AFINITOR 2.5 MG

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only.

AFINITOR

®

Tablets 2.5 mg, 5 mg, 10 mg

Each tablet contains:

Afinitor 2.5 mg: Everolimus 2.5 mg

Afinitor 5 mg:

Everolimus 5 mg

Afinitor 10 mg:

Everolimus 10 mg

Inactive ingredients and allergens: See section 6 “Further Information”.

Afinitor contains lactose.

Read this leaflet carefully in its entirety before using the medicine. Keep this leaflet. You may need

to read it again. This leaflet contains concise information about the medicine. If you have further questions,

refer to the doctor or pharmacist.

This medicine has been prescribed for the treatment of your ailment. Do not pass it on to others. It may harm

them, even if it seems to you that their ailment is similar.

!

Children and adolescents (below 18 years of age)

Afinitor is intended to treat children and adolescents who have normal liver function and brain tumors of the

SEGA type associated with Tuberous Sclerosis Complex (TSC).

The safety and efficacy of Afinitor in children below the age of 1 year with brain tumors of the SEGA type

associated with Tuberous Sclerosis Complex (TSC) have not been established. No data are available.

Afinitor is not intended for children and adolescents for other approved indications.

1. WHAT IS THE MEDICINE INTENDED FOR?

Afinitor Tablets 2.5, 5 and 10 mg:

∙ Treatment of patients with a brain tumor of the Subependymal Giant Cell Astrocytoma (SEGA) type associated

with Tuberous Sclerosis Complex - TSC.

∙ Treatment of adult patients with a kidney tumor known as Angiomyolipoma (AML) when the kidney tumor does

not require immediate surgery. This type of tumor is connected with a genetic condition known as Tuberous

Sclerosis Complex.

∙ Treatment of patients with advanced neuroendocrine tumors of pancreatic origin that cannot be surgically

removed, that are locally advanced or have metastasized.

∙ Treatment of advanced hormone receptor-positive and HER2-negative breast cancer in conjunction with

exemestane, in postmenopausal women without symptomatic metastatic disease spread to internal organs,

after recurrence or progression of the disease, following treatment with nonsteroidal aromatase inhibitors.

∙ For treatment of advanced kidney cancer (Advanced Renal Cell Carcinoma [RCC]), where other treatments

(so-called “VEGF-targeted therapy”) have not helped stop your disease.

∙ For the treatment of locally advanced, metastatic or unresectable, well-differentiated (1 or 2) non-functional

neuroendocrine tumors of lung or gastrointestinal origin in adults with progressive disease.

Therapeutic group: Anticancer medicine

Afinitor is a medicine whose active ingredient is called everolimus. It is an anti-tumor medicine which reduces

the blood supply to cancer cells and can thus reduce the growth and spread of cancer cells. Afinitor can also

reduce the size of kidney tumors called renal angiomyolipomas and brain tumor cells of the SEGA type, the

latter two tumors are caused by a genetic disorder called Tuberous Sclerosis Complex (TSC).

If you have further questions regarding Afinitor or why this medicine has been prescribed for you, consult

your doctor.

2. BEFORE USING THE MEDICINE

Afinitor will only be prescribed to you by a doctor with experience in using anticancer therapies or

in the treatment of patients with Tuberous Sclerosis Complex. Follow all the doctor’s instructions

carefully. They may differ from the general information contained in this leaflet.

X

Do not use the medicine if:

∙ You are allergic (hypersensitive) to everolimus, to similar drugs, such as sirolimus (rapamycin), temsirolimus or

to any of the additional ingredients contained in the medicine and detailed in section 6 “Further Information”

in this leaflet.

In this case, inform the doctor without taking Afinitor.

If you think you are allergic, consult with the doctor.

Special warnings regarding use of the medicine:

!

Before beginning treatment with Afinitor, tell the doctor if one of the following conditions applies to

you:

∙ If you have any problems with your liver or have previously had any diseases which may have affected your

liver. In such a case, it may be necessary for the doctor to modify the dosage of Afinitor you take or to stop

the treatment temporarily or permanently.

∙ If you have diabetes (high levels of sugar in the blood). Treatment with Afinitor may cause an elevation in

blood sugar levels and worsen diabetes. This may lead to a need for medicinal treatment such as insulin

and/or oral anti-diabetic agent therapy. Tell the doctor if you experience increased thirst or an increase in the

frequency of passing urine.

∙ If you are scheduled to receive any vaccination during treatment with Afinitor, it is possible that the vaccination

will be less effective. It is important to consult with the doctor regarding children suffering from brain tumors

of the SEGA type on the subject of completing childhood series of vaccinations before beginning treatment

with Afinitor.

∙ If you have high levels of cholesterol, Afinitor can increase the level of cholesterol and/or other blood fats.

∙ If you have recently had major surgery, or if you still have an unhealed wound following surgery. Afinitor may

increase the risk of problems with wound healing.

∙ If you have any infections. It may be necessary to treat your infection before starting treatment with

Afinitor.

∙ If you have previously had hepatitis B, because it may be reactivated during your treatment with Afinitor (see

section 4: “Side effects”).

∙ If you suffer or have suffered in the past from kidney problems.

Afinitor may also:

∙ Cause mouth sores (oral ulcerations).

∙ Weaken your immune system. Therefore, you may be at risk of getting an infection while you are taking

Afinitor. If you develop a fever or show other signs of infection, consult your doctor.

∙ Impact your kidney function. Therefore, your doctor will monitor your kidney function while you are taking

Afinitor.

∙ Cause shortness of breath, cough and fever (see also section 4 “Side effects”).

Inform your doctor immediately if you experience these symptoms.

!

Taking other medicines

Afinitor may interfere with the efficacy of other medicines. If you are taking other medicines at the same time

as Afinitor, it is possible that your doctor will need to modify the dosage of Afinitor or the dosage of the other

medicines.

If you are taking, or have recently taken, other medicines, including non-prescription medicines

and food supplements, tell the doctor or pharmacist. In particular, inform the doctor or pharmacist if

you are taking the following medicines:

The following medicines can increase the risk of side effects with Afinitor:

∙ Medicines used to treat fungal infections, anti-fungal medicines such as: ketoconazole, itraconazole,

voriconazole, fluconazole.

∙ Medicines to treat types of bacterial infections, antibiotics such as: clarithromycin, telithromycin or

erythromycin.

∙ Medicines used to treat AIDS (HIV) such as: ritonavir.

∙ Some medicines used to treat heart conditions or high blood pressure such as: verapamil or diltiazem.

∙ A medicine used to help regulate your heart beat: dronedarone.

∙ A medicine used to stop the body from rejecting organ transplants: cyclosporine.

∙ A medicine used to inhibit the growth of abnormal cells: imatinib.

∙ Angiotensin Converting Enzyme (ACE) inhibitors, medicines used to treat high blood pressure or other

cardiovascular problems, such as: ramipril.

∙ Nefazodone, a medicine used to treat depression.

The following medicines can reduce the efficacy of Afinitor:

∙ A medicine used to treat tuberculosis: rifampicin.

∙ St. John’s Wort - an herbal medicine used to treat depression and other conditions (also known as Hypericum

Perforatum).

∙ Certain corticosteroids used to treat a wide variety of conditions including inflammatory or immune problems

such as: dexamethasone.

∙ Medicines which stop seizures or epileptic fits, anti-epileptics such as: phenytoin, carbamazepine or

phenobarbital.

∙ Efavirenz, nevirapine - used to treat AIDS (HIV).

These medications should be avoided during your treatment with Afinitor. If you are taking any of these, your

doctor might prescribe a different medicine or change your dosage of Afinitor.

For patients with TSC who are taking anti-seizure medications, a change in anti-seizure medication dosage

(increase or decrease) may require a change in Afinitor dosage. Your doctor will decide this. If the dosage of

your anti-seizure medicine changes, please inform your doctor.

!

Use of the medicine and food

You should take Afinitor every day at the same time, either consistently with food or consistently without food.

Do not drink grapefruit juice or eat grapefruits during treatment with Afinitor.

!

Older people (age 65 years and over)

If you are aged 65 years or over, you can take Afinitor at the same dosage as younger adults.

!

Pregnancy, breast-feeding and fertility

Pregnancy

Afinitor could harm the fetus and is therefore not recommended during pregnancy. Tell your doctor if you are

pregnant or think that you may be pregnant.

Women of child-bearing potential

Women of child-bearing potential should use a highly effective contraceptive method (such as condoms or oral

contraception) during treatment with Afinitor and for 8 weeks after treatment has stopped.

If you think you may have become pregnant, ask your doctor for advice before taking any more Afinitor.

Breast-feeding

Afinitor could harm a baby. Do not breast-feed during treatment with Afinitor. Tell your doctor if you are

breast-feeding.

If you are pregnant or breast-feeding, consult the doctor or pharmacist before beginning treatment with any

medicine.

Fertility

Afinitor may have an impact on male and female fertility. Absence of periods in females who previously had

periods (amenorrhea) has been observed in some female patients receiving Afinitor. If you are interested in

becoming pregnant – consult the doctor.

!

Driving and using machinery

Exercise caution regarding driving or operating dangerous machinery during treatment with this medicine.

This is especially true if you feel fatigued, since excessive fatigue is a common side effect of Afinitor. Children

should be cautioned against riding their bicycles or playing near the road, etc.

!

Important information regarding some of the ingredients in the medicine

Afinitor contains lactose (milk sugar). If you have been told by a doctor that you are sensitive to some sugars,

consult the doctor before taking Afinitor.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use according to the doctor’s instructions.

Check with the doctor or pharmacist if you are not sure.

The dosage and manner of treatment will be determined by the doctor only. Do not take more than the doctor

has instructed you. Do not change the dosage without consulting with the doctor.

If you suffer from certain side effects while you are taking Afinitor, your doctor may need to reduce your dosage

of Afinitor, or to instruct you to stop treatment with Afinitor temporarily or permanently.

Do not exceed the recommended dose.

When to take Afinitor

Take Afinitor once a day, at about the same time each day. It is important to take Afinitor at about the same time

every day, consistently with or without food, so that there is a steady amount of drug in the bloodstream.

How to take Afinitor

Afinitor Tablets are to be taken by mouth.

Do not chew, halve or crush the tablets! Swallow the tablets whole with a glass of water.

If you are taking Afinitor Tablets for the treatment of Tuberous Sclerosis Complex with SEGA and you are unable

to swallow the tablets, you can stir them into a glass of water:

∙ Put the required tablet(s) into a glass containing approximately 30 ml (2 tablespoons) of water.

∙ Gently stir the contents until the tablet(s) break apart (approximately 7 minutes) and drink immediately.

∙ Refill the glass with the same amount of water (approximately 30 ml) and drink the whole content to make

sure that you get the full dose of Afinitor.

∙ If necessary, drink additional water to wash out any residues in your mouth.

Instructions for caregivers regarding use and handling of Afinitor Tablets

Caregivers are advised to avoid contact with suspensions of Afinitor. Wash hands thoroughly before and after

preparation of the suspension.

Tests and Follow-up

Before and during treatment with Afinitor, you should have regular blood tests which will monitor the amount of

blood cells (white blood cells, red blood cells and platelets) in your body, to see if Afinitor is having an adverse

effect on these cells. In addition, tests will be performed to monitor your kidney function (levels of creatinine

in the blood, blood urea nitrogen or protein in the urine), liver function (level of transaminases in the blood)

and blood sugar, lipid and cholesterol levels, because these can all be affected by Afinitor.

If you receive Afinitor for the treatment of a brain tumor of the SEGA type associated with Tuberous Sclerosis

Complex - TSC, regular blood tests are necessary to measure how much Afinitor is in your blood, since this will

help your doctor decide how much Afinitor you need to take.

If you accidentally take too high a dosage

If you took an overdose, or if a child or any other person, has accidentally swallowed the medicine, refer

immediately to a doctor or proceed to a hospital emergency room, and bring the package of the medicine

and the leaflet with you, so that the doctor knows what has been taken. Urgent medical treatment may be

necessary.

If you forget to take the medicine

If you forget to take the medicine at the designated time, take your next dose as scheduled. Do not take a

double dose to make up for the one that you missed.

Be sure to adhere to the treatment as recommended by the doctor.

Even if there is an improvement in your health, do not stop treatment with the medicine without consulting

the doctor.

Do not take medicines in the dark! Check the label and the dose each time you take medicine. Wear glasses

if you need them.

If you have further questions regarding use of the medicine, consult the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Afinitor may cause side effects in some users. Do not be alarmed by the list of side

effects. You may not suffer from any of them. Afinitor may also affect the results of some blood tests.

Stop taking Afinitor and seek medical help immediately if you or your child experience any of the following

signs of an allergic reaction:

∙ Difficulty breathing or swallowing

∙ Swelling of the face, lips, tongue or throat

∙ Severe itching of the skin, with a red rash or raised bumps

Some side effects could be serious:

If you experience any of these side effects, tell your doctor immediately, as these might have life-threatening

consequences.

Serious side effects observed during the treatment of hormone receptor-positive advanced breast

cancer, advanced kidney cancer and advanced neuroendocrine tumors of pancreatic, gastrointestinal

or lung origin:

Very common side effects, effects that may occur in more than 1 out of 10 users

∙ Increased body temperature or chills (signs of infection)

∙ Fever, coughing, difficulty breathing, wheezing, signs of inflammation of the lung (pneumonitis)

Common side effects, effects that may occur in up to 1 out of 10 users

∙ Excessive thirst, high urine output, increased appetite with weight loss, tiredness (signs of diabetes)

∙ Bleeding (hemorrhage), e.g. in the gut wall

∙ Severely decreased urine output, signs of kidney failure (renal failure)

Uncommon side effects, effects that may occur in up to 1 out of 100 users

∙ Fever, skin rash, joint pain and inflammation, fatigue, loss of appetite, nausea, jaundice (yellowing of the skin),

pain in the upper right abdomen, pale stool, dark urine (may also be signs of hepatitis B reactivation)

∙ Breathlessness, difficulty breathing when lying down, swelling of the feet or legs (signs of heart failure)

∙ Swelling and/or pain in one of the legs, usually in the calf. Redness or warm skin in the affected area (signs

of blockade of a blood vessel [vein] in the legs caused by blood clotting)

∙ Sudden onset of shortness of breath, chest pain or coughing up blood (potential signs of pulmonary embolism,

a condition that occurs when one or more arteries in your lungs become blocked)

∙ Severely decreased urine output, swelling in the legs, feeling confused, pain in the back (signs of sudden

kidney failure)

∙ Rash, itching, hives, difficulty breathing or swallowing, dizziness (signs of serious allergic reaction,

hypersensitivity)

Rare side effects, effects that may occur in up to 1 out of 1,000 users

∙ Shortness of breath or rapid breathing (signs of acute respiratory distress syndrome)

∙ Swelling of the airways or tongue, with or without respiratory impairment (angioedema)

If you experience any of these side effects, tell your doctor immediately, as they might have

life-threatening consequences.

Serious side effects observed during the treatment in patients with a kidney tumor known as

Angiomyolipoma associated with Tuberous Sclerosis Complex and in patients with a brain tumor

of the Subependymal Giant Cell Astrocytoma type associated with Tuberous Sclerosis Complex.

