TASIGNA should be given under the supervision of a doctor experienced in the use of anti-cancer drugs. Serious side effects with TASIGNA include:

• Sudden cardiac deaths,
• Prolongation of the QT interval (abnormal electrical signal of the heart),
• Ischemic heart disease (heart disorder), ischemic, cerebrovascular events (stroke or other problems due to decreased blood flow to the brain) and peripheral arterial occlusive disease (PAOD) (problems with decreased blood flow to your leg), rare fatal cases have been reported,
• Liver toxicity (increase of liver enzymes), fatal cases have been reported,
• Pancreatitis (inflammation of the pancreas),
• Myelosuppression (decrease of the production of blood cells).

TASIGNA should not be used in patients who have uncorrectable low levels of potassium or magnesium.

BEFORE you use TASIGNA talk to your doctor or pharmacist if you:

• have a heart disorder, or a heart rhythm disorder (or a family history of heart rhythm disorder) such as an irregular heartbeat or an abnormal electrical signal of the heart called “prolongation of the QT interval”,
• have a personal history of fainting spells,
• have a family history of sudden cardiac death at age of less than 50 years,
• are being treated with medicines that affect the heart beat (antiarrhythmics) or medicines that may have an unwanted effect on the function of the heart (QT prolongation)
• have electrolyte problems (e.g., low blood potassium levels) or conditions that could lead to electrolyte disturbances (e.g., vomiting, diarrhea, dehydration),
• have an eating disorder or are following a strict diet,
• have diabetes, especially with associated nerve disorders,
• had a stroke or other problems due to decreased blood flow to the brain,
• have problems with decreased blood flow to your legs,
• have liver/kidney disease,
• have had pancreatitis (inflammation of the pancreas),
• have intolerance to lactose (milk sugar). TASIGNA contains lactose,
• are pregnant or plan to get pregnant. TASIGNA is not recommended during pregnancy as it may harm the fetus. Women who can get pregnant must use highly effective birth control during treatment with TASIGNA and at least 4 weeks after ending treatment,
• are a male patient and are concerned about your fertility (ability to father a child),
• are a sexually active male. Men who take TASIGNA must use highly effective birth control during treatment with TASIGNA, and at least 4 weeks after ending treatment. Tell your doctor right away if your female partner becomes pregnant,
• breast-feeding or plan to breast-feed. Women should not breast-feed while taking TASIGNA,
• have had a surgical procedure involving the removal of the entire stomach (total gastrectomy).
• have ever had or might now have a hepatitis B virus infection (a viral infection of the liver). This is because during treatment with TASIGNA, hepatitis B may become active again, which can be fatal in some cases. Your doctor will check for signs of this infection before and during treatment with TASIGNA.

TASIGNA can cause a possible life-threatening heart problem called QTc prolongation. QTc prolongation causes an irregular heart beat, which may uncommonly (0.17%) lead to sudden cardiac death. These heart rhythm disturbances are more likely in patients with risk factors, such as heart disease, or in the presence of certain interacting drugs. If you experience any symptoms of a possible heart rhythm disturbance, such as dizziness, palpitations (sensation of rapid, pounding, or irregular heart beat), fainting, or seizures, you should seek immediate medical attention.

Blood tests will also monitor the level of fatty substances (cholesterol and lipids) and sugar (glucose) in your blood.

There is no experience with the use of TASIGNA in children and adolescents.

During the treatment with TASIGNA, you will need to have certain tests, including blood tests, to monitor how TASIGNA works.

TASIGNA may cause dizziness. DO NOT drive or use machines if you feel dizziness or are unable to see well while taking TASIGNA.

As with all medicines, TASIGNA can cause side effects. The side effects of TASIGNA are as follows:

Very common:

• nausea, constipation, vomiting;
• headache;
• muscle pain, pain in joints;
• itching, rash, hives;
• hair loss;
• tiredness (fatigue).

If any of these affects you severely, tell your doctor.

Common:

• upper respiratory tract infections;
• abdominal pain, dyspepsia (digestion problems); diarrhea; eating disorder (anorexia), disturbed sense of taste;
• pain (bone and extremity);
• muscle spasms;
• skin reddening, dry skin;
• insomnia, depression, anxiety;
• weakness;
• dizziness, spinning sensation (vertigo).

If any of these affects you severely, tell your doctor.

