below 18 years of age have not been established. Regorafenib treatment to juvenile animals resulted in delayed development and other adverse effects (see Section 5.3 Preclinical Safety Data, Systemic toxicity).

Use in the elderly.

See Section 4.4 Special Warnings and Precautions for Use.

Patients with hepatic impairment.

See Section 4.4 Special Warnings and Precautions for Use.

Patients with renal impairment.

See Section 4.4 Special Warnings and Precautions for Use.

4.3 Contraindications

Hypersensitivity to any of the ingredients contained in Stivarga.

4.4 Special Warnings and Precautions for Use

Hepatotoxicity.

Severe drug induced liver injury with fatal outcome has been observed in patients receiving Stivarga. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration.
Abnormalities of liver function tests (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) have been frequently observed in patients treated with Stivarga. Severe liver function test abnormalities (grade 3 to 4) and hepatic dysfunction with clinical manifestations (including fatal outcomes) have been reported in a small proportion of patients (see Section 4.8 Adverse Effects (Undesirable Effects)).
It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of treatment with Stivarga and monitor closely (at least every two weeks) during the first two months of treatment. Thereafter, periodic monitoring should be continued at least monthly and as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline.
Regorafenib is a uridine diphosphate glucuronosyl transferase UGT1A1 inhibitor (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert's syndrome.
For patients with observed worsening of liver function tests considered related to treatment with Stivarga (i.e. where no alternative cause is evident, such as posthepatic cholestasis or disease progression), the dose modification and monitoring advice should be followed. This is outlined in Table 2, Recommended measures and dose modifications in case of drug related liver function tests abnormalities (see Section 4.2 Dose and Method of Administration, Dose modification/discontinuations).

Infections.

Stivarga has been associated with an increased incidence of infection events, some of which were fatal (see Section 4.8 Adverse Effects (Undesirable Effects)).
In cases of worsening infection events, interruption of Stivarga treatment should be considered.

Haemorrhage.

Stivarga has been associated with an increased incidence of haemorrhagic events, some of which were fatal (see Section 4.8 Adverse Effects (Undesirable Effects)). Fatal haemorrhage was observed in patients treated with Stivarga and involved the respiratory, gastrointestinal, or genitourinary tracts.
Blood counts and coagulation parameters should be monitored in patients with conditions that predispose to bleeding, and in those treated with anticoagulants (e.g. warfarin) or other concomitant medicinal products that increase the risk of bleeding. International normalised ratio (INR) values are to be more frequently monitored in patients receiving warfarin.
Permanently discontinue Stivarga in patients with severe or life threatening haemorrhage.

Gastrointestinal perforation and fistula.

Gastrointestinal perforation (including fatal outcomes) and fistula have been reported in patients treated with Stivarga (see Section 4.8 Adverse Effects (Undesirable Effects)). These events are also known to be common disease-related complications in patients with intra-abdominal malignancies. Permanent discontinuation of Stivarga is recommended in patients developing gastrointestinal perforation or fistula. The safety of re-initiating Stivarga therapy following gastrointestinal perforation or fistula is not known.

Cardiac ischaemia and infarction.

Stivarga has been associated with an increased incidence of myocardial ischaemia and infarction (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients with a history of ischaemic heart disease should be monitored for clinical signs and symptoms of myocardial ischaemia. In patients who develop new or acute onset cardiac ischaemia and/or infarction, interruption of Stivarga is recommended until resolution. The decision to reinitiate treatment with Stivarga should be based on careful consideration of the potential benefits and risks of the individual patient. Stivarga should be permanently discontinued if there is no resolution.
No differences were observed between Stivarga and placebo in the incidence of clinically relevant cardiac arrhythmias or heart failure.

Reversible posterior leukoencephalopathy syndrome.

Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in association with Stivarga treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).
Signs and symptoms of RPLS include seizures, headache, altered mental status, visual disturbance or cortical blindness, with or without associated hypertension. A diagnosis of RPLS requires confirmation by brain imaging. In patients developing RPLS, discontinuation of Stivarga, along with control of hypertension and supportive medical management of other symptoms is recommended.
The safety of reinitiating Stivarga therapy in patients having previously experienced RPLS is not known.

Arterial hypertension.

Stivarga has been associated with an increased incidence of arterial hypertension (see Section 4.8 Adverse Effects (Undesirable Effects)). The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension.
Hypertensive crisis was observed in patients treated with Stivarga.
Do not initiate Stivarga unless 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 (see Section 4.2 Dose and Method of Administration, Dose modification/ discontinuations). In case of hypertensive crisis, Stivarga should be discontinued.

Aneurysms and artery dissections.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/ or artery dissections. Before initiating regorafenib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Wound healing complications.

No formal studies of the effect of Stivarga on wound healing have been conducted. However, medicines with antiangiogenic properties may suppress or interfere with wound healing; treatment with regorafenib should be stopped at least 2 weeks prior to scheduled surgery. The decision to resume treatment after surgery should be based on clinical judgement of adequate wound healing.
Stivarga should be discontinued in patients with wound dehiscence.

Dermatological toxicity.

Hand foot skin reaction (HFSR)/ palmar plantar erythrodysaesthesia syndrome (PPE) and rash represent the most frequently observed dermatological adverse drug reactions with Stivarga (see Section 4.8 Adverse Effects (Undesirable Effects)).
Measures for the prevention of HFSR include control of calluses and use of shoe cushions and gloves to prevent pressure stress to soles and palms.
Management of HFSR may include the use of keratolytic creams (e.g. urea, salicylic acid, or alpha hydroxyl acid based creams applied sparingly only on affected areas), and moisturising creams (applied liberally) for symptomatic relief.
Stevens-Johnson syndrome and toxic epidermal necrolysis were rarely observed in patients treated with Stivarga.
Dose reduction and/or temporary interruption of Stivarga, or in severe or persistent cases, permanent discontinuation of Stivarga should be considered (see Section 4.2 Dose and Method of Administration, Dose modification/ discontinuations).