Very common side effects, effects that may occur in more than 1 out of 10 users

∙ Fever, coughing, difficulty breathing, wheezing, signs of inflammation of the lung (pneumonia)

Common side effects, effects that may occur in up to 1 out of 10 users

∙ Swelling, feeling of heaviness or tightness, pain, limited mobility of body parts (potential sign of abnormal

buildup of fluid in soft tissue due to a blockage in the lymphatic system - lymphedema)

∙ Rash of small fluid-filled blisters appearing on reddened skin, signs of viral infection that can potentially be

severe (herpes zoster)

∙ Fever, coughing, difficulty breathing, wheezing, signs of inflammation of the lung (pneumonitis)

Uncommon side effects, effects that may occur in up to 1 out of 100 users

∙ Rash, itching, hives, difficulty breathing or swallowing, dizziness, signs of serious allergic reaction

(hypersensitivity)

If you experience any of these side effects, tell your doctor immediately, as they might have

life-threatening consequences.

Additional side effects:

Other side effects observed during treatment of hormone receptor-positive advanced breast cancer,

advanced kidney cancer or advanced neuroendocrine tumors of pancreatic, gastrointestinal or

lung origin:

Very common side effects, effects that may occur in more than 1 out of 10 users

High levels of sugar in the blood (hyperglycemia); loss of appetite; disturbed taste; headache; nose bleeds;

cough; mouth ulcers; stomach upsets including nausea, diarrhea; skin rash; itching (pruritus); feeling weak or

tired; tiredness, breathlessness, dizziness, pale skin, signs of low level of red blood cells (anemia); swelling of

arms, hands, feet, ankles or other part of the body (signs of edema); weight loss; high level of lipids (fats) in

the blood (hypercholesterolemia).

If any of the side effects listed above affect you severely, tell your attending doctor.

Common side effects, effects that may occur in up to 1 out of 10 users

Spontaneous bleeding or bruising, signs of low level of platelets (thrombocytopenia); breathlessness (dyspnea);

thirst, low urine output, dark urine, dry flushed skin, irritability (signs of dehydration); trouble sleeping (insomnia);

headache, dizziness (signs of high blood pressure - hypertension); fever, sore throat or mouth ulcers due

to infections [signs of low level of white blood cells (leukopenia, lymphopenia and/or neutropenia)]; fever;

inflammation of the inner lining of the mouth, stomach, guts; dry mouth; heartburn (dyspepsia); vomiting;

difficulty in swallowing (dysphagia); abdominal pain; acne; rash and pain on the palms of your hands or soles

of your feet (hand foot syndrome); skin reddening (erythema); joint pain; pain in the mouth; menstruation

disorders such as, irregular periods; high level of lipids (fats) in the blood (hyperlipidemia, raised triglycerides);

low level of potassium in the blood (hypokalemia); low level of phosphate in the blood (hypophosphatemia);

low level of calcium in the blood (hypocalcemia); dry skin, skin peeling, skin bruising; nail disorders, brittle

nails; hair loss; abnormal liver blood tests (increased alanine and aspartate aminotransferase); abnormal

renal blood tests (increased creatinine); protein in the urine; discharge from the eyes accompanied by itching,

redness and swelling.

If any of the side effects listed above affect you severely, tell your attending doctor.

Uncommon side effects, effects that may occur in up to 1 out of 100 users

Weakness, spontaneous bleeding or bruising and frequent infections with signs such as fever, chills, sore throat

or mouth ulcers [signs of low level of blood cells (pancytopenia)]; loss of sense of taste (ageusia); coughing up

blood (hemoptysis); absence of periods (amenorrhea); passing urine more often during daytime; chest pain;

abnormal wound healing; hot flushes; pink or red eye (conjunctivitis).

If any of the side effects listed above affect you severely, tell your attending doctor.

Rare side effects, effects that may occur in up to 1 out of 1,000 users

Tiredness, breathlessness, dizziness, pale skin [signs of low levels of red blood cells (a type of anemia called

pure red cell aplasia)].

If these side effects get worse, please tell your doctor, pharmacist, or healthcare provider. Most of the side

effects are mild to moderate and will generally disappear after a few days of treatment interruption.

Other side effects observed during treatment of Tuberous Sclerosis Complex:

Very common side effects, effects that may occur in more than 1 out of 10 users

Upper respiratory tract infection; sore throat and runny nose (nasopharyngitis); headache, pressure in the eyes,

nose or cheek area, signs of inflammation of the sinuses and nasal passages (sinusitis); middle ear infection;

high level of lipids (fats) in the blood (hypercholesterolemia); mouth ulcers; acne; menstruation disorders such

as absence of periods (amenorrhea), irregular periods.

If any of the side effects listed above affect you severely, tell your attending doctor.

Common side effects, effects that may occur in up to 1 out of 10 users

Urinary tract infection; swollen, bleeding gums, signs of gum inflammation (gingivitis); skin inflammation

(cellulitis); sore throat (pharyngitis); high level of lipids (fats) in the blood (hyperlipidemia, raised triglycerides);

low level of phosphate in the blood (hypophosphatemia); high level of sugar in the blood (hyperglycemia);

decreased appetite; tiredness, breathlessness, dizziness, pale skin, signs of low level of red blood cells

(anemia); fever, sore throat or mouth ulcers due to infections, signs of low level of white blood cells (leukopenia,

lymphopenia, neutropenia); headache, dizziness, signs of high blood pressure (hypertension); headache;

disturbed taste; spontaneous bleeding or bruising, signs of low level of platelets (thrombocytopenia); cough;

mouth pain; nose bleeds; inflammation of the stomach lining (gastritis); diarrhea; vomiting; stomach upset such

as nausea; abdominal pain; severe pain in the lower abdomen and pelvic area that may be sharp, with menstrual

irregularities (ovarian cyst); excess amount of gas in the bowels (flatulence); constipation; abdominal pain,

nausea, vomiting, diarrhea, swelling of the abdomen, signs of inflammation of the stomach lining (gastritis, viral

gastroenteritis); dry skin; skin rash; an inflammatory condition of the skin characterized by redness, itching, and

oozing liquid-filled cysts which become scaly, crusted, or hardened (dermatitis acneiform); hair loss; protein in

the urine; menstruation disorders such as delayed periods, heavy periods (menorrhagia), or vaginal bleeding;

feeling tired; irritability; aggression; fever; high level of an enzyme called lactate dehydrogenase in the blood

that gives information about the health of certain organs; higher level of ovulation triggering hormone in the

blood (increased Luteinizing Hormone - LH); weight loss.

If any of the side effects listed above affect you severely, tell your attending doctor.

Uncommon side effects, effects that may occur in up to 1 out of 100 users

Muscle spasm, fever, red-brown urine, these are possibly signs of muscle disorder (rhabdomyolysis); cough

with phlegm, chest pain, fever, signs of inflammation of airways (viral bronchitis); insomnia; higher blood level

of female reproductive hormone (increase in Follicle Stimulating Hormone - FSH).

If these side effects get worse, please tell your doctor, pharmacist, or healthcare provider. Most of the side

effects are mild to moderate and will generally disappear after a few days of treatment interruption.

If a side effect occurs, if one of the side effects worsens or if you suffer from a side effect not mentioned in

this leaflet, consult the doctor.

Hepatitis B reactivation has been observed in some patients taking Afinitor. Tell your doctor if you experience

symptoms of hepatitis B during treatment with Afinitor. The first symptoms include fever, skin rash, joint pain

and inflammation. Other symptoms may include fatigue, loss of appetite, nausea, jaundice (yellowing of the

skin), and pain in the upper right abdomen. Pale stools or dark urine may also be signs of hepatitis.

Side effects and drug interactions in children:

Parents must inform the attending doctor about any side effects, as well as any additional medicines being

given to the child!

Side effects can be reported to the Ministry of Health by clicking on the link “Report Side Effects of Drug

Treatment” found on the Ministry of Health homepage (www.health.gov.il) that directs you to the online form

for reporting side effects,

or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

∙ Avoid poisoning! This medicine, and any other medicine, should be kept in a safe place out of the reach and

sight of children and/or infants in order to avoid poisoning. Do not induce vomiting unless explicitly instructed

to do so by the doctor.

∙ Do not use the medicine after the expiry date (exp. date) appearing on the package. The expiry date refers

to the last day of that month.

∙ Do not store above 25°C.

∙ Store in the original package in order to protect from light and moisture. Do not use if you notice that the

package is damaged.

∙ Open the blister (tray) pack immediately before taking Afinitor tablets.

Do not throw away any medicines via household waste. Ask your pharmacist how to dispose of medicines you

no longer use. These measures will help to protect the environment.

6. FURTHER INFORMATION

∙ In addition to the active ingredient, the medicine also contains:

Lactose anhydrous, crospovidone, hypromellose, lactose monohydrate, magnesium stearate and butylated

hydroxytoluene.

Each Afinitor 2.5 mg tablet contains 71.875 mg lactose anhydrous and 2.450 mg lactose monohydrate.

Each Afinitor 5 mg tablet contains 143.75 mg lactose anhydrous and 4.90 mg lactose monohydrate.

Each Afinitor 10 mg tablet contains 287.50 mg lactose anhydrous and 9.80 mg lactose monohydrate.

∙ What does the medicine look like and what are the contents of the package

The tablets are white to slightly yellowish, elongated with bevelled edges and no score line.

Afinitor 2.5 mg: The tablets are engraved with “LCL” on one side and “NVR” on the other.

Afinitor 5 mg: The tablets are engraved with “5” on one side and “NVR” on the other.

Afinitor 10 mg: The tablets are engraved with “UHE” on one side and “NVR” on the other.

Each package contains 30 tablets.

∙ Registration Holder and address: Novartis Israel Ltd., 36 Shacham St., Petach-Tikva.

∙ Manufacturer and address: Novartis Pharma Stein AG, Switzerland for Novartis Pharma AG, Basel,

Switzerland.

∙ This leaflet was checked and approved by the Ministry of Health in August 2016

∙ Registration numbers of the medicine in the National Drug Registry of the Ministry of Health:

Afinitor 2.5 mg: 146 82 33388

Afinitor 5 mg:

142 86 32045

Afinitor 10 mg:

142 87 32046

SH AFI APL AUG16 CL V7 COR NOV16 CL

SH AFI APL AUG16 CL V7 COR NOV16 CL

ﺮﺒﻛﺃ ﺔﻴﺋﺍﻭﺩ ﺔﻋﺮﺟ ﺄﻄﺨﻟﺎﺑ ﺖﻟﻭﺎﻨﺗ ﺍﺫﺇ ﺔﺒﻠﻋ ﺮﻀﺣﺃﻭ ،ﻰﻔﺸﺘﺴﻤﻟﺍ ﻲﻓ ﺉﺭﺍﻮﻄﻟﺍ ﺔﻓﺮﻐﻟ ﻭﺃ ﺐﻴﺒﻄﻠﻟ

ﻻﺎﺣ ﻪﺟﻮﺗ ،ﺀﺍﻭﺪﻟﺍ ﻦﻣ ﺄﻄﺨﻟﺎﺑ ﺮﺧﺁ ﺺﺨﺷ ﻭﺃ ﻞﻔﻃ ﻊﻠﺑ ﺍﺫﺇ ﻭﺃ ﺔﻃﺮﻔﻣ ﺔﻴﺋﺍﻭﺩ ﺔﻋﺮﺟ ﺖﻟﻭﺎﻨﺗ ﺍﺫﺇ .ﺉﺭﺎﻃ ﻲﺒﻃ ﺝﻼﻌﻟ ﺔﺟﺎﺣ ﻚﻟﺎﻨﻫ ﻥﻮﻜﺗ ﻥﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ .ﺖﻟﻭﺎﻨﺗ ﺍﺫﺎﻣ ﺐﻴﺒﻄﻟﺍ ﻑﺮﻌﻴﻟ ﻚﻌﻣ ﺓﺮﺸﻨﻟﺍﻭ ﺀﺍﻭﺪﻟﺍ ﺀﺍﻭﺪﻟﺍ ﻝﻭﺎﻨﺗ ﺖﻴﺴﻧ ﺍﺫﺇ ﺾﻳﻮﻌﺘﻠﻟ

ﺎﻌﻣ ﻦﻴﺘﻴﺋﺍﻭﺩ ﻦﻴﺘﻋﺮﺟ ﻝﻭﺎﻨﺗ ﺯﻮﺠﻳ ﻻ .ﻱﺩﺎﻴﺘﻋﻹﺍ ﻲﻟﺎﺘﻟﺍ ﺪﻋﻮﻤﻟﺍ ﻲﻓ ﺔﻴﻟﺎﺘﻟﺍ ﺔﻴﺋﺍﻭﺪﻟﺍ ﺔﻋﺮﺠﻟﺍ ﻝﻭﺎﻨﺗ ،ﺏﻮﻠﻄﻤﻟﺍ ﺖﻗﻮﻟﺍ ﻲﻓ ﺀﺍﻭﺪﻟﺍ ﺍﺬﻫ ﻝﻭﺎﻨﺗ ﺖﻴﺴﻧ ﺍﺫﺇ .ﺔﻴﺴﻨﻤﻟﺍ ﺔﻴﺋﺍﻭﺪﻟﺍ ﺔﻋﺮﺠﻟﺍ ﻦﻋ .ﺐﻴﺒﻄﻟﺍ ﺔﻴﺻﻮﺗ ﺐﺴﺣ ﺝﻼﻌﻟﺍ ﻰﻠﻋ ﺔﺒﻇﺍﻮﻤﻟﺍ ﺐﺠﻳ .ﺔﻴﺤﺼﻟﺍ ﻚﺘﻟﺎﺣ ﻰﻠﻋ ﻦﺴﺤﺗ ﺃﺮﻃ ﻮﻟﻭ ﻰﺘﺣ ،ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺇ ﻥﻭﺪﺑ ﺀﺍﻭﺪﻟﺎﺑ ﺝﻼﻌﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺍ ﺯﻮﺠﻳ ﻻ

ﻚﻟﺫ ﺮﻣﻷﺍ ﻡﺰﻟ ﺍﺫﺇ ﺔﻴﺒﻄﻟﺍ ﺕﺍﺭﺎﻈﻨﻟﺍ ﻊﺿ .ﺀﺍﻭﺩ ﺎﻬﻴﻓ ﻝﻭﺎﻨﺘﺗ ﺓﺮﻣ ﻞﻛ ﻲﻓ ﺔﻴﺋﺍﻭﺪﻟﺍ ﺔﻋﺮﺠﻟﺍ ﻦﻣ ﺪﻛﺄﺘﻟﺍﻭ ﺀﺍﻭﺪﻟﺍ ﻊﺑﺎﻃ ﺺﻴﺨﺸﺗ ﺐﺠﻳ !ﺔﻤﺘﻌﻟﺍ ﻲﻓ ﺔﻳﻭﺩﻷﺍ ﻝﻭﺎﻨﺘﺗ ﻻ .ﻲﻟﺪﻴﺼﻟﺍ ﻭﺃ ﺐﻴﺒﻄﻟﺍ ﺮﺸﺘﺳﺇ ،ﺀﺍﻭﺪﻟﺍ ﻝﺎﻤﻌﺘﺳﺇ ﻝﻮﺣ ﺔﻴﻓﺎﺿﺇ ﺔﻠﺌﺳﺃ ﻚﻳﺪﻟ ﺕﺮﻓﻮﺗ ﺍﺫﺇ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ

(٤

ﺎﻳﺃ ﻲﻧﺎﻌﺗ ﻻﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ .ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﺔﻤﺋﺎﻗ ﻦﻣ ﺶﻫﺪﻨﺗ ﻻ .ﻦﻴﻠﻤﻌﺘﺴﻤﻟﺍ ﺾﻌﺑ ﺪﻨﻋ ﺔﻴﺒﻧﺎﺟ

ﺎﺿﺍﺮﻋﺃ ﺐﺒﺴﻳ ﺪﻗ ﺭﻮﺘﻴﻨﻴﻓﺃ ﻝﺎﻤﻌﺘﺳﺇ ﻥﺇ ،ﺀﺍﻭﺩ ﻞﻜﺑ ﺎﻤﻛ .ﺔﻨﻴﻌﻣ ﻡﺩ ﺕﺎﺻﻮﺤﻓ ﺞﺋﺎﺘﻧ ﻰﻠﻋ

ﺎﻀﻳﺃ ﺮﺛﺆﻳ ﻥﺃ ﺭﻮﺘﻴﻨﻴﻓﺃ ـﻟ ﻦﻜﻤﻳ .ﺎﻬﻨﻣ ﻲﺴﺴﺤﺘﻟﺍ ﻞﻌﻔﻟﺍ ﺩﺭ ﺕﺎﻣﻼﻋ ﻯﺪﺣﺇ ﻦﻣ ﻚﻠﻔﻃ ﻭﺃ ﺖﻧﺃ ﺖﻴﺳﺎﻗ ﺍﺫﺇ ﻚﻟﺫﻭ ،ﻱﺭﻮﻓ ﻞﻜﺸﺑ ﺔﻴﺒﻃ ﺓﺪﻋﺎﺴﻣ ﻲﻘﻠﺘﻟ ﻪﺟﻮﺗﻭ ﺭﻮﺘﻴﻨﻴﻓﺃ ﻝﻭﺎﻨﺗ ﻦﻋ ﻒﻗﻮﺗ :ﺔﻴﻟﺎﺘﻟﺍ ﻊﻠﺒﻟﺍ ﻭﺃ ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ ∙ ﺓﺮﺠﻨﺤﻟﺍ ﻭﺃ ﻥﺎﺴﻠﻟﺍ ،ﻦﻴﺘﻔﺸﻟﺍ ،ﻪﺟﻮﻟﺍ ﻲﻓ ﺥﺎﻔﺘﻧﺇ ∙ ﺯﺭﺎﺑ ﺥﺎﻔﺘﻧﺈﺑ ﻭﺃ ﺮﻤﺣﺃ ﻪﻧﻮﻟ ﺢﻔﻄﺑ ﻖﻓﺍﺮﺘﺗ ،ﺪﻠﺠﻟﺍ ﻲﻓ ﺓﺪﻳﺪﺷ ﺔﻜﺣ ∙ :ﺔﻳﺪﺟ ﻥﻮﻜﺗ ﻥﺃ ﺎﻬﻧﺄﺷ ﻦﻣ ﺔﻨﻴﻌﻣ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ .ﺓﺎﻴﺤﻟﺍ ﻰﻠﻋ

ﺍﺮﻄﺧ ﻞﻜﺸﺗ ﺕﺎﺳﺎﻜﻌﻧﺇ ﻚﻟﺬﻟ ﻥﻮﻜﺗ ﻥﺃ ﺔﻴﻧﺎﻜﻣﺇ ﺐﺒﺴﺑ ،ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻩﺬﻫ ﻯﺪﺣﺇ ﻦﻣ ﺖﻴﺳﺎﻗ ﺍﺫﺇ

ﹰ

ﻻﺎﺣ ﺐﻴﺒﻄﻟﺍ ﺔﻌﺟﺍﺮﻣ ﺐﺠﻳ ﺔﻣﺪﻘﺘﻣ ﻡﺍﺭﻭﺃﻭ ﻡﺪﻘﺘﻣ ﻰﻠﻛ ﻥﺎﻃﺮﺳ ،ﻲﺑﺎﺠﻳﺇ ﻲﻧﻮﻣﺭﻮﻫ ﻞﺒﻘﺘﺴﻣ ﻊﻣ ﻡﺪﻘﺘﻤﻟﺍ ﻱﺪﺜﻟﺍ ﻥﺎﻃﺮﺴﺑ ﺝﻼﻌﻟﺍ ﺓﺮﺘﻓ ﺀﺎﻨﺛﺃ ﺎﻬﺘﻈﺣﻼﻣ ﻢﺗ ﺔﻳﺪﺟ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ :ﻦﻴﺘﺋﺮﻟﺍ ﻭﺃ ﻲﻤﻀﻬﻟﺍ ﺯﺎﻬﺠﻟﺍ ،ﺱﺎﻳﺮﻜﻨﺒﻟﺍ ﺎﻫﺭﺪﺼﻣ ﻲﺘﻟﺍ ﺔﻴﺒﺼﻌﻟﺍ ﺀﺎﻤﺼﻟﺍ ﺩﺪﻐﻟﺍ ﻲﻓ ﺓﺮﺸﻋ ﻦﻣ ﺪﺣﺍﻭ ﻞﻤﻌﺘﺴﻣ ﻦﻣ ﺮﺜﻛﺃ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

very common

)

ﹰ

ﺍﺪﺟ ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ (ﺙﻮﻠﺗ ﺙﻭﺪﺤﻟ ﺕﺎﻣﻼﻋ) ﺓﺮﻳﺮﻌﺸﻗ ﻭﺃ ﻢﺴﺠﻟﺍ ﺓﺭﺍﺮﺣ ﺔﺟﺭﺩ ﻲﻓ ﻉﺎﻔﺗﺭﺇ ∙

[pneumonitis]

ﻱﻮﺋﺮﻟﺍ ﺞﻴﺴﻨﻟﺍ ﻲﻓ ﺔﻴﺑﺎﻬﺘﻟﺇ ﺓﺮﻴﺴﻣ) ﻦﻴﺘﺋﺮﻟﺍ ﻲﻓ ﺏﺎﻬﺘﻟﻹ ﺕﺎﻣﻼﻋ ،ﺮﻴﻔﺻ ،ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ ،ﻝﺎﻌﺳ ،ﺔﻧﻮﺨﺳ ∙ ﻦﻴﻠﻤﻌﺘﺴﻣ ١٠ ﻦﻴﺑ ﻦﻣ ١ ﻞﻤﻌﺘﺴﻣ ﻰﺘﺣ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

common

) ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ (ﻱﺮﻜﺳ ﺙﻭﺪﺣ ﺕﺎﻣﻼﻋ) ﻕﺎﻫﺭﺇ ،ﻥﺯﻮﻟﺍ ﻲﻓ ﻥﺎﺼﻘﻨﺑ ﻖﻓﺍﺮﺘﺗ ﻡﺎﻌﻄﻠﻟ ﺓﺪﺋﺍﺯ ﺔﻴﻬﺷ ،ﺔﻴﻟﺎﻋ ﺓﺮﻴﺗﻮﺑ ﻝﻮﺒﺗ ،ﺪﺋﺍﺯ ﺶﻄﻋ ∙ ﺀﺎﻌﻣﻷﺍ ﺭﺍﺪﺟ ﻲﻓ

ﻼﺜﻣ ،ﻑﺰﻧ ∙ (ﻱﻮﻠﻛ ﺭﻮﺼﻗ) ﻱﻮﻠﻛ ﻞﺸﻔﻟ ﺕﺎﻣﻼﻋ ،ﻝﻮﺒﺘﻟﺍ ﻲﻓ ﺪﻳﺪﺷ ﺽﺎﻔﺨﻧﺇ ∙ ﻞﻤﻌﺘﺴﻣ ١٠٠ ﻦﻴﺑ ﻦﻣ ١ ﻞﻤﻌﺘﺴﻣ ﻰﺘﺣ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

uncommon

) ﺔﻌﺋﺎﺷ ﺮﻴﻏ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ،ﻦﻄﺒﻟﺍ ﻦﻣ ﻦﻤﻳﻷﺍ ﻱﻮﻠﻌﻟﺍ ﺀﺰﺠﻟﺍ ﻲﻓ ﻢﻟﺃ ،(ﺪﻠﺠﻟﺍ ﺭﺍﺮﻔﺻﺇ) ﻥﺎﻗﺮﻳ ،ﻥﺎﻴﺜﻏ ،ﻡﺎﻌﻄﻠﻟ ﺔﻴﻬﺸﻟﺍ ﻥﺍﺪﻘﻓ ،ﻕﺎﻫﺭﺇ ،ﺏﺎﻬﺘﻟﺇﻭ ﻞﺻﺎﻔﻤﻟﺍ ﻲﻓ ﻡﻻﺁ ،ﻱﺪﻠﺟ ﺢﻔﻃ ،ﺔﻧﻮﺨﺳ ∙

[hepatitis B] B

ﻉﻮﻧ ﻦﻣ ﺪﺒﻜﻟﺍ ﺏﺎﻬﺘﻟﺇ ﻂﻴﺸﻨﺗ ﺓﺩﺎﻋﻹ ﺕﺎﻣﻼﻋ

ﺎﻀﻳﺃ ﻥﻮﻜﺗ ﻥﺃ ﻦﻜﻤﻳ) ﻦﻛﺍﺩ ﻝﻮﺑ ،ﻥﻮﻠﻟﺍ ﺢﺗﺎﻓ ﺯﺍﺮﺑ (ﺐﻠﻘﻟﺍ ﻲﻓ ﺭﻮﺼﻘﻟ ﺕﺎﻣﻼﻋ) ﻦﻴﻠﺟﺮﻟﺍ ﻭﺃ ﻦﻴﻣﺪﻘﻟﺍ ﻲﺘﺣﺍﺭ ﻲﻓ ﺥﺎﻔﺘﻧﺇ ،ﺀﺎﻘﻠﺘﺳﻹﺍ ﺔﻴﻌﺿﻭ ﺀﺎﻨﺛﺃ ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ ،ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﻖﻴﺿ ∙ ﻲﻓ [ﺪﻳﺭﻭ] ﺔﻳﻮﻣﺪﻟﺍ ﺔﻴﻋﻭﻷﺍ ﺩﺍﺪﺴﻧﻹ ﺕﺎﻣﻼﻋ) ﺓﺮﺛﺄﺘﻤﻟﺍ ﺔﻘﻄﻨﻤﻟﺍ ﻲﻓ ﻦﺧﺎﺳ ﺪﻠﺟ ﻭﺃ ﺭﺍﺮﻤﺣﺇ .ﻕﺎﺴﻟﺍ ﻲﻓ ﺓﺩﺎﻋ ،ﻦﻴﻠﺟﺮﻟﺍ ﻯﺪﺣﺇ ﻲﻓ ﻢﻟﺃ ﻭﺃ/ﻭ ﺥﺎﻔﺘﻧﺍ ∙ (ﺔﻳﻮﻣﺩ ﺓﺮﺜﺧ ﺔﺠﻴﺘﻧ ﻦﻴﻠﺟﺮﻟﺍ ﻲﻓ ﺮﺜﻛﺃ ﻭﺃ ﺪﺣﺍﻭ ﻥﺎﻳﺮﺷ ﺩﺍﺪﺴﻧﺇ ﺪﻨﻋ ﺙﺪﺤﺗ ﺔﻟﺎﺣ ،ﻱﻮﺋﺭ ﻡﺎﻤﺼﻧﻹ ﺔﻠﻤﺘﺤﻣ ﺕﺎﻣﻼﻋ) ﻱﻮﻣﺩ ﻝﺎﻌﺳ ﻭﺃ ﺭﺪﺼﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﻖﻴﻀﻟ ﺔﺌﺟﺎﻔﻣ ﺔﺑﻮﻧ ∙ (ﻚﻴﺘﺋﺭ (ﺊﺟﺎﻔﻣ ﻱﻮﻠﻛ ﻞﺸﻔﻟ ﺕﺎﻣﻼﻋ) ﺮﻬﻈﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﻙﺎﺒﺗﺭﺈﺑ ﺱﺎﺴﺣﺇ ،ﻦﻴﻠﺟﺮﻟﺍ ﻲﻓ ﺥﺎﻔﺘﻧﺇ ،ﻝﻮﺒﺘﻟﺍ ﻲﻓ ﺪﻳﺪﺷ ﺽﺎﻔﺨﻧﺇ ∙ (ﺔﻃﺮﻔﻣ ﺔﻴﺳﺎﺴﺣ ،ﺪﻳﺪﺷ ﻲﺴﺴﺤﺗ ﻞﻌﻓ ﺩﺮﻟ ﺕﺎﻣﻼﻋ) ﺭﺍﻭﺩ ،ﻊﻠﺒﻟﺍ ﻭﺃ ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ ،ﻯﺮﺷ ،ﺔﻜﺣ ،ﺢﻔﻃ ∙ ﻞﻤﻌﺘﺴﻣ ١٠٠٠ ﻦﻴﺑ ﻦﻣ ١ ﻞﻤﻌﺘﺴﻣ ﻰﺘﺣ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

rare

) ﺓﺭﺩﺎﻧ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ (ﺓﺩﺎﺤﻟﺍ ﺔﻴﺴﻔﻨﺘﻟﺍ ﺔﻘﺋﺎﻀﻟﺍ ﺔﻣﺯﻼﺘﻣ ﺕﺎﻣﻼﻋ) ﻊﻳﺮﺳ ﺲﻔﻨﺗ ﻭﺃ ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﻖﻴﺿ ∙ (ﺔﻴﺋﺎﻋﻭ ﺔﻣﺫﻭ) ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﺏﺍﺮﻄﺿﺇ ﻥﻭﺪﺑ ﻭﺃ ﻊﻣ ،ﻥﺎﺴﻠﻟﺍ ﻭﺃ ﺔﻴﺴﻔﻨﺘﻟﺍ ﻕﺮﻄﻟﺍ ﻲﻓ ﺥﺎﻔﺘﻧﺍ ∙ .ﺓﺎﻴﺤﻟﺍ ﻰﻠﻋ

ﹰ

ﺍﺮﻄﺧ ﻞﻜﺸﺗ ﺎﻬﺠﺋﺎﺘﻧ ﻥﻮﻜﺗ ﻥﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ ﻪﻧﻷ

ﹰ

ﻻﺎﺣ ﻚﺒﻴﺒﻃ ﻊﺟﺍﺭ ،ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻚﻠﺗ ﻯﺪﺣﺈﺑ ﺕﺮﻌﺷ ﺍﺫﺇ ﻲﻧﺭﺩ ﺐﻠﺼﺘﺑ ﻂﺒﺗﺮﻤﻟﺍ ﻲﺋﺎﻋﻭ ﻲﻠﻀﻋ ﻲﻤﺤﺷ ﻡﺭﻭ ﻰﻤﺴﻳ ﺔﻴﻠﻜﻟﺍ ﻲﻓ ﻡﺭﻭ ﻢﻬﻳﺪﻟ ﻰﺿﺮﻣ ﻯﺪﻟ ﺝﻼﻌﻟﺍ ﺓﺮﺘﻓ ﺀﺎﻨﺛﺃ ﺎﻬﺘﻈﺣﻼﻣ ﻢﺗ ﺔﻳﺪﺟ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ .ﻲﻧﺭﺩ ﺐﻠﺼﺘﺑ ﻖﻠﻌﺘﻤﻟﺍ ﺔﻧﺎﻄﺒﻟﺍ ﺖﺤﺗ ﺎﻳﻼﺨﻟﺍ ﺔﻤﺨﺿ ﺔﻴﻤﺠﻨﻟﺍ ﻡﺍﺭﻭﻷﺍ ﻉﻮﻧ ﻦﻣ ﻲﻏﺎﻣﺩ ﻡﺭﻭ ﻢﻬﻳﺪﻟ ﻰﺿﺮﻣ ﻯﺪﻟﻭ ﺓﺮﺸﻋ ﻦﻣ ﺪﺣﺍﻭ ﻞﻤﻌﺘﺴﻣ ﻦﻣ ﺮﺜﻛﺃ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

very common

)