TASIGNA may also cause:

• a decrease of the production of blood cells (low levels of white cells, red cells, platelets);
• an increased blood level of lipase or amylase (inflammation of the pancreas);
• an increase in liver enzymes (liver dysfunction or toxicity);
• an increased blood level of creatinine (reduced kidney function), and high or low levels of potassium or low level of magnesium;
• an increase of cholesterol and other fats (lipids) in your blood;
• low blood level of insulin (an enzyme regulating blood sugar level);
• an increase of prothrombin time.
• a previous hepatitis B virus infection (a viral infection of the liver) to become active again when you have had a hepatitis B infection in the past (hepatitis B virus reactivation), which can be fatal in some cases

If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Call your doctor as soon as possible if you faint (loss of consciousness) or have an irregular heartbeat while taking TASIGNA as these may be due to a serious heart condition.

Tell your doctor or pharmacist before taking TASIGNA if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This includes in particular:

• antiarrhythmics such as amiodarone, disopyramide, procainamide, quinidine, sotalol, digoxin, ibutilide, flecainide, propafenone—used to treat irregular heart beat;
• verapamil—used to treat high blood pressure and some types of irregular heart beat;
• chloroquine, halofantrine, clarithromycin, haloperidol, moxifloxacin, methadone, bepridil, pimozide—medicines that may have an unwanted effect on the function of the heart (QT prolongation);
• laxatives, enemas, water pills, amphotericin B, high dose corticosteroids—medicines that can disturb electrolyte levels;
• chlorpromazine, droperidol, ziprasidone—used to stabilize thinking and behaviour;
• fluoxetine, citalopram, venlafaxine, tricyclic/tetracyclic antidepressants e.g. amitriptyline, imipramine, maprotiline—used to treat mood disorder;
• pentamidine—used to prevent and treat Pneumocystis carinii pneumonia;
• chloroquine—used to treat malaria;
• vorinostat, sunitinib, lapatinib—used to treat cancers;
• salmeterol, formoterol—used to treat asthma;
• ketoconazole, itraconazole, voriconazole, levofloxacin, ciprofloxacin, fluconazole, erythromycin, clarithromycin, telithromycin, tacrolimus, cefazolin—used to treat infections;
• domperidone—used to treat gastrointestinal motility disorder;
• metoclopramide, prochlorperazine, ondansetron and dolasetron—used to treat nausea;
• ritonavir—an anti-HIV medicine from the class “antiproteases”;
• carbamazepine, phenobarbital, phenytoin—used to treat epilepsy;
• rifampicin—used to treat tuberculosis;
• St. John's Wort—a herbal product (also known as Hypericum perforatum);
• midazolam—used to relieve anxiety before surgery;
• warfarin—used to treat blood coagulation disorders (such as blood clots or thromboses);
• morphine, methadone—used to treat moderate to severe pain;
• buprenorphine—substitute treatment for opioids dependence;
• cyclosporine A—used to prevent organ transplantations rejections, and to treat autoimmune conditions;
• alfentanil and fentanyl—used to treat pain and used as a sedative before or during surgery or medical procedure;
• cyclosporine, sirolimus and tacrolimus—medicines that suppress the “self-defense” ability of the body and fight infections—commonly used to prevent the rejection of transplanted organs such as liver, heart and kidney;
• dihydroergotamine and ergotamine—used to treat dementia;
• levothyroxine—used to treat thyroid deficiency;
• statins (such as simvastatin and lovastatin)—class of drugs used to treat high level of fats in blood.

In addition, if you are taking TASIGNA, discuss with your doctor before taking antacids (medicines against heartburn). These medications need to be taken separately from TASIGNA:

• antacids called H2 blockers which suppress the production of acid in the stomach—should be taken approximately 10 hours before and approximately 2 hours after you take TASIGNA;
• antacids such as those containing aluminum hydroxide, magnesium hydroxide and simethicone which neutralize the high acidity of the stomach—should be taken approximately 2 hours before or approximately 2 hours after you take TASIGNA.

If you need to see other doctors, you should also tell him or her that you are taking TASIGNA.

Do not take TASIGNA with food. Take the capsules at least 2 hours after any food and then wait at least 1 hour before eating again. Taking TASIGNA with food may increase the amount of TASIGNA in the blood, possibly to a harmful level.

Do not take any products or juices containing grapefruit, star fruit, pomegranate, Seville oranges or similar fruits while taking TASIGNA. This may increase the amount of TASIGNA in blood, possibly to a harmful level.