Use in hepatic impairment.

Regorafenib is eliminated mainly via the hepatic route.
In clinical studies, no relevant differences in safety or efficacy were observed between patients with mild hepatic impairment (Child-Pugh A) and normal hepatic function. No dose adjustment is required in patients with mild hepatic impairment.
Since limited data is available in patients with moderate hepatic impairment (Child-Pugh B), no dose recommendation can be provided. Close monitoring of overall safety is recommended in these patients.
Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Stivarga has not been studied in this population.

Use in renal impairment.

Available clinical data indicate similar exposure of regorafenib and its metabolites M-2 and M-5 in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. No dose adjustment is required in patients with mild, moderate or severe renal impairment (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

In clinical studies, cardiac disorder events (all grades) have been more often (20.5% vs. 10.4%) reported in Stivarga treated patients aged 75 years or older (N = 78) compared to Stivarga treated patients below 75 years (N = 995).

Paediatric use.

The safety and efficacy of Stivarga in children and adolescents below 18 years of age have not been established. Regorafenib treatment to juvenile animals resulted in delayed development and other adverse effects (see Section 5.3 Preclinical Safety Data, Systemic toxicity).

Effects on laboratory tests.

Biochemical and metabolic laboratory test abnormalities.

Stivarga has been associated with an increased incidence of electrolyte abnormalities (including hypophosphatemia, hypocalcaemia, hyponatremia and hypokalaemia) and metabolic abnormalities (including increases in thyroid stimulating hormone, lipase and amylase).
The abnormalities are generally mild to moderate severity, not associated with clinical manifestations, and do not usually require dose interruptions or reductions. It is recommended to monitor biochemical and metabolic parameters during Stivarga treatment and to institute appropriate replacement therapy according to standard clinical practice if required.
Dose interruption or reduction, or permanent discontinuation of Stivarga should be considered in case of persistent or recurrent significant abnormalities (see Section 4.2 Dose and Method of Administration, Dose modification/ discontinuations).

Effect of race.

No relevant differences in exposure or efficacy have been seen between Asian and Caucasian subjects in clinical trials, and no dose adjustment based on race is necessary. However, a higher incidence of HFSR, severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Stivarga as compared with Caucasians.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Inhibitors/ inducers of CYP3A4.

In vitro data indicate that regorafenib is metabolised largely by the cytochrome CYP3A4 and the uridine diphosphate glucuronosyl transferase UGT1A9.
Administration of ketoconazole (400 mg for 18 days), a strong CYP3A4 inhibitor, with a single dose of regorafenib (160 mg on day 5) resulted in an increase in mean exposure (AUC) of regorafenib of approximately 33%, and a decrease in mean exposure of the active metabolites, M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), of approximately 90%.
It is recommended to avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole and voriconazole) as their influence on the steady-state exposure of regorafenib and its metabolites (M-2 and M-5) has not been studied.
Administration of rifampicin (600 mg for 9 days), a strong CYP3A4 inducer, with a single dose of regorafenib (160 mg on day 7) resulted in a reduction in mean exposure (AUC) of regorafenib of approximately 50%, a 3 to 4-fold increase in mean exposure of the active metabolite M-5, and no change in exposure of active metabolite M-2.
Other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital, rifabutin, dexamethasone and St. John's wort) may also increase metabolism of regorafenib. Since a reduction in plasma regorafenib concentrations may result in decreased efficacy, strong inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.

UGT1A1 and UGT1A9 substrates.

In vitro data indicate that regorafenib and its active metabolite M-2 inhibit glucuronidation mediated by uridine diphosphate glucuronosyl transferases UGT1A1 and UGT1A9, and the active metabolite M-5 inhibits UGT1A1 at concentrations which are achieved in vivo at steady state.
Administration of regorafenib with a 5 day break prior to administration of irinotecan resulted in an increase of approximately 44% in mean exposure (AUC) of SN-38, a substrate of UGT1A1 and an active metabolite of irinotecan. An increase in AUC of irinotecan of approximately 28% was also observed. This indicates that coadministration of regorafenib may increase systemic exposure to UGT1A1 and UGT1A9 substrates. The clinical significance of these findings is unknown.

Inhibitors/ inducers of P-glycoprotein and breast cancer resistance protein (BCRP).

In vitro data indicate that the active metabolites M-2 and M-5 of regorafenib (but not regorafenib itself) are substrates for P-glycoprotein and BCRP. The effect of inducers or inhibitors of these transporters on the exposure to total pharmacologically active material is unknown.

Breast cancer resistance protein (BCRP) and P-glycoprotein substrates.

Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of rosuvastatin (5 mg), a BCRP substrate, resulted in a 3.8-fold increase in mean exposure (AUC) of rosuvastatin and a 4.6-fold increase in Cmax.
This indicates that co-administration of regorafenib may increase the plasma concentrations of other concomitant BCRP substrates (e.g. methotrexate, fluvastatin, atorvastatin). Therefore, it is recommended to monitor patients closely for signs and symptoms of increased exposure to BCRP substrates.
Clinical data indicate that regorafenib has no effect on digoxin pharmacokinetics, therefore can be given concomitantly with P-glycoprotein substrates, such as digoxin, without a clinically meaningful drug interaction.