ﹰ

ﺍﺪﺟ ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ

[pneumonia]

ﻦﻴﺘﺋﺮﻟﺍ ﺏﺎﻬﺘﻟﺇ) ﺔﺋﺮﻟﺍ ﻲﻓ ﺏﺎﻬﺘﻟﻹ ﺕﺎﻣﻼﻋ ،ﺮﻴﻔﺻ ،ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ ،ﻝﺎﻌﺳ ،ﺔﻧﻮﺨﺳ ∙ ﻦﻴﻠﻤﻌﺘﺴﻣ ١٠ ﻦﻴﺑ ﻦﻣ ١ ﻞﻤﻌﺘﺴﻣ ﻰﺘﺣ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

common

) ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﺯﺎﻬﺠﻟﺍ ﻲﻓ ﺩﺍﺪﺴﻧﺇ ﺔﺠﻴﺘﻧ ﻮﺧﺮﻟﺍ ﺞﻴﺴﻨﻟﺍ ﻲﻓ ﻞﺋﺍﻮﺴﻟ ﻱﺩﺎﻴﺘﻋﺇ ﺮﻴﻏ ﻢﻛﺍﺮﺘﻟ ﺔﻠﻤﺘﺤﻣ ﺔﻣﻼﻋ) ﻢﺴﺠﻟﺍ ﻑﺍﺮﻃﻷ ﺓﺩﻭﺪﺤﻣ ﺔﻛﺮﺣ ،ﻢﻟﺃ ،ﻖﻴﺿ ﻭﺃ ﻞﻘﺜﺑ ﺭﻮﻌﺸﻟﺍ ،ﺥﺎﻔﺘﻧﺇ ∙

(lymphedema

ـ ﻱﻭﺎﻔﻤﻴﻠﻟﺍ ﻸﺤﻟﺍ]

herpes zoster

ﺍﺮﻴﻄﺧ ﻥﻮﻜﻳ ﻥﺃ ﺔﻴﻧﺎﻜﻣﺇ ﻭﺫ ﻲﺳﻭﺮﻴﭬ ﺙﻮﻠﺘﻟ ﺕﺎﻣﻼﻋ ،ﺮﻤﺤﻣ ﺪﻠﺟ ﻰﻠﻋ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﻞﺋﺎﺴﺑ ﺔﺌﻴﻠﻣ ﺓﺮﻴﻐﺻ ﺕﻼﺼﻳﻮﺤﻟ ﺢﻔﻃ ∙ ([ﻲﻗﺎﻄﻨﻟﺍ

pneumonitis

) ﻱﻮﺋﺮﻟﺍ ﺞﻴﺴﻨﻟﺍ ﻲﻓ ﺔﻴﺑﺎﻬﺘﻟﺇ ﺓﺮﻴﺴﻣ ،ﺔﺋﺮﻟﺍ ﻲﻓ ﺏﺎﻬﺘﻟﻹ ﺕﺎﻣﻼﻋ ،ﺮﻴﻔﺻ ،ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ ،ﻝﺎﻌﺳ ،ﺔﻧﻮﺨﺳ ∙ ﻞﻤﻌﺘﺴﻣ ١٠٠ ﻦﻴﺑ ﻦﻣ ١ ﻞﻤﻌﺘﺴﻣ ﻰﺘﺣ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

uncommon

) ﺔﻌﺋﺎﺷ ﺮﻴﻏ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ (ﺔﻃﺮﻔﻣ ﺔﻴﺳﺎﺴﺣ) ﺪﻳﺪﺷ ﻲﺴﺴﺤﺗ ﻞﻌﻓ ﺩﺮﻟ ﺕﺎﻣﻼﻋ ،ﺭﺍﻭﺩ ،ﻊﻠﺒﻟﺍ ﻭﺃ ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ ،ﻯﺮﺷ ،ﺔﻜﺣ ،ﺢﻔﻃ ∙ .ﺓﺎﻴﺤﻟﺍ ﻰﻠﻋ

ﹰ

ﺍﺮﻄﺧ ﻞﻜﺸﺗ ﺎﻬﺠﺋﺎﺘﻧ ﻥﻮﻜﺗ ﻥﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ ﻪﻧﻷ

ﹰ

ﻻﺎﺣ ﻚﺒﻴﺒﻃ ﻊﺟﺍﺭ ،ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻚﻠﺗ ﻯﺪﺣﺈﺑ ﺕﺮﻌﺷ ﺍﺫﺇ :ﺔﻴﻓﺎﺿﺇ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻡﺍﺭﻭﺃ ﻭﺃ ﻡﺪﻘﺘﻤﻟﺍ ﻰﻠﻜﻟﺍ ﻥﺎﻃﺮﺳ ،ﻲﺑﺎﺠﻳﺇ ﻲﻧﻮﻣﺭﻮﻫ ﻞﺒﻘﺘﺴﻣ ﻊﻣ ﻡﺪﻘﺘﻤﻟﺍ ﻱﺪﺜﻟﺍ ﻥﺎﻃﺮﺴﺑ ﺝﻼﻌﻟﺍ ﺓﺮﺘﻓ ﺀﺎﻨﺛﺃ ﺎﻬﺘﻈﺣﻼﻣ ﻢﺗ ﻯﺮﺧﺃ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ :ﻦﻴﺘﺋﺮﻟﺍ ﻭﺃ ﻲﻤﻀﻬﻟﺍ ﺯﺎﻬﺠﻟﺍ ،ﺱﺎﻳﺮﻜﻨﺒﻟﺍ ﺎﻫﺭﺪﺼﻣ ﻲﺘﻟﺍ ﺔﻴﺒﺼﻌﻟﺍ ﺀﺎﻤﺼﻟﺍ ﺩﺪﻐﻟﺍ ﻲﻓ ﺔﻣﺪﻘﺘﻣ ﺓﺮﺸﻋ ﻦﻣ ﺪﺣﺍﻭ ﻞﻤﻌﺘﺴﻣ ﻦﻣ ﺮﺜﻛﺃ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

very common

)

ﹰ

ﺍﺪﺟ ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﺝﺎﻋﺰﻧﺇ ؛ﻢﻔﻟﺍ ﻲﻓ ﺕﺎﺣﺮﻘﺗ ؛ﻝﺎﻌﺳ ؛ﻑﺎﻋﺭ ؛ﻉﺍﺪﺻ ؛ﻕﺍﺬﻤﻟﺍ ﺔﺳﺎﺣ ﻲﻓ ﺏﺍﺮﻄﺿﺇ ؛ﻡﺎﻌﻄﻠﻟ ﺔﻴﻬﺸﻟﺍ ﻥﺍﺪﻘﻓ ؛

(hyperglycemia)

ﻡﺪﻟﺍ ﻲﻓ ﺮﻜﺴﻟﺍ ﻦﻣ ﺔﻌﻔﺗﺮﻣ ﺐﺴﻧ ﺕﺎﻣﻼﻋ ،ﺏﻮﺤﺷ ،ﺭﺍﻭﺩ ،ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﻖﻴﺿ ،ﻕﺎﻫﺭﺇ ؛ﻕﺎﻫﺭﺇ ﻭﺃ ﻒﻌﻀﺑ ﺭﻮﻌﺸﻟﺍ ؛(

pruritus

) ﺔﻜﺣ ؛ﺪﻠﺠﻟﺍ ﻲﻓ ﺢﻔﻃ ؛ﻝﺎﻬﺳﺇ ،ﻥﺎﻴﺜﻏ ﻚﻟﺫ ﻲﻓ ﺎﻤﺑ ﻦﻄﺒﻟﺍ ﻲﻓ ﻢﺴﺠﻟﺍ ﻦﻣ ﻯﺮﺧﺃ ﺔﻘﻄﻨﻣ ﻭﺃ ﻦﻴﻠﺣﺎﻜﻟﺍ ،ﻦﻴﻣﺪﻘﻟﺍ ﻲﺘﺣﺍﺭ ،ﻦﻳﺪﻴﻟﺍ ،ﻦﻴﻋﺍﺭﺬﻟﺍ ﻲﻓ ﺥﺎﻔﺘﻧﺇ ؛(ﻡﺪﻟﺍ ﺮﻘﻓ) ﺀﺍﺮﻤﺤﻟﺍ ﻡﺪﻟﺍ ﺎﻳﻼﺧ ﻦﻣ ﺔﻀﻔﺨﻨﻣ ﺔﺒﺴﻨﻟ .(ﻡﺪﻟﺍ ﻲﻓ ﻝﻭﺮﺘﺴﻟﻮﻜﻟﺍ ﻁﺮﻓ ) ﻡﺪﻟﺍ ﻲﻓ ﻡﻮﺤﺸﻟﺍ ﻦﻣ ﺔﻌﻔﺗﺮﻣ ﺐﺴﻧ ؛ﻥﺯﻮﻟﺍ ﻥﺍﺪﻘﻓ ؛(ﺔﻣﺫﻮﻟ ﺕﺎﻣﻼﻋ) .ﺞﻟﺎﻌﻤﻟﺍ ﻚﺒﻴﺒﻃ ﻊﺟﺍﺭ ،ﺮﻴﻄﺧ ﻞﻜﺸﺑ ﻩﻼﻋﺃ ﺓﺭﻮﻛﺬﻤﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﻚﻴﻠﻋ ﺮﺛﺆﺗ ﺍﺫﺇ ﻦﻴﻠﻤﻌﺘﺴﻣ ١٠ ﻦﻴﺑ ﻦﻣ ١ ﻞﻤﻌﺘﺴﻣ ﻰﺘﺣ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

common

) ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ،ﺶﻄﻋ ؛(

dyspnea

) ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﻖﻴﺿ ؛

(thrombocytopenia)

ﺔﻳﻮﻣﺪﻟﺍ ﺕﺎﺤﻴﻔﺼﻟﺍ ﻦﻣ ﺔﻀﻔﺨﻨﻣ ﺔﺒﺴﻨﻟ ﺕﺎﻣﻼﻋ ،ﻱﻮﻔﻋ ﻞﻜﺸﺑ ﻥﺎﺛﺪﺤﺗ ﺔﻣﺪﻛ ﻭﺃ ﻑﺰﻧ ـ ﻊﻔﺗﺮﻣ ﻡﺩ ﻂﻐﻀﻟ ﺕﺎﻣﻼﻋ) ﺭﺍﻭﺩ ،ﻉﺍﺪﺻ ؛(ﻕﺭﺃ) ﻡﻮﻨﻟﺍ ﻲﻓ ﻞﻛﺎﺸﻣ ؛(ﻑﺎﻔﺠﺗ ﺙﻭﺪﺤﻟ ﺕﺎﻣﻼﻋ) ﺀﻭﺪﻫ ﻡﺪﻋ ،ﻑﺎﺟﻭ ﺩﺭﻮﺘﻣ ﺪﻠﺟ ،ﻦﻛﺍﺩ ﻝﻮﺑ ،ﻝﻮﺒﺘﻟﺍ ﺔﻠﻗ ﺕﺎﻳﺮﻜﻟﺍ ﺔﻠﻗ) ﺀﺎﻀﻴﺒﻟﺍ ﻡﺪﻟﺍ ﺎﻳﻼﺧ ﻦﻣ ﺔﻀﻔﺨﻨﻣ ﺔﺒﺴﻨﻟ ﺕﺎﻣﻼﻋ] ﺕﺎﺛﻮﻠﺗ ﺔﺠﻴﺘﻧ ﻢﻔﻟﺍ ﻲﻓ ﺕﺎﺣﺮﻘﺗ ﻭﺃ ﺓﺮﺠﻨﺤﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﺔﻧﻮﺨﺳ ؛(ﻡﺪﻟﺍ ﻂﻐﺿ ﻉﺎﻔﺗﺭﺇ ؛(ﻢﻀﻬﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ) ﻥﺎﻗﺮﺣ ؛ﻢﻔﻟﺍ ﻲﻓ ﻑﺎﻔﺟ ؛ﺀﺎﻌﻣﻷﺍ ،ﺓﺪﻌﻤﻟﺍ ،ﻢﻔﻠﻟ ﻲﻠﺧﺍﺪﻟﺍ ﺭﺍﺪﺠﻟﺍ ﻲﻓ ﺙﻮﻠﺗ ؛ﺔﻧﻮﺨﺳ ؛[(ﺕﻻﺪﻌﻟﺍ ﺔﻠﻗ ﻭﺃ/ﻭ ﺕﺎﻳﻭﺎﻔﻤﻠﻟﺍ ﺔﻠﻗ ،ﺾﻴﺒﻟﺍ

(hand foot syndrome)

ﻦﻴﻣﺪﻘﻟﺍ ﻲﺘﺣﺍﺭ ﻭﺃ ﻦﻳﺪﻴﻟﺍ ﻲﺘﺣﺍﺭ ﻲﻓ ﻢﻟﺃﻭ ﺢﻔﻃ ؛ﺏﺎﺒﺸﻟﺍ ﺐﺣ ؛ﻦﻄﺒﻟﺍ ﻲﻓ ﻢﻟﺃ ؛

(dysphagia)

ﻊﻠﺒﻟﺍ ﻲﻓ ﺕﺎﺑﻮﻌﺻ ؛ﺕﺍﺆﻴﻘﺗ ﻡﻮﺤﺸﻠﻟ ﺔﻌﻔﺗﺮﻣ ﺔﺒﺴﻧ ؛ﺔﻳﺮﻬﺸﻟﺍ ﺕﺍﺭﻭﺪﻟﺍ ﻡﺎﻈﺘﻧﺇ ﻡﺪﻋ ﻞﺜﻣ ﺔﻳﺮﻬﺸﻟﺍ ﺓﺭﻭﺪﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﺇ ؛ﻢﻔﻟﺍ ﻲﻓ ﻢﻟﺃ ؛ﻞﺻﺎﻔﻤﻟﺍ ﻲﻓ ﻢﻟﺃ ؛

(erythema)

ﺪﻠﺠﻟﺍ ﺭﺍﺮﻤﺣﺇ ﻲﻓ ﺭﻮﻔﺳﻮﻔﻠﻟ ﺔﻀﻔﺨﻨﻣ ﺔﺒﺴﻧ ؛

(hypokalemia)