If you are unable to swallow capsules, you may mix the content of each capsule in one teaspoon of applesauce (pureed apple) and swallow the mixture immediately. No other food should be used.

Capsules to be taken orally on an empty stomach, at least two hours after any food and wait at least 1 hour before eating again.

Swallow the capsules whole with water. Do not open the capsules.

If you are unable to swallow capsules:

• Open the capsules
• Mix the content of each capsule in one teaspoon of applesauce (pureed apple)
• Use only one single teaspoon of applesauce (not more).
• Use only applesauce (no other food).

Swallow the mixture immediately

Overdose:

If you have taken more TASIGNA than you should have, or if someone else accidentally takes your capsules, contact your doctor or the nearest hospital emergency room or a local poison control centre immediately. You may be asked to show them the pack of capsules.

Missed dose:

If you miss a dose, take your next dose as scheduled. Do not take a double dose to make up for the forgotten capsules.

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Long-term safety of topical calcineurin inhibitors (a new class of eczema medication that includes Protopic) has not been established. Although a link has not been established, rare cases of skin cancer and lymphomas (cancer of certain white blood cells) have been reported in patients treated with topical calcineurin inhibitors, including Protopicointment 0.1% and 0.03%.

Therefore:

• Continuous long-term use of Protopic ointment 0.1% and 0.03% should be avoided, and application limited to areas that have eczema.
• Protopic ointment is not indicated in children less than 2 years of age. Only 0.03% Protopic ointment is indicated for use in children 2-15 years of age.

BEFORE you start using Protopic, be sure to tell your doctor if you:

• are using any other prescription medicines.
• are receiving any form of light therapy (phototherapy or UV) to your skin.
• are using any over-the-counter medicines or any natural/herbal remedies.
• are using any other type of skin product.
• are pregnant or planning to become pregnant or breast-feeding.
• are suffering from any kidney problems or disease.
• have an inherited skin barrier disease such as Netherton's syndrome, lamellar ichthyosis, or if you suffer from generalized erythrodema (inflammatory reddening and scaling of the entire skin).
• have a cutaneous Graft Versus Host Disease (a immune reaction of the skin which is a common complication in patients who have undergone a bone marrow transplant).

Avoid sunlight and sun lamps, tanning salons, and treatment with UVA or UVB light. If you need to be outdoors after applying Protopic, wear clothing that protects the treated area from the sun. In addition, you should ask your doctor what other type of protection from the sun you should use.

As with all medicines, Protopic can cause side effects. The most common side effects of Protopic are stinging, a burning feeling or itching of the skin that is being treated with Protopic. These side effects are usually mild to moderate and usually go away after the first few days of using Protopic.

Less common side effects include acne, allergic reaction, fever, diarrhea, swollen or infected hair follicles, headache, increased sensitivity of the skin to hot or cold temperature, or flu-like symptoms (common cold, congestion, upper respiratory infection). While you are using Protopic, drinking alcohol may cause the skin or face to become flushed or red and feel hot. Some people may develop skin tingling, upset stomach, herpes zoster (chickenpox or shingles), muscle pain, cyst, an infection on the skin where Protopic was applied or a bacterial infection of the skin called impetigo. Call your doctor if side effects persist or become bothersome.

Although a link has not been established, rare cases of skin cancer and lymphomas (cancer of certain white blood cells) have also been reported in postmarketing reports (reporting of adverse events by health care professionals and consumers after the launch of the product) for patients treated with topical calcineurin inhibitors, including Protopic ointment 0.1% and 0.03%.

Rare cases of renal (kidney) problems have also been reported in postmarketing use.

For any unexpected effects while taking Protopic, contact your doctor or pharmacist.

No drug interaction studies have been done with Protopic.

Be sure to check with your doctor or pharmacist before you start taking any new medicines while using Protopic. Also, before you use any other ointments, lotions, or creams on your skin, discuss it with your doctor or pharmacist.

• Wash your hands before applying Protopic.
• If your hands are not being treated, wash your hands with soap and water after applying Protopic. This should remove any ointment left on the hands.
• Apply a thin layer of Protopic to all skin areas that your doctor has diagnosed as eczema. Try to cover the affected areas completely. Most people find that a pea-sized amount squeezed from the tube covers an area about the size of a 5 centimeter (two-inch) circle.
• Protopic should be applied twice a day, about 12 hours apart for treating flares.
• Protopic should be applied once a day twice a week for preventing flares from coming back if you have a high frequency of flares (5 or more times per year).
• Do not cover the skin being treated with bandages, dressings, or wraps. However, you can wear normal clothing.
• Do not bathe, shower or swim right after applying Protopic. This could wash off the ointment.
• Before applying Protopic after a bath or shower, be sure your skin is completely dry.
• Protopic must be used only on your skin. Protopic can also be safely used on your eyelids but it is recommended that you avoid direct contact with the eyes. Do not swallow Protopic.