CYP isoform selective substrates.

In vitro data indicate that regorafenib is a competitive inhibitor of the cytochromes CYP2C8 (Ki value of 0.6 microM), CYP2C9 (Ki value of 4.7 microM) and CYP2B6 (Ki value of 5.2 microM) at concentrations which are achieved in vivo at steady state (peak plasma concentration of 8.1 microM). The in vitro inhibitory potency towards CYP3A4 (Ki value of 11.1 microM) and CYP2C19 (Ki value of 16.4 microM) was less pronounced. The active metabolite, M-2, showed a broadly similar CYP isoform inhibitory profile to parent drug while M-5 only inhibited CYP2C8 at clinically relevant concentrations.
A clinical probe substrate study was performed to evaluate the effect of 14 days of dosing with 160 mg regorafenib on the pharmacokinetics of probe substrates CYP2C8 (rosiglitazone), CYP2C9 (S-warfarin), CYP2C19 (omeprazole) and CYP3A4 (midazolam).
Pharmacokinetic data indicate that regorafenib may be given concomitantly with substrates of CYP2C8, CYP2C9, CYP3A4 and CYP2C19 without a clinically meaningful drug interaction (see Section 4.4 Special Warnings and Precautions for Use).

Antibiotics.

The concentration time profile indicates that regorafenib and its metabolites may undergo enterohepatic circulation (see Section 5.2 Pharmacokinetic Properties). Coadministration with neomycin, a poorly absorbed antimicrobial agent used for eradicating the gastrointestinal microflora (which may interfere with the enterohepatic circulation of regorafenib) had no effect on the regorafenib exposure. There was a significant decrease in the exposure of the active metabolites M-2 and M-5. Effects of other antibiotics have not been studied. The clinical significance of the neomycin effect and potential interactions with other antibiotics is unknown, but may result in decreased efficacy of regorafenib.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There is no data on the effect of Stivarga on human fertility. Based on histological changes (mostly atrophic) in the testes, ovaries and uterus observed after repeated dosing with regorafenib in rats and dogs at exposures below the anticipated human exposure (based on AUC), regorafenib has the potential to adversely affect male and female reproduction in humans.
Women of childbearing potential must be informed that regorafenib may cause foetal harm.
(Category D)
There are no adequate or well controlled studies with Stivarga in pregnant women. Based on its mechanism of action and findings in animal studies, regorafenib may cause fetal harm when administered during pregnancy.
A teratogenic effect was observed in pregnant rats and rabbits treated orally with regorafenib during the period of organogenesis at exposures below the anticipated human exposure (based on AUC). The main findings were malformations of the urinary system (rabbits only), the heart and major vessels, and the skeleton and embryofetal deaths.
Regorafenib/ metabolites crossed the placenta in rats.
Stivarga should not be used during pregnancy unless necessary and after careful consideration of the benefits for the mother and the risk to the foetus. Women of childbearing potential and men should ensure effective contraception during treatment and up to 8 weeks after completion of therapy.
 It is unknown whether regorafenib and/or its metabolites are excreted in human milk. In rats, regorafenib and/or its metabolites are excreted in milk.
A risk to the breastfed child cannot be excluded. Regorafenib could harm infant growth and development (see Section 5.3 Preclinical Safety Data, Systemic toxicity). Breastfeeding must be discontinued during treatment with Stivarga.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Stivarga on the ability to drive or use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The overall safety profile of Stivarga is based on data from more than 4,800 treated patients in clinical trials including placebo controlled phase III data for 636 patients with metastatic colorectal cancer, 132 patients with GIST, and 374 patients with hepatocellular carcinoma (HCC).
The most frequently observed adverse drug reactions (≥ 30%) in patients receiving Stivarga are pain, hand-foot skin reaction, asthenia/ fatigue, decreased appetite and food intake, diarrhoea, infection, and hypertension.
The most serious adverse drug reactions in patients receiving Stivarga are severe liver injury, haemorrhage, gastrointestinal perforation and infection.

Metastatic colorectal cancer.

The safety data in the pivotal study (CORRECT) were derived from a randomised (2:1), double blind, placebo controlled trial in which 500 patients with previously treated metastatic colorectal cancer received Stivarga as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients received placebo.
The incidence of severe treatment emergent adverse events (TEAEs) (≥ grade 3) was higher with regorafenib (78%) than placebo (49%).
The rate of death due to adverse events not associated with disease progression was slightly higher with regorafenib (1.6% vs 1.2%). Five deaths were considered to be regorafenib related: one case each of liver dysfunction; sudden death; cerebrovascular incident; pulmonary haemorrhage, bronchus; haemorrhage, gastrointestinal, anus and haemorrhage, genitourinary, vagina (the last two occurred in one patient).
Overall treatment discontinuation due to adverse drug reactions (all grades) was reported in 8.2% of patients treated with Stivarga compared to 1.2% of patients who received placebo. Hand foot skin reaction and rash were the most common reasons leading to treatment discontinuation of Stivarga.
A dose modification due to adverse events occurred in 67% and 22% of patients in the Stivarga and placebo group, respectively. The rates of dose reductions were also higher with Stivarga (38% vs 3%) as were the rates of dose interruptions (61% vs 22%) and treatment cessations (18% vs 13%) compared to placebo.
Table 3 compares the incidence of adverse reactions (≥ 10%) in patients receiving Stivarga and reported more commonly than in patients receiving placebo in the pivotal CORRECT study.
In the pivotal CORRECT study, other adverse reactions observed in patients treated with regorafenib than placebo and that occurred in < 10% (all grades) were: dry skin (8.8% vs 3.2%); proteinuria (8.6% vs 2.4%); alopecia (7.6% vs 1.6%); hypokalaemia (7.6% vs 1.9%); taste disorder (7.6% vs 2.4%); increase in transaminases (7.6% vs 4.4%); hypophosphatemia (6.4% vs 0.8%); increase in lipase (6.2% vs 1.2%); muscle spasms (5.4% vs 2.0%); hypocalcemia (5.8% vs 0.4%); hyponatremia (5.8% vs 2.4%); dry mouth (4.8% vs 2.0%); leukopenia (4.2% vs 0.8%); hypothyroidism (4.2% vs 0.4%); increase in amylase (3.0% vs 0.4%); abnormal international normalised ratio (INR) (2.4% vs 0.8%); hypomagnesemia (2.2% vs 0.4%); tremor (2.0% vs 0%); gastroesophageal reflux (1.4% vs 0%); hyperuricemia (1.2% vs 0%); gastroenteritis (1.2% vs 0.4%); nail disorder (1.0% vs 0%); exfoliative rash (1.4% vs 0.4%); erythema multiforme (0.8% vs 0.4%); gastrointestinal fistula (0.8% vs 0.4%); myocardial ischemia (0.6% vs 0.4%); myocardial infarction (0.4% vs 0%).