ﻡﺪﻟﺍ ﻲﻓ ﻡﻮﻴﺳﺎﺗﻮﭙﻟﺍ ﻦﻣ ﺔﻀﻔﺨﻨﻣ ﺔﺒﺴﻧ ؛(ﺕﺍﺪﻳﺮﻴﺴﻴﻠﭽﻳﺮﺘﻟﺍ ﻉﺎﻔﺗﺭﺇ ،ﻡﺪﻟﺍ ﻲﻓ ﻡﻮﺤﺸﻟﺍ ﻁﺮﻓ) ﻡﺪﻟﺍ ﻲﻓ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﺇ ؛ﺪﻠﺠﻟﺍ ﻲﻓ ﺕﺎﻣﺪﻛ ،ﺪﻠﺠﻟﺍ ﺮﺸﻘﺗ ،ﺪﻠﺠﻟﺍ ﻑﺎﻔﺟ ؛(

hypocalcemia

) ﻡﺪﻟﺍ ﻲﻓ ﻡﻮﻴﺴﻟﺎﻜﻠﻟ ﺔﻀﻔﺨﻨﻣ ﺔﺒﺴﻧ ؛

(hypophosphatemia)

ﻡﺪﻟﺍ ﺔﻴﻠﻜﻠﻟ ﺔﻤﻴﻠﺳ ﺮﻴﻏ ﻡﺩ ﺕﺎﺻﻮﺤﻓ ؛(ﺯﺍﺮﻴﻔﺴﻧﺮﺗﻮﻨﻴﻣﺃ ﺕﺎﺗﺭﺎﭙﺳﺃ ﻭ ﻦﻴﻧﻻﺁ ﻲﻓ ﺓﺩﺎﻳﺯ)ﺪﺒﻜﻠﻟ ﺔﻤﻴﻠﺳ ﺮﻴﻏ ﻡﺩ ﺕﺎﺻﻮﺤﻓ ؛ﺮﻌﺷ ﻂﻗﺎﺴﺗ ؛ﺮﻓﺎﻇﻷﺍ ﻒﺼﻘﺗ ،ﺮﻓﺎﻇﻷﺍ .ﺥﺎﻔﺘﻧﺇﻭ ﺭﺍﺮﻤﺣﺇ ،ﺔﻜﺤﺑ ﻖﻓﺍﺮﺘﺗ ﻦﻴﻨﻴﻌﻟﺍ ﻦﻣ ﺕﺍﺯﺍﺮﻓﺇ ؛ﻝﻮﺒﻟﺍ ﻲﻓ ﻦﻴﺗﻭﺮﭘ ؛(ﻦﻴﻨﻴﺗﺎﻳﺮﻜﻟﺍ ﻲﻓ ﺓﺩﺎﻳﺯ) .ﺞﻟﺎﻌﻤﻟﺍ ﻚﺒﻴﺒﻃ ﻊﺟﺍﺭ ،ﺮﻴﻄﺧ ﻞﻜﺸﺑ ﻩﻼﻋﺃ ﺓﺭﻮﻛﺬﻤﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﻚﻴﻠﻋ ﺕﺮﺛﺃ ﺍﺫﺇ ﻞﻤﻌﺘﺴﻣ ١٠٠ ﻦﻴﺑ ﻦﻣ ١ ﻞﻤﻌﺘﺴﻣ ﻰﺘﺣ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

uncommon

) ﺔﻌﺋﺎﺷ ﺮﻴﻏ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﺔﺒﺴﻨﻟ ﺕﺎﻣﻼﻋ] ﻢﻔﻟﺍ ﻲﻓ ﺕﺎﺣﺮﻘﺗ ﻭﺃ ﺓﺮﺠﻨﺤﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﺓﺮﻳﺮﻌﺸﻗ ،ﺔﻧﻮﺨﺳ ﻞﺜﻣ ﺕﺎﻣﻼﻌﺑ ﻖﻓﺍﺮﺘﺗ ﺔﻌﺋﺎﺷ ﺕﺎﺛﻮﻠﺗﻭ ﻱﻮﻔﻋ ﻞﻜﺸﺑ ﺔﻣﺪﻛ ﻭﺃ ﻑﺰﻧ ،ﻒﻌﺿ ﻝﻮﺒﺗ ؛(ﺚﻤﻄﻟﺍ ﻉﺎﻄﻘﻧﺇ) ﺔﻳﺮﻬﺸﻟﺍ ﺓﺭﻭﺪﻟﺍ ﺏﺎﻴﻏ ؛(ﻡﺩ ﻖﺼﺑ) ﻱﻮﻣﺩ ﻝﺎﻌﺳ ؛

(ageusia)

ﻕﺍﺬﻤﻟﺍ ﺔﺳﺎﺣ ﻥﺍﺪﻘﻓ ؛[(

pancytopenia

) ﻡﺪﻟﺍ ﺎﻳﻼﺨﻟ ﺔﻀﻔﺨﻨﻣ .(ﺔﻤﺤﺘﻠﻤﻟﺍ ﺏﺎﻬﺘﻟﺇ) ﺮﻤﺣﺃ ﻭﺃ ﻱﺩﺭﻭ ﻥﻮﻠﺑ ﻦﻴﻋ ؛ﺮﺤﻟﺍ ﻦﻣ ﺕﺎﺒﻫ ؛ﺡﻭﺮﺠﻠﻟ ﻲﻌﻴﺒﻃ ﺮﻴﻏ ﺀﺎﻔﺷ ؛ﺭﺪﺼﻟﺍ ﻲﻓ ﻡﻻﺁ ؛ﻡﻮﻴﻟﺍ ﻝﻼﺧ ﻰﻠﻋﺃ ﺓﺮﻴﺗﻮﺑ .ﺞﻟﺎﻌﻤﻟﺍ ﻚﺒﻴﺒﻃ ﻊﺟﺍﺭ ،ﺮﻴﻄﺧ ﻞﻜﺸﺑ ﻩﻼﻋﺃ ﺓﺭﻮﻛﺬﻤﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﻚﻴﻠﻋ ﺕﺮﺛﺃ ﺍﺫﺇ ﻞﻤﻌﺘﺴﻣ ١٠٠٠ ﻦﻴﺑ ﻦﻣ ١ ﻞﻤﻌﺘﺴﻣ ﻰﺘﺣ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

rare

) ﺓﺭﺩﺎﻧ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ

(pure red cell aplasia

ﻰﻤﺴﻤﻟﺍ ﻡﺪﻟﺍ ﺮﻘﻓ ﻦﻣ ﻉﻮﻧ

ﺀﺍﺮﻤﺤﻟﺍ ﻡﺪﻟﺍ ﺎﻳﻼﺨﻟ ﺔﻀﻔﺨﻨﻣ ﺔﺒﺴﻨﻟ ﺕﺎﻣﻼﻋ] ﺏﻮﺤﺷ ،ﺭﺍﻭﺩ ،ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﻖﻴﺿ ،ﻕﺎﻫﺭﺇ ﻝﻭﺰﺗ ﺓﺩﺎﻋﻭ ﺔﻄﺳﻮﺘﻣ ﻰﺘﺣ ﺔﻔﻴﻔﺧ ﻲﻫ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﺔﻴﺒﻟﺎﻏ .ﻲﺒﻄﻟﺍ ﻢﻗﺎﻄﻟﺍ ﻦﻣ ﺺﺨﺷ ﻭﺃ ﻲﻟﺪﻴﺼﻟﺍ ،ﻚﺒﻴﺒﻃ ﻊﺟﺍﺭ ﺀﺎﺟﺮﻟﺍ ،ﺽﺍﺮﻋﻷﺍ ﻩﺬﻫ ﺖﻤﻗﺎﻔﺗ ﺍﺫﺇ .ﺝﻼﻌﻟﺍ ﻒﻗﻮﺗ ﻦﻣ ﻡﺎﻳﺃ ﺓﺪﻋ ﺪﻌﺑ

:(

Tuberous

Sclerosis Complex

)ﻲﻧﺭﺪﻟﺍ ﺐﻠﺼﺘﻟﺎﺑ ﻖﻠﻌﺘﻤﻟﺍ ﺝﻼﻌﻟﺍ ﺓﺮﺘﻓ ﺀﺎﻨﺛﺃ ﺎﻬﺘﻈﺣﻼﻣ ﻢﺗ ﺔﻴﻓﺎﺿﺇ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﺓﺮﺸﻋ ﻦﻣ ﺪﺣﺍﻭ ﻞﻤﻌﺘﺴﻣ ﻦﻣ ﺮﺜﻛﺃ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

very common

)

ﹰ

ﺍﺪﺟ ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﺕﺎﻣﻼﻋ ،ﻦﻳﺪﺨﻟﺍ ﺔﻘﻄﻨﻣ ﻲﻓ ﻭﺃ ﻒﻧﻷﺍ ﻲﻓ ،ﻦﻴﻨﻴﻌﻟﺍ ﻲﻓ ﻂﻐﺿ ،ﻉﺍﺪﺻ ؛

(nasopharyngitis)

ﻒﻧﺃ ﻥﻼﻴﺳﻭ ﺓﺮﺠﻨﺤﻟﺍ ﻲﻓ ﻢﻟﺃ ؛ﺔﻳﻮﻠﻌﻟﺍ ﺔﻴﺴﻔﻨﺘﻟﺍ ﻕﺮﻄﻟﺍ ﺏﺎﻬﺘﻟﺇ ؛ﻢﻔﻟﺍ ﻲﻓ ﺕﺎﺣﺮﻘﺗ ؛(ﻡﺪﻟﺍ ﻲﻓ ﻝﻭﺮﺘﺴﻟﻮﻜﻟﺍ ﻁﺮﻓ) ﻡﺪﻟﺍ ﻲﻓ ﻡﻮﺤﺸﻠﻟ ﺔﻌﻔﺗﺮﻣ ﺔﺒﺴﻧ ؛ﻰﻄﺳﻮﻟﺍ ﻥﺫﻷﺍ ﻲﻓ ﺙﻮﻠﺗ ؛

(sinusitis)

ﺔﻴﻔﻧﻷﺍ ﻱﺭﺎﺠﻤﻟﺍﻭ ﺏﻮﻴﺠﻟﺍ ﺏﺎﻬﺘﻟﻹ .ﺔﻤﻈﺘﻨﻣ ﺮﻴﻏ ﺔﻳﺮﻬﺷ ﺕﺍﺭﻭﺩ ،(ﺚﻤﻄﻟﺍ ﻉﺎﻄﻘﻧﺇ) ﺔﻳﺮﻬﺸﻟﺍ ﺓﺭﻭﺪﻟﺍ ﺏﺎﻴﻏ ﻞﺜﻣ ،ﺔﻳﺮﻬﺸﻟﺍ ﺓﺭﻭﺪﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﺇ ؛ﺏﺎﺒﺸﻟﺍ ﺐﺣ .ﺞﻟﺎﻌﻤﻟﺍ ﻚﺒﻴﺒﻃ ﻊﺟﺍﺭ ،ﺮﻴﻄﺧ ﻞﻜﺸﺑ ﻩﻼﻋﺃ ﺓﺭﻮﻛﺬﻤﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﻚﻴﻠﻋ ﺕﺮﺛﺃ ﺍﺫﺇ ﻦﻴﻠﻤﻌﺘﺴﻣ ١٠ ﻦﻴﺑ ﻦﻣ ١ ﻞﻤﻌﺘﺴﻣ ﻰﺘﺣ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

common

) ﺔﻌﺋﺎﺷ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﺏﺎﻬﺘﻟﺇ) ﺓﺮﺠﻨﺤﻟﺍ ﻲﻓ ﻢﻟﺃ ؛(

cellulitis

) ﺪﻠﺠﻟﺍ ﻲﻓ ﺏﺎﻬﺘﻟﺇ ؛(gingivitis) ﺔﺜﻠﻟﺍ ﻲﻓ ﺙﻮﻠﺘﻟ ﺕﺎﻣﻼﻋ ،ﺔﺜﻠﻟﺍ ﻲﻓ ﻑﺰﻧﻭ ﺥﺎﻔﺘﻧﺇ ؛ﺔﻴﻟﻮﺒﻟﺍ ﻚﻟﺎﺴﻤﻟﺍ ﻲﻓ ﺙﻮﻠﺗ ﻡﺪﻟﺍ ﻲﻓ ﺭﻮﻔﺳﻮﻔﻟﺍ ﻦﻣ ﺔﻀﻔﺨﻨﻣ ﺔﺒﺴﻧ ؛(ﺕﺍﺪﻳﺮﻴﺴﻴﻠﭽﻳﺮﺘﻟﺍ ﻲﻓ ﻉﺎﻔﺗﺭﺇ ،ﻡﺪﻟﺍ ﻲﻓ ﻡﻮﺤﺸﻟﺍ ﻁﺮﻓ) ﻡﺪﻟﺍ ﻲﻓ ﻡﻮﺤﺸﻟﺍ ﻦﻣ ﺔﻌﻔﺗﺮﻣ ﺔﺒﺴﻧ ؛(ﻡﻮﻌﻠﺒﻟﺍ ،ﺏﻮﺤﺷ ،ﺭﺍﻭﺩ ،ﺲﻔﻨﺘﻟﺍ ﻲﻓ ﻖﻴﺿ ،ﻕﺎﻫﺭﺇ ؛ﻡﺎﻌﻄﻠﻟ ﺔﻴﻬﺸﻟﺍ ﺔﻠﻗ ؛(

hyperglycemia

) ﻡﺪﻟﺍ ﻲﻓ ﺮﻜﺴﻟﺍ ﻦﻣ ﺔﻌﻔﺗﺮﻣ ﺔﺒﺴﻧ ؛(

hypophosphatemia

ﺎﻳﻼﺨﻟ ﺔﻀﻔﺨﻨﻣ ﺔﺒﺴﻨﻟ ﺕﺎﻣﻼﻋ ،ﺕﺎﺛﻮﻠﺗ ﺮﺛﺇ ﻢﻔﻟﺍ ﻲﻓ ﺕﺎﺣﺮﻘﺗ ﻭﺃ ﺓﺮﺠﻨﺤﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﺔﻧﻮﺨﺳ ؛(ﻡﺪﻟﺍ ﺮﻘﻓ) ﺀﺍﺮﻤﺤﻟﺍ ﻡﺪﻟﺍ ﺎﻳﻼﺨﻟ ﺔﻀﻔﺨﻨﻣ ﺔﺒﺴﻨﻟ ﺕﺎﻣﻼﻋ ﺔﺳﺎﺣ ﻲﻓ ﺏﺍﺮﻄﺿﺇ ؛ﻉﺍﺪﺻ ؛(ﻡﺪﻟﺍ ﻂﻐﺿ ﻁﺮﻓ) ﻊﻔﺗﺮﻣ ﻡﺩ ﻂﻐﻀﻟ ﺕﺎﻣﻼﻋ ،ﺭﺍﻭﺩ ،ﻉﺍﺪﺻ ؛

(leukopenia, lymphopenia, neutropenia)