Usual dose:

Protopic comes in two strengths (0.03% or 0.1%). The 0.1% strength is for use in patients age 16 and over. The 0.03% strength is for patients age 2 and over. Your doctor will tell you how to use Protopic based on your medical condition and response to the drug. Do not use any more or any less of the drug than your doctor says.

Treating eczema (atopic dermatitis):

Protopic 0.03% or 0.1% should be applied topically morning and evening twice daily as a thin layer to affected areas of skin.

Protopic usually begins to provide relief from the symptoms of eczema within a few weeks. It is important to use Protopic as instructed by your doctor.

If you do not notice an improvement in your eczema within the first 6 weeks of treatment or if your eczema gets worse, tell your doctor.

Preventing eczema (atopic dermatitis) from coming back:

You may be told by your doctor to continue using Protopic once your eczema has cleared. Protopic 0.03% or 0.1% should be applied once a day twice per week (e.g., Monday and Thursday) to the areas normally affected by eczema. Between applications there should be 2 to 3 days without Protopic treatment. If your eczema comes back, you should call your doctor.

After 12 months of treatment you should see your doctor so that he or she can assess your atopic dermatitis and determine if you should keep using Protopic.

Overdose:

Do not swallow Protopic, if you do, call your doctor immediately. Oral ingestion of Protopic may lead to adverse effects not associated with application of tacrolimus on the skin.

In case of drug overdose, particularly accidental oral ingestion, contact a health care practitioner, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms.

Missed dose:

If you forget to use Protopic as directed, apply it as soon as possible, then go back to your regular schedule. If you forget to use Protopic, do not apply twice as much Protopic the next time you use it.

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.

BEFORE you use Prograf be sure you have told your doctor the following:

• If you have taken Prograf, FK506 or tacrolimus before and had a bad, unusual or allergic reaction
• About all other medicines or treatments you use, including any products you buy off the shelf such as over-the-counter drugs and herbal or home remedies
• If you have the heart problem: congenital or acquired QT prolongation.
• About all other health conditions you have now, or have had in the past
• If you are pregnant, plan to become pregnant, or are breastfeeding a baby. Prograf may cause fetal abnormalities and malformations. Pregnancy should be avoided while taking Prograf because its effect on pregnancy or on an unborn baby is not known. You must use a reliable method of birth control before, during your treatment and for 6 weeks after stopping your treatment with Prograf. Breast-feeding is not recommended while taking Prograf. It is important to notify your doctor right away if you become pregnant or father a child while taking Prograf. It is recommended that you do not take Prograf if you are, or become, pregnant. However, never stop taking Prograf without first consulting your doctor
• It is not known what effect Prograf has on the effectiveness of vaccinations and on the risk of getting an illness from vaccination with a live vaccine. Do discuss this with your doctor before you get any vaccinations or immunizations
• If you have a rare hereditary disease of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, because the capsules contain lactose

Prograf may cause new onset diabetes in kidney transplant patients. Your doctor may order tests to monitor your blood glucose levels.

Precautions:

• Prograf is often given with other medications. Make sure you know if you are to stop, or continue, other immunosuppressive drugs you had been taking.
• Be sure that you are taking the correct dose and correct formulation of tacrolimus (Prograf, immediate release capsules) prescribed by your doctor.
• Be sure to keep all appointments at your transplant clinic. This is very important to help ensure that you receive the maximum benefit from your medications
• As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using sunscreen with a high protection factor
• Tell all health professionals you see that you are taking Prograf. It is also a good idea to wear a Medic-Alert bracelet

Like other medicines, Prograf may cause side effects in some people. If you think that you are having side effects, talk to your doctor right away. DO NOT stop taking Prograf on your own.