Laboratory abnormalities.

Tables 4 and 5 compares the incidence of laboratory test abnormalities in patients receiving Stivarga and in patients receiving placebo in the pivotal CORRECT study (see Section 4.4 Special Warnings and Precautions for Use).

Gastrointestinal stromal tumours.

The safety of Stivarga in the pivotal study (GRID) were derived from a randomised (2:1), double blind, placebo controlled trial in which 132 patients with previously treated advanced/ metastatic GIST received Stivarga as a single agent at a dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 66 patients received placebo.
Table 6 compares the incidence of adverse reactions (≥ 10%) in GIST patients receiving Stivarga and reported more commonly than in patients receiving placebo.
In the pivotal GRID study, other adverse reactions observed in less than 10% of Stivarga treated patients and at a higher incidence than in placebo treated patients included the following: hyperbilirubinemia (9.9 vs. 3.0); taste disorders (9.9 vs. 3.0); leukopenia (8.3 vs. 6.1); proteinuria (7.6 vs. 1.5); thrombocytopenia (6.1 vs. 0.0); dry mouth (6.1 vs. 4.6); peripheral sensory neuropathy (6.1 vs. 1.5); hypophosphatemia (5.3 vs. 0.0); dry skin (4.6 vs. 0.0); hypoalbuminaemia (4.5 vs. 0.0); vertigo (4.5 vs. 0.0); hypokalaemia (3.8 vs. 3.0); acute kidney injury (2.3 vs. 0.0); ear discomfort (2.3 vs. 0.0); tinnitus (2.3 vs. 0.0); gastroenteritis (1.5 vs. 0.0); gastrointestinal fistula (1.5 vs. 0.0); hypocalcaemia (1.5 vs. 0.0); increase in lipase (1.5 vs. 0.0); abnormal international normalised ratio (INR) (0.8 vs. 0.0); tremor (0.8 vs. 0.0).
The following events were reported with similar or lower frequencies in patients treated with Stivarga than placebo but are considered as adverse reactions based on safety data from other placebo controlled clinical trials: hyponatremia (3.0 vs. 4.6), hypomagnesemia (0.8 vs. 1.5), hyperuricemia (0.8 vs. 1.5), acute coronary syndrome (0.8 vs. 0.0), gastroesophageal reflux (0.0 vs. 0.0), nail disorder (0.0 vs. 0.0), myocardial ischemia (0.0 vs. 0.0), myocardial infarction (0.0 vs. 0.0), pancreatitis (0.0 vs. 0.0), increase in amylase (0.0 vs. 0.0), exfoliative rash (0.0 vs. 0.0), erythema multiforme (0.0 vs. 0.0). There was one report each for nail disorder and myocardial ischemia during the open label treatment phase of the phase III trial in patients with GIST (GRID).

Laboratory abnormalities.

Table 7 compares the incidence of laboratory test abnormalities in patients receiving Stivarga and in patients receiving placebo in the pivotal GRID study.
Additional safety data is available from a postregistration phase III trial carried out in Asian patients with CRC (CONCUR). The safety profile in this study was generally consistent with the global phase III CRC trial (CORRECT). Of note, however, a higher incidence of liver enzyme increases was observed in Stivarga treated patients in the CONCUR trial (> 90% East Asian) compared to in the CORRECT trial (~80% Caucasian).

Hepatocellular carcinoma (HCC).