ﺀﺎﻀﻴﺒﻟﺍ ﻡﺪﻟﺍ ؛ﻑﺎﻋﺭ ؛ﻢﻔﻟﺍ ﻲﻓ ﻢﻟﺃ ؛ﻝﺎﻌﺳ ؛(

thrombocytopenia

) ﺔﻳﻮﻣﺪﻟﺍ ﺕﺎﺤﻴﻔﺼﻟﺍ ﻦﻣ ﺔﻀﻔﺨﻨﻣ ﺔﺒﺴﻨﻟ ﺕﺎﻣﻼﻋ ،ﻱﻮﻔﻋ ﻞﻜﺸﺑ ﻥﺎﺛﺪﺤﻳ ﺔﻣﺪﻛ ﻭﺃ ﻑﺰﻧ ؛ﻕﺍﺬﻤﻟﺍ ﺔﻘﻄﻨﻣﻭ ﻦﻄﺒﻟﺍ ﻦﻣ ﻲﻠﻔﺴﻟﺍ ﺀﺰﺠﻟﺍ ﻲﻓ ﺪﻳﺪﺷ ﻢﻟﺃ ؛ﻦﻄﺒﻟﺍ ﻲﻓ ﻢﻟﺃ ؛ﻥﺎﻴﺜﻏ ﻞﺜﻣ ﻦﻄﺒﻟﺍ ﻲﻓ ﺝﺎﻋﺰﻧﺇ ؛ﺆﻴﻘﺗ ؛ﻝﺎﻬﺳﺇ ؛(

gastritis

) ﺓﺪﻌﻤﻟﺍ ﺭﺍﺪﺟ ﺏﺎﻬﺘﻟﺇ ؛ﻙﺎﺴﻣﺇ ؛(ﺔﺨﻔﻧ) ﺀﺎﻌﻣﻷﺍ ﻲﻓ ﺕﺍﺯﺎﻐﻟﺍ ﻦﻣ ﺔﻀﺋﺎﻓ ﺔﻴﻤﻛ ؛(ﺾﻴﺒﻤﻟﺍ ﻲﻓ ﺔﺴﻴﻛ) ﺔﻳﺮﻬﺸﻟﺍ ﺓﺭﻭﺪﻟﺍ ﻲﻓ ﺕﺎﺷﻮﺸﺘﺑ ﻖﻓﺍﺮﺘﻳ ،

ﺍﺩﺎﺣ ﻥﻮﻜﻳ ﻥﺃ ﻪﻧﺄﺷ ﻦﻣ ﻱﺬﻟﺍ ﺽﻮﺤﻟﺍ ﺓﺪﻌﻤﻠﻟ ﻲﺳﻭﺮﻴﭬ ﺏﺎﻬﺘﻟﺇ ،ﺓﺪﻌﻤﻟﺍ ﺏﺎﻬﺘﻟﺇ) ﺓﺪﻌﻤﻠﻟ ﻦﻄﺒﻤﻟﺍ ﻲﻃﺎﺨﻤﻟﺍ ﺀﺎﺸﻐﻟﺍ ﺏﺎﻬﺘﻟﻹ ﺕﺎﻣﻼﻋ ،ﻦﻄﺒﻟﺍ ﻲﻓ ﺥﺎﻔﺘﻧﺇ ،ﻝﺎﻬﺳﺇ ،ﺆﻴﻘﺗ ،ﻥﺎﻴﺜﻏ ،ﻦﻄﺒﻟﺍ ﻲﻓ ﻢﻟﺃ ،ﺓﺮﺸﻘﺑ ﻲﺴﺘﻜﺗ ﻢﺛ ﻦﻣﻭ ﻞﺋﺍﻮﺳ ﺎﻬﻨﻣ ﺏﺮﺴﺘﺗ ﻲﺘﻟﺍ ﺕﺎﺴﻴﻛ ،ﺔﻜﺣ ،ﺭﺍﺮﻤﺣﺈﺑ ﺰﻴﻤﺘﺗ ﻲﺘﻟﺍ ﺪﻠﺠﻠﻟ ﺔﻴﺑﺎﻬﺘﻟﺇ ﺔﻟﺎﺣ ؛ﺪﻠﺠﻟﺍ ﻲﻓ ﺢﻔﻃ ؛ﺪﻠﺠﻟﺍ ﻲﻓ ﻑﺎﻔﺟ ؛(ﺀﺎﻌﻣﻷﺍﻭ ﻁﺮﻔﻣ ﻲﺜﻤﻃ ﻑﺰﻧ ،ﺚﻤﻄﻟﺍ ﺮﺧﺄﺗ ﻞﺜﻣ ﺔﻳﺮﻬﺸﻟﺍ ﺓﺭﻭﺪﻟﺍ ﻲﻓ ﺕﺎﺑﺍﺮﻄﺿﺇ ؛ﻝﻮﺒﻟﺍ ﻲﻓ ﻦﻴﺗﻭﺮﭘ ؛ﺮﻌﺸﻟﺍ ﻂﻗﺎﺴﺗ ؛

(dermatitis acneiform)

ﺔﺒﻠﺻ ﺢﺒﺼﺗ ﻭﺃ ﺮﺸﻘﺘﺗ ،ﺯﺎﻨﻴﺟﻭﺭﺪﻴﻬﻳﺩ ﺕﺎﺘﻛﻻ ﻰﻤﺴﻤﻟﺍ ﻡﺪﻟﺍ ﻲﻓ ﻢﻳﺰﻧﻹﺍ ﻦﻣ ﺔﻌﻔﺗﺮﻣ ﺔﺒﺴﻧ ؛ﺔﻧﻮﺨﺳ ؛ﺔﻴﻧﺍﻭﺪﻋ ؛ﺀﻭﺪﻫ ﻡﺪﻋ ؛ﻕﺎﻫﺭﺈﺑ ﺭﻮﻌﺸﻟﺍ ؛ﻲﻠﺒﻬﻣ ﻑﺰﻧ ﻭﺃ

(menorrhagia)

ﺽﺎﻔﺨﻧﺇ ؛(

ﻦﺗﻮﻠﻤﻟﺍ ﻥﻮﻣﺭﻮﻬﻟﺍ ﻲﻓ ﻉﺎﻔﺗﺭﺇ) ﺔﺿﺎﺑﻹﺍ ﻰﻠﻋ ﺚﺤﻳ ﻱﺬﻟﺍ ﻥﻮﻣﺭﻮﻬﻠﻟ ﻡﺪﻟﺍ ﻲﻓ ﺮﺜﻛﺃ ﺔﻌﻔﺗﺮﻣ ﺔﺒﺴﻧ ؛ﺔﻨﻴﻌﻣ ﺀﺎﻀﻋﺃ ﺔﺤﺻ ﻦﻋ ﺕﺎﻣﻮﻠﻌﻣ ﺮﻓﻮﻳ ﻱﺬﻟﺍ .ﺞﻟﺎﻌﻤﻟﺍ ﻚﺒﻴﺒﻃ ﻊﺟﺍﺭ ،ﺮﻴﻄﺧ ﻞﻜﺸﺑ ﻩﻼﻋﺃ ﺓﺭﻮﻛﺬﻤﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﻚﻴﻠﻋ ﺕﺮﺛﺃ ﺍﺫﺇ .ﻥﺯﻮﻟﺍ ﻲﻓ ﻞﻤﻌﺘﺴﻣ ١٠٠ ﻦﻴﺑ ﻦﻣ ١ ﻞﻤﻌﺘﺴﻣ ﻰﺘﺣ ﻯﺪﻟ ﺮﻬﻈﺗ ﻲﺘﻟﺍ ﺽﺍﺮﻋﺃ (

uncommon

) ﺔﻌﺋﺎﺷ ﺮﻴﻏ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻲﻓ ﻢﻟﺃ ،ﻢﻐﻠﺒﺑ ﻖﻓﺍﺮﺘﻣ ﻝﺎﻌﺳ ؛(

rhabdomyolysis

) ﻲﻠﻀﻋ ﺏﺍﺮﻄﺿﻹ ﺕﺎﻣﻼﻋ ﻚﻠﺗ ﻥﻮﻜﺗ ﻥﺃ ﺰﺋﺎﺠﻟﺍ ﻦﻣ ،ﻲﻨﺑ ـ ﺮﻤﺣﺃ ﻪﻧﻮﻟ ﻝﻮﺑ ،ﺔﻧﻮﺨﺳ ،ﺔﻴﻠﻀﻋ ﺕﺎﺠﻨﺸﺗ ﻥﻮﻣﺭﻮﻬﻟ ﺮﺜﻛﺃ ﺔﻌﻔﺗﺮﻣ ﺔﺒﺴﻧ ؛ﻕﺭﺃ ؛(

viral bronchitis

/ﻲﺳﻭﺮﻴﭭﻟﺍ ﺔﻴﺋﺍﻮﻬﻟﺍ ﺕﺎﺒﺼﻘﻟﺍ ﺏﺎﻬﺘﻟﺇ) ﺔﻴﺴﻔﻨﺘﻟﺍ ﻕﺮﻄﻟﺍ ﻲﻓ ﺏﺎﻬﺘﻟﻹ ﺕﺎﻣﻼﻋ ،ﺔﻧﻮﺨﺳ ،ﺭﺪﺼﻟﺍ

،ﺕﺎﺒﻳﺮﺠﻠﻟ ﻂﺸﻨﻣ ﻥﻮﻣﺭﻮﻫ ﻉﺎﻔﺗﺭﺇ) ﻡﺪﻟﺍ ﻲﻓ ﻱﻮﺜﻧﻷﺍ ﺮﺛﺎﻜﺘﻟﺍ ﺓﺩﺎﻋﻭ ﺔﻄﺳﻮﺘﻣ ﻰﺘﺣ ﺔﻄﻴﺴﺑ ﻲﻫ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﺔﻴﺒﻟﺎﻏ .ﻲﺒﻄﻟﺍ ﻢﻗﺎﻄﻟﺍ ﻦﻣ ﺩﺮﻓ ﻭﺃ ﻲﻟﺪﻴﺼﻟﺍ ،ﻚﺒﻴﺒﻃ ﻊﺟﺍﺭ ﺀﺎﺟﺮﻟﺍ ،ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻩﺬﻫ ﺖﻤﻗﺎﻔﺗ ﺍﺫﺇ .ﺝﻼﻌﻟﺍ ﻦﻋ ﻒﻗﻮﺘﻟﺍ ﻦﻣ ﻡﺎﻳﺃ ﺓﺪﻋ ﺪﻌﺑ ﻝﻭﺰﺗ .ﺐﻴﺒﻄﻟﺍ ﺓﺭﺎﺸﺘﺳﺇ ﻚﻴﻠﻋ ،ﺓﺮﺸﻨﻟﺍ ﻩﺬﻫ ﻲﻓ ﺮﻛﺬﻳ ﻢﻟ ﻲﺒﻧﺎﺟ ﺽﺮﻋ ﻦﻣ ﻲﻧﺎﻌﺗ ﺎﻣﺪﻨﻋ ﻭﺃ ،ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻷﺍ ﻯﺪﺣﺇ ﺖﻤﻗﺎﻔﺗ ﺍﺫﺇ ،ﻲﺒﻧﺎﺟ ﺽﺮﻋ ﺮﻬﻇ ﺍﺫﺇ ﺽﺍﺮﻋﺄﺑ ﺮﻌﺸﺗ ﺖﻨﻛ ﺍﺫﺇ ﻚﺒﻴﺒﻃ ﻎﻠﺑ .ﺭﻮﺘﻴﻨﻴﻓﺃ ﻥﻮﻟﻭﺎﻨﺘﻳ ﻦﻳﺬﻟﺍ ﻰﺿﺮﻣ ﺓﺪﻋ ﻯﺪﻟ ﻪﺼﻴﺨﺸﺗ ﻢﺗ (

Hepatitis B

ﻉﻮﻧ ﻦﻣ ﺪﺒﻜﻟﺍ ﺏﺎﻬﺘﻟﺇ ﻂﻴﺸﻨﺗ ﺓﺩﺎﻋﺇ ﻯﺮﺧﺃ ﺽﺍﺮﻋﺃ .ﻞﺻﺎﻔﻤﻟﺍ ﻲﻓ ﺏﺎﻬﺘﻟﺇﻭ ﻡﻻﺁ ،ﻱﺪﻠﺟ ﺢﻔﻃ ،ﺔﻧﻮﺨﺳ ﻞﻤﺸﺗ ﺔﻴﻟﻭﻷﺍ ﺽﺍﺮﻋﻷﺍ .ﺭﻮﺘﻴﻨﻴﻓﺃ ـﺑ ﺝﻼﻌﻟﺍ ﺓﺮﺘﻓ ﻝﻼﺧ

ﻉﻮﻧ ﻦﻣ ﺪﺒﻜﻟﺍ ﺏﺎﻬﺘﻟﺇ ﻥﻮﻠﻟﺍ ﻦﻛﺍﺩ ﻝﻮﺑ ﻭﺃ ﺢﺗﺎﻓ ﺯﺍﺮﺑ .ﻦﻄﺒﻟﺍ ﻦﻣ ﻦﻤﻳﻷﺍ ﻱﻮﻠﻌﻟﺍ ﺀﺰﺠﻟﺍ ﻲﻓ ﻡﻻﺁﻭ (ﺪﻠﺠﻟﺍ ﺭﺍﺮﻔﺻﺇ) ﻥﺎﻗﺮﻳ ،ﻥﺎﻴﺜﻏ ،ﻡﺎﻌﻄﻠﻟ ﺔﻴﻬﺸﻟﺍ ﻥﺍﺪﻘﻓ ،ﻕﺎﻫﺭﺇ ﻞﻤﺸﺗ ﻥﺃ ﻦﻜﻤﻳ .ﻥﺎﻗﺮﻴﻟ ﺕﺎﻣﻼﻋ ﻥﻮﻜﺗ ﻥﺃ ﻦﻜﻤﻳ

ﺎﻀﻳﺃ :ﻝﺎﻔﻃﻷﺍ ﻯﺪﻟ ﺔﻳﻭﺩﻷﺍ ﻦﻴﺑ ﺕﻼﻋﺎﻔﺘﻟﺍﻭ ﺔﻴﺒﻧﺎﺠﻟﺍ ﺽﺍﺮﻋﻻﺃ !ﺔﻠﻔﻄﻠﻟ/ﻞﻔﻄﻠﻟ ﻰﻄﻌﻳ ﻲﻓﺎﺿﺇ ﺀﺍﻭﺩ ﻱﺃ ﻦﻋ ﻚﻟﺬﻛﻭ ﻲﺒﻧﺎﺟ ﺽﺮﻋ ﻱﺃ ﻦﻋ ﺞﻟﺎﻌﻤﻟﺍ ﺐﻴﺒﻄﻟﺍ ﻍﻼﺑﺇ ﻦﻳﺪﻟﺍﻮﻟﺍ ﻰﻠﻋ ﺔﻴﺴﻴﺋﺮﻟﺍ ﺔﺤﻔﺼﻟﺍ ﻰﻠﻋ ﺩﻮﺟﻮﻤﻟﺍ åﻲﺋﺍﻭﺩ ﺝﻼﻋ ﺐﻘﻋ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻦﻋ ﻎﻴﻠﺒﺗò ﻂﺑﺍﺮﻟﺍ ﻰﻠﻋ ﻂﻐﻀﻟﺍ ﺔﻄﺳﺍﻮﺑ ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻮﻟ ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻦﻋ ﻎﻴﻠﺒﺘﻟﺍ ﻥﺎﻜﻣﻹﺎﺑ :ﻂﺑﺍﺮﻟﺍ ﺢﻔﺼﺗ ﻖﻳﺮﻃ ﻦﻋ ﻭﺃ ،ﺔﻴﺒﻧﺎﺟ ﺽﺍﺮﻋﺃ ﻦﻋ ﻎﻴﻠﺒﺘﻠﻟ ﺮﺷﺎﺒﻤﻟﺍ ﺝﺫﻮﻤﻨﻟﺍ ﻰﻟﺇ ﻚﻬﺟﻮﻳ ﻱﺬﻟﺍ (

www.health.gov.il

) ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻭ ﻊﻗﻮﻤﻟ ؟ﺀﺍﻭﺪﻟﺍ ﻦﻳﺰﺨﺗ ﺔﻴﻔﻴﻛ (٥ ﻢﻬﺘﺑﺎﺻﺇ ﻱﺩﺎﻔﺘﻟ ﻚﻟﺫﻭ ،ﻊﺿﺮﻟﺍ ﻭﺃ/ﻭ ﻝﺎﻔﻃﻷﺍ ﺔﻳﺅﺭ ﻝﺎﺠﻣﻭ ﻱﺪﻳﺃ ﻝﻭﺎﻨﺘﻣ ﻦﻋ