• Because Prograf decreases the function of your immune system you may be more likely to get an infection. Tell your doctor right away about any cold or flu-like symptoms (such as fever or sore throat), any mouth sores or burning discomfort with urination
• Be sure to tell your doctor right away if you notice any of these symptoms, and especially if they continue, bother you in any way, or seem to increase in intensity
  • diarrhea, nausea, constipation, vomiting, loss of appetite, stomach pain
  • headache, tremors, convulsions, tiredness or fatigue, difficulty sleeping, nightmares
  • urinary tract infection, weakness
  • decreased or increased urine volumes, kidney or liver problems
  • diabetes/increased blood sugar, swelling or tingling in your hands and feet
  • palpitations, abnormal heart rhythms, chest pain, high blood pressure
  • fever, back pain, changes in mood or emotions, difficulty in breathing
  • progressive weakness on one side of the body, clumsiness of limbs, disturbance of vision, changes in thinking, memory and orientation, confusion, personality changes, which could be symptoms of a rare brain infection called progressive multifocal leukoencephalopathy (PML)
  • headache, seizures, visual disturbances or altered mental state, which could be symptoms of posterior encephalopathy syndrome (PRES)
• Immunosuppressive drugs including Prograf may also increase your chances of developing certain types of cancer. The following are possible warning signs of cancer and should be reported to your doctor as soon as possible:
• any sore that does not heal
  • unusual bleeding or discharge
  • the appearance of a lump or thickened areas in your breast or anywhere else on your body
  • unexplained stomach upset or any trouble with swallowing
  • any noticeable change in a wart or a mole
  • a nagging cough or hoarseness
  • night sweats
  • persistent and severe headaches
  • swollen lymph nodes
  • a change in your bowel or bladder habits
• Cases of pure red cell aplasia (PRCA- bone marrow stops producing red blood cells) have occurred in patients taking tacrolimus. Contact your doctor immediately if you suffer symptoms such as fatigue, malaise, weakness, dizziness, fainting, shortness of breath, rapid heartbeat, pallor (paleness of skin), pale stool.
• Cases of gastrointestinal perforation (hole in the stomach or intestine) have occurred in patients taking tacrolimus. If you suffer symptoms such as severe abdominal pain, burning pain, nausea, vomiting and later possibly chills or fever, get medical attention immediately.

Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate or extended release tacrolimus oral formulations, have been observed. This has led to serious adverse events, including graft rejection, or other side effects which could be a consequence of either under- or over-exposure to tacrolimus. You should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist.

It is important to regularly tell your doctor how you are feeling and if you have developed any new symptoms while taking Prograf.

Tell your doctor, dentist, nurse, and pharmacist about all the drugs that you are taking. Prograf blood levels can be affected by other medicines you take, and blood levels of other medicines can be affected by taking Prograf, which may require an increase or decrease in Prograf dose. In particular, you should tell your doctor if you are taking or have recently taken medicines such as:

• Antacids: magnesium aluminum hydrochloride
• Antiarythmic: amiodarone
• Antifungals: clotrimazole, fluconazole, ketoconazole, itraconazole, voriconazole
• Calcium channel blockers: diltiazem, nicardipine, nifedipine, verapamil
• Gastrointestinal prokinetic agents: cisapride*, metoclopramide
• Macrolide antibiotics: erythromycin, clarithromycin, troleandomycin
• Proton pump inhibitors: lansoprazole, omeprazole
• Other drugs: bromocriptine, cimetidine, chloramphenicol, cyclosporine, danazol, ethinyl estradiol, methylprednisolone, nefazodone
• Protease inhibitors: boceprevir, nelfinavir, ritonavir, saquinavir, telaprevir
• Anticonvulsants: carbamazepine, phenobarbital, phenytoin
• Anti-infectives: rifampin, rifabutin, capsofungin
• Calcineurin inhibitor: sirolimus
• Potassium sparing diuretics

Do not take any other drugs without asking your doctor first. This includes anything you can buy off the shelf such as over-the-counter drugs and herbal, especially St. John's Wort (Hypericum perforatum), Schisandra sphenanthera extracts, or home remedies.

A high intake of potassium should be avoided during Prograf treatment.

Prograf should not be taken with grapefruit or grapefruit juice.

Usual dose:

Your doctor will give you specific instructions about how much Prograf you should take each day. Your doctor has decided the dose you should take based on your medical condition and response to the drug. It is very important to take the exact amount of Prograf that your doctor has told you.