The data described in Table 8 reflect exposure to Stivarga in over 4,800 patients with different tumour types, including 374 patients with HCC treated with Stivarga in a randomised, double-blind, placebo controlled trial (RESORCE study) with 193 patients receiving placebo.
Other adverse reactions observed in less than 10% of Stivarga treated patients and at a higher incidence than placebo treated patients included the following: hypophosphatemia (9.9 vs. 2.1), leukopenia (8.8 vs. 3.6), proteinuria (8.8 vs. 1.6), rash (8.6 vs. 8.3), stomatitis (8.3 vs. 2.1), increase in lipase (7.2 vs. 3.1), alopecia (7.0 vs. 2.6), hypokalemia (7.0 vs. 2.6), hypothyroidism (6.7 vs. 0.0), headache (6.4 vs. 6.2), hyponatremia (5.9 vs. 3.1), dry mouth (5.9 vs. 4.7), hypomagnesaemia (3.2 vs. 0.0), taste disorder (3.2 vs. 1.0), increase in amylase (2.9 vs. 0.0), mucosal inflammation (2.9 vs. 0.0), hypocalcemia (2.4 vs. 0.0), pancreatitis (1.6 vs. 0.0), exfoliative rash (1.3 vs. 0.0), tremor (1.3 vs. 0.0), hyperuricaemia (1.1 vs. 1.0), erythema multiforme (0.8 vs. 0.0), myocardial ischemia (0.8 vs. 0.0), gastroenteritis (0.5 vs. 0.0), gastrointestinal fistula (0.3 vs. 0.0), myocardial infarction (0.3 vs. 0.0), nail disorder (0.3 vs. 0.0).
The following events were reported with similar or lower frequencies in patients treated with Stivarga than placebo but are considered as adverse reactions based on safety data from other placebo controlled clinical trials: dry skin (2.4 vs. 2.6), gastroesophageal reflux (0.8 vs. 1.6), abnormal international normalised ratio (INR) (0.3 vs. 0.5).
Other adverse reactions were observed in patients treated with Stivarga in open label or placebo controlled clinical trials (more than 4,800 Stivarga treated patients): gastrointestinal perforation* (0.63%), severe liver injury*° (0.10%), hypertensive crisis (0.17%), and reversible posterior leukoencephalopathy syndrome (RPLS) (0.02%) (see Table 9).
*Fatal outcome has been observed.
°According to drug induced liver injury (DILI) criteria of the international DILI expert working group.

Clinical trials experience, other.

Other adverse reactions were observed in patients treated with Stivarga in open label or placebo controlled clinical trials: gastrointestinal perforation* (0.58%), severe liver injury*# (0.25%), hypertensive crisis (0.25%), hypersensitivity reaction (0.44%), toxic epidermal necrolysis (TEN) (0.02%), reversible posterior leukoencephalopathy syndrome (RPLS) (0.08%), Stevens-Johnson syndrome (SJS) (0.02%) and keratoacanthoma/ squamous cell carcinoma of the skin (0.04%).
*Fatal outcome has been observed.
#According to drug induced liver injury (DILI) criteria of the international DILI expert working group.

Description of selected adverse reactions.

Haemorrhage.

In the placebo controlled phase III trials, the overall incidence of haemorrhage was 18.2% in patients treated with Stivarga and 9.5% in patients receiving placebo. Most cases of bleeding events were mild to moderate in severity (grades 1 and 2: 15.2%), most notably epistaxis (6.1%). Fatal outcome was uncommon (0.7%), and included cerebral respiratory, gastrointestinal and genitourinary events.

Infection.

In the placebo controlled phase III trials, infections were more often observed in patients treated with Stivarga compared to patients receiving placebo (all grades: 31.6% vs. 17.2%). Most infections in patients treated with Stivarga were mild to moderate in severity (grades 1 and 2: 23.0%), and included urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) as well as pneumonia (2.6%). Fatal outcomes associated with infection were observed more often in patients treated with Stivarga (1.0%) as compared to patients receiving placebo (0.3%), and were mainly respiratory events.

Hand-foot skin reaction.

In the placebo controlled phase III trials, HFSR were observed more often in patients treated with Stivarga as compared to patients receiving placebo (all grades: 51.4% vs. 6.5%, CRC, 66.7% vs 15.2%, GIST and 51.6% vs. 7.3% HCC). Most cases of HFSR in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (grades 1 and 2: 34.3%, CRC, 44.7%, GIST and 39.3% HCC). The incidence of grade 3 HFSR was 17.1% (CRC), 22.0% (GIST) and 12.3% (HCC). A higher incidence of HFSR was observed in Stivarga treated Asian patients compared to other racial groups (74.8% vs. 39.2% CRC, 88.2% vs. 59.6% GIST and 67.1% HCC). The incidence of grade 3 HFSR in Asians was 20.5% (CRC), 23.5% (GIST) and 13.5% (HCC).

Hypertension.

In the placebo controlled phase III trials, the overall incidence of hypertension was higher in patients treated with Stivarga as compared to patients receiving placebo (29.6% vs. 7.5% CRC, 60.6% vs. 25.8% GIST and 31.0% vs. 6.2% HCC). Most cases of hypertension in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (grades 1 and 2: 20.9%, CRC, 31.8% GIST and 15.8% HCC). The incidence of grade 3 hypertension was 8.7% (CRC), 28.0% (GIST) and 15.2% (HCC). One case of grade 4 hypertension was reported in the GIST trial and associated with RPLS.

Severe liver injury.

In most cases of severe liver injury, liver dysfunction had an onset within the first 2 months of therapy, and was characterised by a hepatocellular pattern of injury with transaminase elevations > 20 x ULN, followed by an increase in bilirubin. In clinical trials, a higher incidence of severe liver injury with fatal outcome was observed in Japanese patients (~1.5%) treated with Stivarga compared with non-Japanese patients (< 0.1%).

Post-marketing experience.

Vascular disorders.

Cases of aneurysms and artery dissections, sometimes fatal, have been reported with VEGFR pathway inhibitors.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no specific antidote for Stivarga overdose.
The highest dose of Stivarga studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhoea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue.
In the event of suspected overdose, Stivarga should be withheld immediately with best supportive care initiated by a doctor. The patient should be observed until clinical stabilisation.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Regorafenib is an oral antitumour agent that potently blocks multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, 2, 3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R). In particular, regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumours and thereby blocks tumour cell proliferation. In nonclinical studies regorafenib has demonstrated antitumour activity in a broad spectrum of in vivo tumour models including colorectal, gastrointestinal stromal and hepatocellular tumour models presumed to be mediated both by its antiangiogenic and antiproliferative effects. In addition, regorafenib reduced the levels of tumour associated macrophages and has shown antimetastatic effects in breast cancer and colorectal cancer models in vivo. Major human metabolites M-2 (N-oxide) and M-5 (N-oxide and desmethyl) exhibited similar efficacies to regorafenib in in vitro and in vivo models.