ﺍﺪﻴﻌﺑ ﻖﻠﻐﻣ ﻥﺎﻜﻣ ﻲﻓ ﺀﺍﻭﺩ ﻞﻛﻭ ﺀﺍﻭﺪﻟﺍ ﺍﺬﻫ ﻆﻔﺣ ﺐﺠﻳ !ﻢﻤﺴﺘﻟﺍ ﺐﻨﺠﺗ ∙ .ﺐﻴﺒﻄﻟﺍ ﻦﻣ ﺔﺤﻳﺮﺻ ﺕﺎﻤﻴﻠﻌﺗ ﻥﻭﺪﺑ ﺆﻴﻘﺘﻟﺍ ﺐﺒﺴﺗ ﻻ .ﻢﻤﺴﺘﻟﺎﺑ

ﺮﻬﺸﻟﺍ ﺲﻔﻧ ﻦﻣ ﺮﻴﺧﻷﺍ ﻡﻮﻴﻟﺍ ﻰﻟﺇ ﺔﻴﺣﻼﺼﻟﺍ ﺦﻳﺭﺎﺗ ﺮﻴﺸﻳ .ﺔﺒﻠﻌﻟﺍ ﺮﻬﻇ ﻰﻠﻋ ﺮﻬﻈﻳ ﻱﺬﻟﺍ

(exp. date)

ﺔﻴﺣﻼﺼﻟﺍ ﺦﻳﺭﺎﺗ ﺀﺎﻀﻘﻧﺇ ﺪﻌﺑ ﺀﺍﻭﺪﻟﺍ ﻝﺎﻤﻌﺘﺳﺇ ﺯﻮﺠﻳ ﻻ

.ﺔﻳﻮﺌﻣ ﺔﺟﺭﺩ ٢٥ ﻕﻮﻓ ﺓﺭﺍﺮﺣ ﺔﺟﺭﺪﺑ ﻦﻳﺰﺨﺘﻟﺍ ﺯﻮﺠﻳ ﻻ ∙ .ﺔﺒﻠﻌﻟﺍ ﻲﻓ ﺐﻄﻋ ﺖﻈﺣﻻ ﺍﺫﺇ ﻞﻤﻌﺘﺴﺗ ﻻ.ﺔﺑﻮﻃﺮﻟﺍﻭ ﺀﻮﻀﻟﺍ ﻦﻣ ﺔﻳﺎﻤﺤﻠﻟ ﺔﻴﻠﺻﻷﺍ ﺔﺒﻠﻌﻟﺍ ﻲﻓ ﻦﻳﺰﺨﺘﻟﺍ ﺐﺠﻳ ∙ .ﺭﻮﺘﻴﻨﻴﻓﺃ ﺹﺍﺮﻗﺃ ﻝﻭﺎﻨﺗ ﻞﺒﻗ

ﻻﺎﺣ (ﺮﺘﺴﻴﻠﺑ) ﺔﺤﻳﻮﻠﻟﺍ ﺔﺒﻠﻋ ﺢﺘﻓﺇ ∙ .ﺔﺌﻴﺒﻟﺍ ﻰﻠﻋ ﻆﻓﺎﺤﺗ ﻚﻟﺬﺑ ،ﻝﺎﻤﻌﺘﺳﻹﺍ ﺪﻴﻗ ﺖﺴﻴﻟ ﺔﻳﻭﺩﺃ ﻲﻣﺮﺗ ﻦﻳﺃ ﻲﻟﺪﻴﺼﻟﺍ ﻝﺄﺳﺇ ،ﺔﻴﻟﺰﻨﻤﻟﺍ ﺔﻣﺎﻤﻘﻟﺍ ﻰﻟﺇ ﺔﻳﻭﺩﻷﺍ ﻲﻣﺭ ﺯﻮﺠﻳ ﻻ ﺔﻴﻓﺎﺿﺇ ﺕﺎﻣﻮﻠﻌﻣ (٦

:

ﹰ

ﺎﻀﻳﺃ ﺔﻟﺎﻌﻔﻟﺍ ﺓﺩﺎﻤﻠﻟ ﺔﻓﺎﺿﻹﺎﺑ ﺀﺍﻭﺪﻟﺍ ﻱﻮﺘﺤﻳ ∙

.lactose monohydrate

ﻎﻠﻣ ٢٫٤٥٠ ﻰﻠﻋﻭ

lactose anhydrous

ﻎﻠﻣ ٧١٫٨٧٥ ﻰﻠﻋ ﻱﻮﺘﺤﻳ ﻎﻠﻣ ٢٫٥ ﺭﻮﺘﻴﻨﻴﻓﺃ ﻦﻣ ﺹﺮﻗ ﻞﻛ

.lactose monohydrate

ﻎﻠﻣ ٤٫٩٠ ﻰﻠﻋﻭ

lactose anhydrous

ﻎﻠﻣ ١٤٣٫٧٥ ﻰﻠﻋ ﻱﻮﺘﺤﻳ ﻎﻠﻣ ٥ ﺭﻮﺘﻴﻨﻴﻓﺃ ﻦﻣ ﺹﺮﻗ ﻞﻛ

.lactose monohydrate

ﻎﻠﻣ ٩٫٨٠ ﻰﻠﻋﻭ

lactose anhydrous

ﻎﻠﻣ ٢٨٧٫٥٠ ﻰﻠﻋ ﻱﻮﺘﺤﻳ ﻎﻠﻣ ١٠ ﺭﻮﺘﻴﻨﻴﻓﺃ ﻦﻣ ﺹﺮﻗ ﻞﻛ ﺔﺒﻠﻌﻟﺍ ﻯﻮﺘﺤﻣ ﻮﻫ ﺎﻣﻭ ﺀﺍﻭﺪﻟﺍ ﻭﺪﺒﻳ ﻒﻴﻛ ∙ .ﺮﻄﺸﻠﻟ ﻖﺷ ﻥﻭﺪﺑﻭ ﺔﻠﺋﺎﻣ ﻑﺍﺮﻃﺃ ﻊﻣ ،ﺔﻟﻭﺎﻄﻣ ،

ﻼﻴﻠﻗ ﺮﻔﺻﻷﺍ ﻰﻟﺇ ﻞﺋﺎﻣ ﺾﻴﺑﺃ ﻥﻮﻠﺑ ﺹﺍﺮﻗﻷﺍ

.ﻲﻧﺎﺜﻟﺍ ﺐﻧﺎﺠﻟﺍ ﻲﻓ

“NVR”

ـ ﻭ ﺪﺣﺍﻭ ﺐﻧﺎﺟ ﻲﻓ

“LCL”

ﺔﻋﺎﺒﻄﻟﺍ ﺎﻬﻴﻠﻋ ﺵﻮﻘﻨﻣ ﺹﺍﺮﻗﻷﺍ :ﻎﻠﻣ ٢٫٥ ﺭﻮﺘﻴﻨﻴﻓﺃ

.ﻲﻧﺎﺜﻟﺍ ﺐﻧﺎﺠﻟﺍ ﻲﻓ

“NVR”

ـ ﻭ ﺪﺣﺍﻭ ﺐﻧﺎﺟ ﻲﻓ

“5”

ﺔﻋﺎﺒﻄﻟﺍ ﺎﻬﻴﻠﻋ ﺵﻮﻘﻨﻣ ﺹﺍﺮﻗﻷﺍ :ﻎﻠﻣ ٥ ﺭﻮﺘﻴﻨﻴﻓﺃ

.ﻲﻧﺎﺜﻟﺍ ﺐﻧﺎﺠﻟﺍ ﻲﻓ

“NVR”

ـ ﻭ ﺪﺣﺍﻭ ﺐﻧﺎﺟ ﻲﻓ

“UHE”

ﺔﻋﺎﺒﻄﻟﺍ ﺎﻬﻴﻠﻋ ﺵﻮﻘﻨﻣ ﺹﺍﺮﻗﻷﺍ :ﻎﻠﻣ ١٠ ﺭﻮﺘﻴﻨﻴﻓﺃ

ﺎﺻﺮﻗ ٣٠ ﻰﻠﻋ ﻱﻮﺘﺤﺗ ﺔﺒﻠﻋ ﻞﻛ

.ﺎﭭﻜﺗ ـ ﺢﺘﻴﭘ ،٣٦ ﻡﺎﺣﺎﺷ ﻉﺭﺎﺷ ،.ﺽ.ﻡ ﻞﻴﺋﺍﺮﺳﺇ ﺲﻴﺗﺭﺎﭬﻮﻧ :ﻪﻧﺍﻮﻨﻋﻭ ﺯﺎﻴﺘﻣﻹﺍ ﺐﺣﺎﺻ ∙ .ﺍﺮﺴﻳﻮﺳ ،ﻝﺯﺎﺑ ،ﻲﺟ ﻲﻳﺍ ﺎﻣﺭﺎﻓ ﺲﻴﺗﺭﺎﭬﻮﻧ ﻞﺟﺃ ﻦﻣ ﺍﺮﺴﻳﻮﺳ ،ﻲﺟ ﻲﻳﺍ ﻦﻳﺎﻄﺷ ﺎﻣﺭﺎﻓ ﺲﻴﺗﺭﺎﭬﻮﻧ :ﻪﻧﺍﻮﻨﻋﻭ ﺞﺘﻨﻤﻟﺍ ﻢﺳﺇ ∙ ٢٠١٦ ﺏﺁ :ﺦﻳﺭﺎﺗ ﻲﻓ ﺺﺧ

ﺭﻭ ﺺﺤ

ﻓ ﺎﻫﺍﻮﺘﺤﻣﻭ ﺓﺮﺸﻨﻟﺍ ﻩﺬﻫ ﺔﻐﻴﺻ ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻭ ﺕﺮﻗﺃ

:ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻭ ﻲﻓ ﻲﻣﻮﻜﺤﻟﺍ ﺔﻳﻭﺩﻷﺍ ﻞﺠﺳ ﻲﻓ ﺀﺍﻭﺪﻟﺍ ﻞﺠﺳ ﻢﻗﺭ ∙ ١٤٦ ٨٢ ٣٣٣٨٨ :ﻎﻠﻣ ٢٫٥ ﺭﻮﺘﻴﻨﻴﻓﺃ

١٤٢ ٨٦ ٣٢٠٤٥ : ﻎﻠﻣ ٥ ﺭﻮﺘﻴﻨﻴﻓﺃ

١٤٢ ٨٧ ٣٢٠٤٦ :ﻎﻠﻣ ١٠ ﺭﻮﺘﻴﻨﻴﻓﺃ

.ﻦﻴﺴﻨﺠﻟﺍ ﻼﻜﻟ ﺺﺼﺨﻣ ﺀﺍﻭﺪﻟﺍ ﻥﺈﻓ ،ﻚﻟﺫ ﻦﻣ ﻢﻏﺮﻟﺍ ﻰﻠﻋ .ﺮﻛﺬﻤﻟﺍ ﺔﻐﻴﺼﺑ ﺓﺮﺸﻨﻟﺍ ﻩﺬﻫ ﺔﻏﺎﻴﺻ ﺖﻤﺗ ،ﺓﺀﺍﺮﻘﻟﺍ ﻦﻳﻮﻬﺗﻭ ﺔﻟﻮﻬﺳ ﻞﺟﺃ ﻦﻣ ∙

Lactose anhydrous, crospovidone, hypromellose, lactose monohydrate, magnesium stearate and butylated

hydroxytoluene.

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

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1. NAME OF THE MEDICINAL PRODUCT

AFINITOR

(everolimus)

Afinitor

2.5 mg

Afinitor

5 mg

Afinitor

10 mg

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Afinitor

2.5 mg tablets

Each tablet contains 2.5 mg everolimus.

Excipient with known effect:

Each tablet contains 74 mg lactose.

Afinitor

5 mg tablets

Each tablet contains 5 mg everolimus.

Excipient with known effect:

Each tablet contains 149 mg lactose.

Afinitor

10 mg tablets

Each tablet contains 10 mg everolimus.

Excipient with known effect:

Each tablet contains 297 mg lactose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.

White to slightly yellowish, elongated tablets with a bevelled edges and no score.

Afinitor 2.5 mg tablets

The tablets are debossed with “LCL” on one side and “NVR” on the other.

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Afinitor 5 mg tablets

The tablets are debossed with “5” on one side and “NVR” on the other.

Afinitor 10 mg tablets

The tablets are debossed with “UHE” on one side and “NVR” on the other.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Afinitor 2.5, 5 & 10 mg are indicated for the:

Treatment of patients with SEGA associated with tuberous sclerosis complex (TSC) who require

therapeutic intervention but are not candidates for curative surgical resection.

The effectiveness of AFINITOR is based on an analysis of change in SEGA volume. Clinical

benefit such as improvement in disease-related symptoms or increase in overall survival has not

been demonstrated.

Treatment of progressive neuroendocrine tumors of pancreatic origin (PNET) in patients with

unresectable, locally advanced or metastatic disease. The safety and effectiveness of

AFINITOR

in the treatment of patients with carcinoid tumors have not been established.

Treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in

combination with exemestane, in postmenopausal women without symptomatic visceral disease

after recurrence or progression following a non-steroidal aromatase inhibitor.

4. Treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex

(TSC), not requiring immediate surgery. The effectiveness of AFINITOR in treatment of

renal angiomyolipoma is based on an analysis of durable objective responses in patients

treated for a median of 8.3 months. Further follow-up of patients is required to determine

long-term outcomes.

5. Treatment of patients with advanced renal cell carcinoma, whose disease has progressed

on or after treatment with VEGF-targeted therapy.

6. Treatment of unresectable, locally advanced or metastatic, well-differentiated (Grade 1 or

Grade 2) non-functional neuroendocrine tumours of gastrointestinal or lung origin in adults with

progressive disease (see sections 4.4 and 5.1).

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4.2

Posology and method of administration

Treatment with Afinitor should be initiated and supervised by a physician experienced in the use of

anticancer therapies or in the treatment of patients with TSC and therapeutic drug monitoring.

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

Posology

For the different dose regimens Afinitor is available as 2.5 mg, 5 mg and 10 mg tablets.

Oncology patients

The recommended dose is 10 mg everolimus once daily.

Renal angiomyolipoma associated with TSC

The recommended dose is 10 mg of everolimus once daily.

SEGA associated with TSC

Careful titration may be required to obtain the optimal therapeutic effect. Doses that will be tolerated

and effective vary between patients. Concomitant antiepileptic therapy may affect the metabolism of

everolimus and may contribute to this variance (see section 4.5).

Dosing is individualized based on Body Surface Area (BSA, in m

) using the Dubois formula, where

weight (W) is in kilograms and height (H) is in centimeters:

BSA = (W

0.425

0.725

) x 0.007184

The recommended starting daily dose for Afinitor for the treatment of patients with TSC who have

SEGA is 4.5 mg/m

.Different strengths of Afinitor tablets can be combined to attain the desired dose.