Once your doctor has told you when and how many times a day to take Prograf:

• Try to take your doses at the same time every day. This will help keep the same amount of Prograf in your body so it can continue to protect your transplanted organ
• Space your doses of Prograf as evenly as you can throughout the day. For example, if you take Prograf twice a day, doses should be 12 hours apart. Ask your transplant nurse or pharmacist about a dosing schedule that best fits your lifestyle
• Prograf may be taken with or without food. But it is best to be consistent. Once you decide when you are going to take it in relation to food, do it the same way each time
• Swallow the capsules whole. Do not cut, crush, or chew the Prograf capsule
• Make sure that you receive the same tacrolimus medicine every time you collect your prescription, unless your transplant specialist has agreed to change to a different tacrolimus medicine. If the appearance of this medicine is not the same as usual, or if dosage instructions have changed, speak to your doctor or pharmacist as soon as possible to make sure that you have the right medicine

Blood tests are one of the ways your doctor decides how much Prograf you need. Based on these tests and your response to Prograf, your doctor may change your dose from time to time. Do not change your dose on your own.

Overdose:

In case of drug overdose, contact a healthcare practitioner (e.g. doctor), hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms.

Missed dose:

Missing even a few doses of Prograf may cause your body to reject your transplanted organ. That is why it is very important to take each dose as your doctor prescribed. If you have trouble remembering doses, or if you are uncertain about how to take them, talk to your doctor, nurse or pharmacist and be sure to discuss any concerns you have about taking Prograf as prescribed.

If you do miss a dose of Prograf do not try to catch up on your own (do not take twice your dose); instead call your doctor or pharmacist right away for advice. It is also a good idea to ask your doctor ahead of time what to do about missed doses.

Never allow your medication to run out between refills and be sure to take enough medication with you when you will be away from home for any extended period of time.

Treatment with STIVARGA may lead to:

• Liver problems which may cause death.
• Bleeding problems which may cause death.
• Chest pain or heart problems.
• Headache, confusion, seizures and visual loss.
• Severe bowel problems.
• High blood pressure.
• Redness, pain, swelling, or blisters on the palms of your hands and soles of your feet.

BEFORE you use STIVARGA talk to your doctor if you have or have had any of the following conditions:

• Liver disease with yellowish discoloration of the skin and the whites of the eyes (jaundice), dark urine, confusion and/or disorientation. Treatment withSTIVARGA may lead to a higher risk of liver problems. Prior to and during the treatment with STIVARGA your doctor will do blood tests to monitor your liver function.
• Any bleeding problems or if you are taking warfarin or a medicine that thins the blood to prevent blood clots. Treatment with STIVARGA may lead to a higher risk of bleeding. Before you start treatment your doctor may decide to do blood tests.
• Heart problems. Before you start STIVARGA and during treatment your doctor will check how well your heart is working.
• High blood pressure. STIVARGA can raise your blood pressure, and your doctor will monitor your blood pressure prior to and during the treatment and may give you a medicine to treat high blood pressure. If you develop severe and persistent headache and/or visual disturbances contact your doctor immediately.
• Skin problems. STIVARGA can cause redness, pain, swelling, or blisters on the palms of your hands or soles of your feet. If you notice any changes be sure to contact your doctor. To manage your symptoms, your doctor may recommend the use of creams and/or the use of shoe cushions and gloves. If you get this side effect, your doctor may change your dose or temporarily stop your treatment until this skin condition improves.
• Upcoming surgery. STIVARGA might affect the way your wounds heal and treatment may need to be stopped until your wound heals.
• You are pregnant, or you or your partner could become pregnant. Your doctor will discuss with you the risks and benefits of using STIVARGA during pregnancy. Reliable birth control should be used by both males and females and for 8 weeks after the last dose of STIVARGA.
• You are breastfeeding. Do not use STIVARGA if you are breastfeeding.

STIVARGA should not be given to patients under 18 years of age.

STIVARGA can have side effects, like all medicines, but not everybody gets them. For further information about any of these effects, ask a doctor or pharmacist. If you experience any symptom that bothers you or does not go away, or you develop a severe side effect such as high blood pressure, bleeding or skin reactions, contact your doctor or seek medical attention as soon as possible.

The most common side effects of regorafenib may include:

• tiredness, fatigue
• loss of appetite
• rash, redness, itching or peeling of your skin
• diarrhea (frequent or loose bowel movements)
• weight loss
• infections
• increase in blood pressure
• voice changes or hoarseness

Tell your healthcare provider right away, if you get high fever, nausea, vomiting or severe abdominal pain.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. STIVARGA may affect the way other medicines work, and other medicines may affect how STIVARGA works. You may need to change the dosage or stop taking one of the medicines.