Clinical trials.

Metastatic colorectal cancer.

The clinical efficacy and safety of Stivarga has been evaluated in an international, multicentre, randomised, double blind, placebo controlled phase III study (CORRECT) in heavily pretreated patients with metastatic colorectal cancer who have progressed after failure of standard therapy.
The primary efficacy endpoint was overall survival (OS). Secondary endpoints were progression free survival (PFS), objective tumour response rate and disease control rate.
In total, 760 patients were randomised 2:1 to receive 160 mg regorafenib (four Stivarga tablets each containing 40 mg regorafenib) orally once daily (N = 505) plus best supportive care (BSC) or matching placebo (N = 255) plus BSC for three weeks on therapy followed by one week off therapy. The mean daily regorafenib dose received was 147 mg.
Patients continued therapy until disease progression or unacceptable toxicity. A preplanned interim analysis for efficacy was performed when 432 deaths had occurred. The study was unblinded after this planned interim analysis as OS had crossed the prespecified efficacy boundary, showing evidence of prolonged survival with Stivarga plus BSC compared to placebo plus BSC. The median (range) duration of treatment (months) in patients treated with Stivarga was 1.7 (0.1-10.8) and with placebo was 1.6 (0.1-8.9).
Of the 760 randomised patients, the median age was 61 years, 61% were male, 78% were Caucasian, and all patients had baseline ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 0 or 1. See Table 10 for the demographic data from the trial. The primary site of disease was colon (65%), rectum (29%), or both (6%). A KRAS (Kirsten rat sarcoma viral oncogene homolog) mutation was reported in 57% of patients at study entry.
Most patients (52%) had received three or fewer previous lines of treatment for metastatic disease. Therapies included treatment with fluoropyrimidine, oxaliplatin and irinotecan based chemotherapy, an anti-VEGF therapy, and, if the patient was KRAS wild type, an anti-EGFR therapy.
The addition of Stivarga to BSC resulted in significantly longer survival compared to placebo plus BSC (p = 0.005178 stratified log rank test) with a hazard ratio of 0.774 [95% CI 0.636, 0.942] and a median OS of 6.4 months vs. 5.0 months (see Table 11 and Figure 1). PFS was significantly longer in patients receiving Stivarga plus BSC (HR: 0.494, p < 0.000001, see Table 11 and Figure 2).
The response rate (complete response or partial response) was 1% and 0.4% for Stivarga and placebo treated patients respectively, however the difference was not statistically significant (p = 0.188432, 1 sided). The disease control rate (complete response or partial response or stable disease) was significantly higher in patients treated with Stivarga (41.0% vs 14.9%, p < 0.000001, 1 sided).
Subgroup analyses for OS and PFS according to age (< 65; ≥ 65), gender, ECOG PS, primary site of disease, time from first diagnosis of metastatic disease, prior anticancer treatment, prior treatment lines for metastatic disease, and KRAS mutation showed a treatment effect favouring the regorafenib regimen over the placebo regimen.
Subgroup analysis results by historical KRAS mutational status showed a treatment effect for OS in favour of regorafenib over placebo for patients with KRAS wild type tumours whereas a numerically lower effect was reported in patients with KRAS mutant tumours; the treatment effect for PFS favouring regorafenib was observed regardless of KRAS mutational status. The hazard ratio (95% CI) of overall survival was 0.653 (0.476 to 0.895) for patients with KRAS wild type tumours and 0.867 (0.670 to 1.123) for patients with KRAS mutant tumours, with no evidence of heterogeneity in treatment effect (nonsignificant interaction test). The hazard ratio (95% CI) of progression free survival was 0.475 (0.362 to 0.623) for patients with KRAS wild type tumours and 0.525 (0.425 to 0.649) for patients with KRAS mutant tumours.

Gastrointestinal stromal tumours.

The clinical efficacy and safety of Stivarga has been evaluated in an international, multicentre, randomised, double blind, placebo controlled phase III study (GRID) in patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) who were previously treated with imatinib and sunitinib. Patients were treated with Stivarga if they experienced disease progression or intolerance to imatinib and disease progression while on sunitinib.
The analysis of the primary efficacy endpoint PFS was conducted after 144 PFS events (central blinded assessment). Secondary endpoints including time to progression (TTP) and overall survival (OS) (interim analysis) were also assessed. PFS was assessed using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumour nodule within a pre-existing tumour mass was progression.
In total, 199 patients with GIST were randomised 2:1 to receive either 160 mg regorafenib (four Stivarga tablets each containing 40 mg) plus best supportive care (BSC; n = 133) orally once daily or matching placebo plus BSC (n = 66) for three weeks on therapy followed by one week off therapy per treatment cycle. The mean daily regorafenib dose received was 140 mg.
Patients continued therapy until disease progression or unacceptable toxicity. Patients receiving placebo who experienced disease progression were offered open label Stivarga (crossover option). Patients receiving Stivarga who experienced disease progression and for whom in the investigator's opinion, treatment with Stivarga was providing clinical benefit were offered the opportunity to continue open label Stivarga.
Of the 199 randomised patients, the median age was 60 years (range 18-87), 64% were male, 68% were Caucasian, and all patients had baseline ECOG PS of 0 or 1. The overall median time since most recent progression or relapse to randomisation was 6 weeks.
The majority of patients presented with metastatic disease (61.3%). 56.8% of the patients had received 2 prior lines of treatment for metastatic and/or unresectable GIST, and 43.2% had received more than 2 prior lines of treatment.
Stivarga significantly increased PFS and TTP and there was a trend to increased OS (see Table 12, Figures 3 and 4). The increase in PFS was consistent independent of age, sex, geographic region, prior lines of treatment, ECOG performance status.
At progression, crossover from placebo to Stivarga was allowed. Fifty six patients randomised to placebo (85%) crossed over to Stivarga and 41 patients randomised to Stivarga (31%) continued on Stivarga. The median secondary PFS (as measured by the investigator) was 5.0 months for those randomised to placebo and 4.5 months for those randomised to Stivarga.

Hepatocellular carcinoma (HCC).

The clinical efficacy and safety of Stivarga have been evaluated in an international, multi- centre, randomised, double-blind, placebo-controlled phase III study (RESORCE) in patients with hepatocellular carcinoma who have been previously treated with sorafenib.
The primary efficacy endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), time to progression (TTP), objective tumour response rate (ORR) and disease control rate (DCR).
In total, 573 patients with HCC were randomised 2:1 to receive either 160 mg regorafenib orally once daily (n = 379) plus best supportive care (BSC) or matching placebo (n = 194) plus BSC for 3 weeks on therapy followed by 1 week off therapy. The mean daily regorafenib dose received was 144 mg. Patients were eligible to participate in the study if they experienced radiological disease progression during treatment with sorafenib and if they had a liver function status of Child-Pugh class A. Patients who permanently discontinued sorafenib therapy due to sorafenib-related toxicity or who tolerated less than 400 mg sorafenib once daily prior to withdrawal were excluded from the study. Randomisation was performed within 10 weeks after the last treatment with sorafenib. Patients continued therapy with Stivarga until clinical or radiological disease progression or unacceptable toxicity. However, patients could continue Stivarga therapy past progression at the discretion of the investigator.
Demographics and baseline disease characteristics were similar between the Stivarga and placebo-treated groups and are shown in Table 13 for all 573 randomised patients:
The median duration of treatment was 3.6 months on Stivarga and 1.9 months on placebo.
The addition of Stivarga to BSC resulted in a significantly longer overall survival as compared to placebo plus BSC (p = 0.000017 stratified log rank test) with a hazard ratio of 0.624 [95% CI 0.498 to 0.782], and a median OS of 10.6 months vs. 7.8 months (see Table 14 and Figure 5).
The median OS from start of sorafenib in the Stivarga treatment arm was 26.0 months [95% CI 22.6 to 28.1] and 19.2 months [95% CI 16.0 to 22.8] in the placebo arm.
PFS was significantly better in patients receiving Stivarga plus BSC, than in patients receiving placebo plus BSC (p < 0.000001 stratified log rank test) with a hazard ratio of 0.453 [95% CI 0.369 to 0.555], and a median PFS of 3.1 months vs. 1.5 months (see Table 14 and Figures 5 and 6).
TTP was significantly better in patients receiving Stivarga plus BSC, than in patients receiving placebo plus BSC (p < 0.000001 stratified log rank test) with a hazard ratio of 0.439 [95% CI 0.355 to 0.542], and a median TTP of 3.2 months vs. 1.5 months (see Table 14). OS, PFS and TTP advantages were consistent across all subsets analysed.
The response rate (complete response or partial response) was 11% for Stivarga and 4% for placebo treated patients (p = 0.003650). The disease control rate (complete response, partial response and stable disease maintained for 6 weeks) was significantly higher in patients treated with Stivarga (65% vs. 36%, p < 0.000001).
Patients' health-related quality-of-life and health utility values were measured with FACT-Hepatobiliary (FACT-HEP) and EQ-5D questionnaires, respectively. There was no clinically meaningful difference between Stivarga and placebo as measured by FACT-HEP total score, EQ-5D index score and EQ-5D VAS.

5.2 Pharmacokinetic Properties

Absorption.

Regorafenib reaches mean peak plasma levels of approximately 2.5 mg/L at approximately three to four hours after a single oral dose of 160 mg regorafenib (given as four tablets each containing 40 mg). The mean relative bioavailability of the tablets compared to an oral solution is 69-83%.
The concentration of regorafenib and its major pharmacologically active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) were highest when given after a low fat (light) breakfast compared to either a high fat breakfast or fasting condition. The exposure for regorafenib was increased by 48% when administered with a high fat breakfast, and 36% when administered with a low fat breakfast, compared to fasting. The exposures of metabolite M-2 and M-5 were higher when regorafenib is given with low fat breakfast as compared to fasting condition and lower when given with a high fat meal as compared to fasting.

Distribution.

Plasma concentration time profiles for regorafenib as well as for the major circulating metabolites showed multiple peaks across the 24 hour dosing interval and can be attributed to enterohepatic circulation. In vitro protein binding of regorafenib to human plasma proteins is high (99.5%).

Metabolism.