STIVARGA may interact with the following medications:

• rifampin (ROFACT, RIFADIN)
• phenytoin (DILANTIN), carbamazepine (TEGRETOL), phenobarbital (BELLERGAL SPACETABS)
• methotrexate (METHOTREXATE)
• digoxin

Usual dose:

The recommended daily dose in adults is four STIVARGA 40 mg tablets (160 mg of regorafenib). Your doctor may change your dose. Take the dose of STIVARGA that your doctor prescribes for you.

Take STIVARGA at the same time each day after a light (low fat) meal. An example of a low-fat, low-calorie meal is two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly and 8 ounces of skim milk (approximately 319 calories and 8.2 grams of fat). The tablets should be swallowed whole with water.

Overdose:

In case of drug overdose, contact your doctor, or a poison control center, or go to the emergency room of the hospital near you immediately, even if there are no symptoms.

Missed dose:

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

How long will I take STIVARGA?

Your doctor will usually ask you to take STIVARGA for 3 weeks and then to stop for 1 week. This is 1 cycle of treatment. Your doctor may need to reduce your dose or may decide to interrupt or discontinue the treatment permanently if necessary. You will usually take STIVARGA as long as you are benefitting from treatment and not suffering unacceptable side effects.

BEFORE you use TUDORZA PRESSAIR talk to your doctor or pharmacist if you:

• are pregnant or planning to become pregnant
• are a breastfeeding mother
• are taking any medications including eye drops, this includes medications you can buy without prescription
• have had heart problems recently
• have eye problems such as glaucoma, eye pain, blurred vision, see halos around lights or coloured images
• have an enlarged prostate, problems passing urine, or painful urination
• have a severe allergy to milk proteins. Ask your doctor if you are not sure
• have had allergies to atropine or related medicines, for example ipratropium, tiotropium or oxitropium
• have allergies to food or drugs

TUDORZA PRESSAIR should not be used more frequently than twice daily. Do not exceed the prescribed dose.

This medication has been prescribed for you and should not be given to other people.

Stop taking TUDORZA PRESSAIR and seek medical help immediately:

• if you get tightness of the chest, coughing, wheezing or breathlessness immediately after using the medicine. These may be signs of a condition called bronchospasm.

Remember to tell any other doctor, dentist or pharmacist you consult that you are taking this medication.

Driving and using machines:

This medicine may cause headache and blurred vision. If you are affected by either of these side effects do not drive or use machinery until the headache has cleared and your vision has returned to normal.

Side effects may include:

• headache,
• nasopharyngitis (inflammation or irritation of the nose and throat),
• cough,
• diarrhea,
• falls and injury,
• sinus inflammation (sinusitis),
• vomiting,
• blurred vision,
• hoarseness,
• dizziness,
• mouth or tooth infection.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Inform your doctor if you have been or are using similar medicines for breathing problems, e.g., medicines containing tiotropium, ipratropium or glycopyrronium. Ask your doctor or pharmacist if you are not sure. The use of TUDORZA PRESSAIR with these medicines is not recommended.

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

• The recommended dose is one inhalation twice a day, once in the morning and once in the evening.
• Use TUDORZA PRESSAIR even when you have no breathing problems or other symptoms of COPD.
• Do not stop using the drug without consulting your doctor.
• You can use TUDORZA PRESSAIR anytime before or after food or drink.

Usual dose:

The recommended dose is one inhalation twice a day, once in the morning and once in the evening.

The recommended dose can be used for elderly patients and for patients with kidney or liver problems. No dose adjustments are necessary.

Overdose:

If you think you may have used more TUDORZA PRESSAIR than you should, contact your doctor or pharmacist.

In case of drug overdose, contact a health care practitioner, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms.

Missed dose:

If you forget a dose of TUDORZA PRESSAIR, inhale the dose as soon as you remember. However, if it is nearly time for your next dose, skip the missed dose.

Do not take a double dose to make up for a forgotten dose.

Common side effects are:

• nose and throat irritation,
• nose bleeding and crusting

Other side effects include:

• itchy and sore throat
• cough
• fatigue
• nausea/dizziness
• headache

Uncommon side effects that may occur when also taking an oral steroid:

• asthma
• skin rash
• itching or swelling in the face
• Cushing’s syndrome (hypercorticism)

As with most medicines, interactions with other drugs are possible. Tell your doctor, nurse, or pharmacist about all the medicines you take, including drugs prescribed by other doctors, vitamins, minerals, natural supplements, or alternative medicines.