Regorafenib is metabolised primarily in the liver by oxidative metabolism mediated by CYP3A4, as well as by glucuronidation mediated by UGT1A9. Two major and six minor metabolites of regorafenib have been identified in plasma. The main circulating metabolites of regorafenib in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), which are pharmacologically active and have similar concentrations as regorafenib at steady state. In vitro protein binding of M-2 and M-5 is higher (99.8% and 99.95%, respectively) than regorafenib (99.5%).
Metabolites may be reduced or hydrolysed in the gastrointestinal tract by microbial flora, allowing reabsorption of the unconjugated drug and metabolites (enterohepatic circulation). Co-administration of a single dose of regorafenib after pre-treatment with neomycin (a poorly absorbed antimicrobial agent that eradicates the gastrointestinal microflora) had no significant effect on the exposure of regorafenib. There was a decrease in the exposure of M-2 and M-5 by 76% and 86%, respectively.

Excretion.

The mean elimination half-life for regorafenib and its metabolite M-2 in plasma ranges from 20 to 30 hours in different studies following oral administration. The mean elimination half-life for the metabolite M-5 is approximately 60 hours (ranges from 40 to 100 hours).
Approximately 90% of the radioactive dose was recovered within 12 days after administration, with approximately 71% of the dose excreted in faeces (47% as parent compound, 24% as metabolites), and approximately 19% of the dose excreted in urine as glucuronides. Urinary excretion of glucuronides decreased below 10% under steady-state conditions. Parent compound found in the faeces could be derived from unabsorbed drug, intestinal degradation of glucuronides or reduction of metabolite M-2.

Linearity/ nonlinearity.

At steady state the systemic exposure of regorafenib increases proportionally up to doses of 60 mg and is less proportional at doses greater than 60 mg. Accumulation of regorafenib at steady state results in approximately a 2-fold increase in plasma concentrations, which is consistent with the elimination half-life and dosing frequency.
At steady state, regorafenib reaches mean peak plasma levels of approximately 3.9 mg/L (8.1 micromolar) after oral administration of 160 mg regorafenib and the peak to trough ratio of mean plasma concentrations is less than 2.
Both metabolites, M-2 and M-5, exhibit nonlinear accumulation. Whereas plasma concentrations of M-2 and M-5 after a single dose of regorafenib are much lower than those of parent compound, steady-state plasma concentrations of M-2 and M-5 are comparable to those of regorafenib.

Hepatic impairment.

The exposure of regorafenib and its metabolites M-2 and M-5 is comparable in patients with mild hepatic impairment (Child-Pugh A) and patients with normal hepatic function.
Limited data in patients with moderate hepatic impairment (Child-Pugh B) indicate similar exposure compared to patients with normal hepatic function after a single 100 mg dose of regorafenib.
The pharmacokinetics of regorafenib has not been studied in patients with severe hepatic impairment (Child-Pugh C).

Renal impairment.

The steady-state exposure of regorafenib, M-2 and M-5 is comparable in patients with mild renal impairment and patients with normal renal function. Limited data from phase I and II studies indicate that the range of exposure in patients with moderate or severe renal impairment is comparable to that seen in patients with normal renal function.
The pharmacokinetics of regorafenib has not been studied in patients with endstage renal disease.

Cardiac electrophysiology/QT prolongation.

No QTc prolonging effects were observed after administration of 160 mg regorafenib at steady state in a dedicated QT study in male and female cancer patients.

5.3 Preclinical Safety Data

Genotoxicity.

There was no indication of a genotoxic potential for regorafenib when tested in standard assays in vitro (bacterial gene mutation and chromosomal aberration assay in Chinese hamster V79 cells) and in vivo (mouse micronucleus test). The N-oxide and N-desmethyl metabolite (M-5), a major human active metabolite, did not induce gene mutation or chromosome aberration in the in vitro assays. The other major human active metabolite, M-2 (N-oxide), was negative in the bacterial gene mutation test, but was positive in the chromosomal aberration assay.

Carcinogenicity.

Studies on the carcinogenic potential of regorafenib have not been performed.

Systemic toxicity.

After repeated dosing in mice, rats and dogs, adverse effects were observed in a number of organs, primarily in the kidneys, liver, digestive tract, heart, thyroid gland, lympho/ hematopoietic system, endocrine system, reproductive system and skin. These effects occurred at systemic exposures in the range of or below the anticipated human exposure (based on AUC comparison). Alterations of teeth and bones and adverse effects in the reproductive system were more pronounced in young and growing animals, and delayed development and retarded growth were observed in juvenile rats indicating a potential risk for children and adolescents.

6 Pharmaceutical Particulars

6.1 List of Excipients

Croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone, silica colloidal anhydrous, iron oxide red, iron oxide yellow, lecithin, macrogol 3350, polyvinyl alcohol, purified talc and titanium dioxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.
Do not remove the desiccant. Keep the bottle tightly closed after first opening. Once the bottle is opened the tablets are to be discarded after 28 days.

6.5 Nature and Contents of Container

The tablets are packed in a white HDPE bottle containing a molecular sieve desiccant capsule.
Stivarga is available in pack sizes of 28, 28 (starter pack) and 84 (3 bottles of 28) tablets.
Not all pack sizes are marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Regorafenib (as monohydrate) is a white to pink or brownish solid substance. Regorafenib (as monohydrate) is practically insoluble in water between pH 1 and 13. Regorafenib monohydrate is not hygroscopic. Regorafenib monohydrate is practically insoluble in 0.1 M HCl, slightly soluble in methanol and ethanol and sparingly soluble in acetone.
Experimental determination of pKa is not possible.
As a consequence of the extremely low solubility of regorafenib (as monohydrate) in aqueous systems, the partition coefficient has not been determined experimentally.

Chemical structure.


Chemical name.

4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate.

Molecular formula.

C21H15ClF4N4O3.

CAS number.

755037-03-7.

7 Medicine Schedule (Poisons Standard)

(S4) Prescription Only Medicine.

Summary Table of Changes