Drugs that may interact with RHINOCORT AQUA include:

• ritonavir used to treat HIV or AIDS;

• ketoconazole/ itraconazole used to treat fungal infections.

This medicine is prescribed for you by your doctor. Never give it to someone else. It may harm them even if their symptoms are the same as yours.

RHINOCORT AQUA:

• Is for use in the nose only. Do not use it in your eyes or mouth.
• May take 2-3 days (and up to 2 weeks) to work. Take it each day without missing a dose to get the best results.

Take RHINOCORT AQUA exactly as recommended by your doctor. Follow your doctor’s directions carefully. They may differ from the information in this leaflet.

Do not take more of your medicine or take it more often than your doctor tells you. Do not stop taking RHINOCORT AQUA even if you feel better unless told to do so by your doctor.

For seasonal allergic rhinitis, RHINOCORT AQUA works best if it is started before allergy season begins.

If your nose is blocked, decongestant nose drops may be used during the first 2-3 days of the treatment.

This drug does not relieve allergy symptoms in the eyes. If your eyes bother you, your doctor may be able to give you some additional medicine to relieve these symptoms.

Tell your doctor if:

• your symptoms have not improved after 3 weeks of taking RHINOCORT AQUA.
• your nose becomes irritated.
• you have a yellow or green discharge from your nose.
• you have repeated nose bleeds.

Children using RHINOCORT AQUA should be supervised by an adult. This is to ensure that the correct dose is given as prescribed by the doctor.

Adults and Children (6 years and older):

Depending on how RHINOCORT AQUA works for you, your doctor may change your dose.

Rhinitis:

RHINOCORT AQUA can be taken once a day or twice a day.

Usual once a day starting dose: 2 sprays into each nostril once a day (in the morning)

Usual twice a day starting dose: 1 spray into each nostril twice a day (in the morning and evening)

Maintenance dose: Use the lowest effective dose necessary to control symptoms.

Nasal Polyps:

Usual Dose: 1 spray into each nostril twice a day (in the morning and evening)

Treatment with RHINOCORT AQUA should not be stopped abruptly, but tapered off gradually.

Overdose:

In case of drug overdose, contact a health care practitioner, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms.

Missed dose:

• If you miss a dose take it as soon as possible. Then go back to your regular schedule.
• If it is almost time to take your next dose, skip the missed dose and take the next dose at the usual time.
• Do NOT take a double dose of RHINOCORT AQUA to make up for a missed dose. If you are still unsure, check with your doctor or pharmacist to see what you should do.

How to use your RHINOCORT AQUA:

Before you start using RHINOCORT AQUA for the first time, it is important that you read the instructions below and follow them carefully (see package insert for illustrations).

1. How to prepare a NEW sprayer for use:
2. When using the spray for the first time, you must prepare the spray.
3. Step 1: Turn the bottle upside-down 3 to 4 times. Remove the protective cap from the nose piece.
4. Step 2: Load the pump by pressing downwards on the collar. Use your index and middle fingers while supporting the base of the bottle with your thumb (Figure 1). Press down 5 to 10 times until a fine mist spray appears. Avoid spraying the mist in your eyes.
5. NOTE: If not used daily the pump must be loaded again. This time you just need to pump once into the air.
6. The spray is now ready for use.
7. How to take a dose:
8. Step 1: Turn the bottle upside-down 3 to 4 times. Remove the protective cap from the nose piece.
9. Step 2: If you did not use your spray yesterday, make sure you prepare the pump by pressing down once only (Figure 1).
10. Step 3: Gently blow your nose. Hold the bottle as shown. Tilt your head forward slightly. Close one nostril with a finger and gently insert the tip of the nose piece into the other nostril (Figure 2).
11. Step 4: For each spray your doctor has instructed you to take, press firmly downwards once on the collar. Breathe gently inwards through the nostril, then breathe out through the mouth.
12. Step 5: Repeat the procedure for the other nostril.
13. Step 6: Replace the protective cap on the nose piece. Keep the bottle in an upright position.

Cleaning:

Clean the nose piece and protective cap regularly. To clean the nose piece, remove the protective cap, press upwards on the collar and the nose piece will come off. Wash the nose piece and protective cap under lukewarm water. Air dry and replace the nose piece and the protective cap back on the bottle and reload as in Step #2. Do not try to clean the nasal applicator by using a pin or sharp object.