Everolimus whole blood trough concentrations should be assessed at least 1 week after commencing

treatment for patients <3 years of age and approximately 2 weeks after commencing treatment for

patients ≥3 years of age. Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml. The

dose may be increased to attain a higher trough concentration within the target range to obtain optimal

efficacy, subject to tolerability.

Dosing recommendations for paediatric patients with SEGA are consistent with those for the adult

SEGA population, except for patients with hepatic impairment (see “Hepatic impairment” below and

section 5.2).

SEGA volume should be evaluated approximately 3 months after commencing Afinitor therapy, with

subsequent dose adjustments taking changes in SEGA volume, corresponding trough concentration, and

tolerability into consideration.

Once a stable dose is attained, trough concentrations should be monitored every 3 to 6 months in patients

with changing BSA, or every 6 to 12 months in patients with stable BSA, for the duration of treatment.

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For all indications:

If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next

dose.

Dose adjustments due to adverse drug reactions

Management of severe and/or intolerable suspected adverse drug reactions may require dose reduction

and/or temporary interruption of Afinitor therapy. For adverse reaction of Grade 1, dose adjustment is

usually not required. If dose reduction is required for oncology patients, the recommended dose is 5 mg

daily and must not be lower than 5 mg daily.

If dose reduction is required for TSC patients the recommended dose is approximately 50% lower than

the daily dose previously administered .For dose reductions below the lowest available strength,

alternate day dosing should be considered.

Table 1 summarises dose adjustment recommendations for specific adverse reactions (see also section

4.4).

Table 1

Afinitor dose adjustment recommendations

Adverse Drug

reaction

Severity

1

Afinitor dose adjustment

Non-infectious

pneumonitis

Grade 2

Consider interruption of therapy, until symptoms improve to

Grade≤ 1.

Re-initiate Afinitor (5 mg daily for oncology patients and

approximately 50% lower than the daily dose previously

administered for TSC patients).

Discontinue treatment if failure to recover within 4 weeks.

Grade 3

Interrupt treatment until symptoms resolve to Grade ≤1.

Consider re-initiating Afinitor (5 mg daily for oncology

patients and approximately 50% lower than the daily dose

previously administered for TSC patients).

If toxicity recurs at Grade 3, consider discontinuation.

Grade 4

Discontinue treatment.

Stomatitis

Grade 2

Temporary dose interruption until recovery to Grade

Re-initiate treatment at same dose.

If stomatitis recurs at Grade 2, interrupt dose until recovery to

Grade

Re-initiate Afinitor (5 mg daily for oncology patients and

approximately 50% lower than the daily dose previously

administered for TSC patients).

Grade 3

Temporary dose interruption until recovery to Grade

Re-initiate treatment (5 mg daily for oncology patients and

approximately 50% lower than the daily dose previously

administered for TSC patients).

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Adverse Drug

reaction

Severity

1

Afinitor dose adjustment

Grade 4

Discontinue treatment.

Other non-

hematologic

toxicities

(excluding metabolic

events)

Grade 2

If toxicity is tolerable, no dose adjustment required.

If toxicity becomes intolerable, temporary dose interruption

until recovery to Grade

1. Re-initiate Afinitor at same dose.

If toxicity recurs at Grade 2, interrupt Afinitor until recovery

to Grade

Re-initiate Afinitor (5 mg daily for oncology patients and

approximately 50% lower than the daily dose previously

administered for TSC patients).

Grade 3

Temporary dose interruption until recovery to Grade

Consider re-initiating Afinitor (5 mg daily for oncology

patients and approximately 50% lower than the daily dose

previously administered for TSC patients).

If toxicity recurs

at Grade 3, consider discontinuation.

Grade 4

Discontinue Afinitor treatment.

Metabolic events

(e.g.

hyperglycemia,

dyslipidemia)

Grade 2

No dose adjustment required.

Grade 3

Temporary dose interruption.

Re-initiate Afinitor (5 mg daily for oncology patients and

approximately 50% lower than the daily dose previously

administered for TSC patients).

Grade 4

Discontinue Afinitor treatment.

Thrombocytopenia

Grade 2

(<75, ≥50x10

Grade 3 & 4

(<50x10

Temporary dose interruption until recovery to Grade

(≥75x10

/l). Re-initiate treatment at same dose.

Temporary dose interruption until recovery to Grade

(≥75x10

/l). Re-initiate treatment (5 mg daily for oncology

patients and approximately 50% lower than the daily dose

previously administered for TSC patients).

Neutropenia

Grade 2

(≥1x10

Grade 3

(<1, ≥0.5x10

Grade 4

(<0.5x10

No dose adjustment required.

Temporary dose interruption until recovery to Grade

(≥1x10

/l). Re-initiate treatment at same dose.

Temporary dose interruption until recovery to Grade

(≥1x10

/l). Re-initiate treatment(5 mg daily for oncology

patients and approximately 50% lower than the daily dose

previously administered for TSC patients).

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Adverse Drug

reaction

Severity

1

Afinitor dose adjustment

Febrile neutropenia

Grade 3

Grade 4

Temporary dose interruption until recovery to Grade

(≥1.25x109/l) and no fever.

Re-initiate treatment (5 mg daily for oncology patients and

approximately 50% lower than the daily dose previously

administered for TSC patients).

Discontinue Afinitor treatment.

Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events

(CTCAE) v3.0

Therapeutic drug monitoring

for patients treated for TSC

Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is

required

for patients treated for SEGA. Trough concentrations should be assessed approximately 2 weeks after

the initial dose, after any change in dose or pharmaceutical form, after initiation of or change in

co-administration of CYP3A4 inducers or inhibitors (see sections 4.4 and 4.5) or after any change in

hepatic status (Child-Pugh) (see “Hepatic impairment” below and section 5.2). For patients <3 years of

age, trough concentrations should be monitored at least 1 week after start of treatment or after any

change in dose or pharmaceutical form (see section 5.2).

Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is an

option

to be considered for patients treated for renal angiomyolipoma associated with TSC (see section 5.1)

after initiation of or change in co-administration of CYP3A4 inducers or inhibitors (see sections 4.4

and 4.5) or after any change in hepatic status (Child-Pugh) (see “Hepatic impairment” below and

section 5.2).

When possible, the same assay and laboratory for therapeutic drug monitoring should be used

throughout the treatment.

Special populations – For all indications

Elderly patients (≥65 years)

No dose adjustment is required (see section 5.2).

Renal impairment

No dose adjustment is required (see section 5.2).

Hepatic impairment

For Oncology patients and patients treated for TSC with renal angiomyolipoma:

- Mild hepatic impairment (Child-Pugh A) – the recommended dose is 7.5 mg daily.

- Moderate hepatic impairment (Child-Pugh B) – the recommended dose is 5 mg daily.

- Severe hepatic impairment (Child-Pugh C) – Afinitor is only recommended if the desired benefit

outweighs the risk. In this case, a dose of 2.5 mg daily must not be exceeded.

Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment

(see also sections 4.4 and 5.2).

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Patients with SEGA associated with TSC:

Patients <18 years of age:

Afinitor is not recommended for patients <18 years of age with SEGA and hepatic impairment.

Patients ≥18 years of age:

Mild hepatic impairment (Child-Pugh A): 75% of the recommended starting dose calculated

based on BSA (rounded to the nearest strength)

Moderate hepatic impairment (Child-Pugh B): 25% of the recommended starting dose

calculated based on BSA (rounded to the nearest strength)

Severe hepatic impairment (Child-Pugh C): not recommended

Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after any

change in hepatic status (Child-Pugh).

Paediatric population

The safety and efficacy of Afinitor in children aged 0 to 18 years oncology patients have not been

established. No data are available.

The safety and efficacy of Afinitor in children aged 0 to 18 years with renal angiomyolipoma

associated with TSC in the absence of SEGA have not been established. No data are available.

The safety, efficacy and pharmacokinetic profile of Afinitor in children below the age of 1 year with

TSC who have SEGA have not been established. No data are available (see sections 5.1 and 5.2).

Clinical study results did not show an impact of Afinitor on growth and pubertal development.

Method of Administration

Afinitor must be administered orally once daily at the same time every day, consistently either with or

without food (see section 5.2). Afinitor tablets should be swallowed whole with a glass of water.

No information is available for tablets crushed, split or chewed.

For patients with TSC who have SEGA and are unable to swallow tablets, Afinitor Tablet(s) can be

dispersed completely in a glass with approximately 30 mL of water by gently stirring until the tablet(s)

is fully disintegrated (approximately 7 minutes), immediately prior to drinking. After the dispersion

has been swallowed, any residue must be re-dispersed in the same volume of water and swallowed

(see section 5.2).

4.3

Contraindications

Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients listed

in section 6.1.

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4.4

Special warnings and precautions for use

Non-infectious pneumonitis

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus.

Non-infectious pneumonitis (including interstitial lung disease) has been frequently reported in patients

taking Afinitor and was described very commonly in patients taking Afinitor in the advanced renal cell

carcinoma (RCC) setting (see section 4.8). Some cases were severe and on rare occasions, a fatal

outcome was observed. A diagnosis of non-infectious pneumonitis should be considered in patients

presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough

or dyspnoea, and in whom infectious, neoplastic, and other non-medicinal causes have been excluded

by means of appropriate investigations. Opportunistic infections such as

pneumocystis jirovecii (carinii)

pneumonia (PJP/PCP) should be ruled out in the differential diagnosis of non-infectious pneumonitis

(see section “Infections” below). Patients should be advised to report promptly any new or worsening

respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or

no symptoms may continue Afinitor therapy without dose adjustments.

For oncology patients, if symptoms are moderate (Grade 2), or severe (Grade 3) the use of corticosteroids

may be indicated until clinical symptoms resolve.

For TSC patients, if symptoms are moderate, consideration should be given to interruption of therapy

until symptoms improve. The use of corticosteroids may be indicated. Afinitor may be reinitiated at a

daily dose approximately 50% lower than the dose previously administered.

For cases of TSC patients where symptoms of non-infectious pneumonitis are severe, Afinitor therapy

should be discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve.

Afinitor may be reinitiated at a daily dose approximately 50% lower than the dose previously

administered depending on the individual clinical circumstances.

For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis

for PJP/PCP may be considered.

Infections

Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or

protozoan infections, including infections with opportunistic pathogens (see section 4.8). Localised and

systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as

aspergillosis, candidiasis, or PJP/PCP and viral infections including reactivation of hepatitis B virus,

have

been described in patients taking Afinitor. Some of these infections have been severe (e.g. leading

to sepsis [including septic shock], respiratory or hepatic failure) and occasionally fatal in adult and

paediatric patients (see section 4.8).

Physicians and patients should be aware of the increased risk of infection with Afinitor. Pre-existing

infections should be treated appropriately and should have resolved fully before starting treatment with

Afinitor. While taking Afinitor, be vigilant for symptoms and signs of infection; if a diagnosis of

infection is made, institute appropriate treatment promptly and consider interruption or discontinuation

of Afinitor.

If a diagnosis of invasive systemic fungal infection is made, the Afinitor treatment should be promptly

and permanently discontinued and the patient treated with appropriate antifungal therapy.

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Cases

PJP/PCP,

some

with

fatal

outcome,

have

been

reported

patients

received

everolimus. PJP/PCP

associated

with

concomitant

corticosteroids

other

immunosuppressive agents. Prophylaxis for PJP/PCP should be considered when concomitant use of

corticosteroids or other immunosuppressive agents are required.

Hypersensitivity reactions

Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnoea,

flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory

impairment) have been observed with everolimus (see section 4.3).

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors

Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for

angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment). (See

section 4.5)

Stomatitis

Stomatitis, including mouth ulcerations and oral mucositis, is the most commonly reported adverse

reaction in patients treated with Afinitor (see section 4.8). Stomatitis mostly occurs within the first

8 weeks of treatment. A single-arm study in postmenopausal breast cancer patients treated with Afinitor

(everolimus) plus exemestane suggested that an alcohol-free corticosteroid oral solution, administered

as a mouthwash during the initial 8 weeks of treatment, may decrease the incidence and severity of

stomatitis (see section 5.1). Management of stomatitis may therefore include prophylactic (in adults)

and/or therapeutic use of topical treatments, such as an alcohol-free corticosteroid oral solution as a

mouthwash. However, products containing alcohol, hydrogen-peroxide, iodine and thyme derivatives

should be avoided as they may exacerbate the condition. Monitoring for and treatment of fungal infection

is recommended, especially in patients being treated with steroid-based medicinal products. Antifungal

agents should not be used unless fungal infection has been diagnosed (see section 4.5).

Haemorrhage

Serious cases of haemorrhage, some with a fatal outcome, have been reported in patients treated with

everolimus in the oncology setting. No serious cases of renal haemorrhage were reported in the TSC

setting.

Caution is advised in patients taking Afinitor, particularly during concomitant use with active

substances known to affect platelet function or that can increase the risk of haemorrhage as well as in

patients with a history of bleeding disorders. Healthcare professionals and patients should be vigilant

for signs and symptoms of bleeding throughout the treatment period, especially if risk factors for

haemorrhage are combined.

Renal failure events

Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in

patients treated with Afinitor (see section 4.8). Renal function of patients should be monitored

particularly where patients have additional risk factors that may further impair renal function.

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Laboratory tests and monitoring

Renal function

Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients treated with

Afinitor (see section 4.8).

Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or

serum creatinine, is recommended prior to the start of Afinitor therapy and periodically thereafter.

Blood glucose

Hyperglycaemia has been reported in patients taking Afinitor (see section 4.8) Monitoring of fasting

serum glucose is recommended prior to the start of Afinitor therapy and periodically thereafter. More

frequent monitoring is recommended when Afinitor is co-administered with other medical products that

may induce hyperglycemia. When possible optimal glycaemic control should be achieved before starting

a patient on Afinitor.

Blood lipids

Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported in patients

taking Afinitor. Monitoring of blood cholesterol and triglycerides prior to the start of Afinitor therapy

and periodically thereafter as well as management with appropriate medical therapy is recommended.

Hematological parameters

Decreased haemoglobin, lymphocytes, platelets and neutrophils have been reported (see section 4.8).

Monitoring of complete blood count is recommended prior to the start of Afinitor therapy and

periodically thereafter.

Functional carcinoid tumours

In a randomised, double-blind, multi-centre trial in patients with functional carcinoid tumours,

Afinitor plus depot octreotide was compared to placebo plus depot octreotide. The study did not meet

the primary efficacy endpoint (progression-free-survival [PFS]) and the overall survival (OS) interim

analysis numerically favoured the placebo plus depot octreotide arm. Therefore, the safety and

efficacy of Afinitor in patients with functional carcinoid tumours have not been established.

Prognostic factors in neuroendocrine tumours of gastrointestinal or lung origin

In patients with non-functional gastrointestinal or lung neuroendocrine tumours and good prognostic

baseline factors, e.g. ileum as primary tumour origin and normal chromogranin A values or without

bone involvement, an individual benefit-risk assessment should be performed prior to the start of

Afinitor therapy. Limited evidence of PFS benefit was reported in the subgroup of patients with ileum

as primary tumour origin (see section 5.1).

Interactions

Co-administration with inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump

P-glycoprotein (PgP) should be avoided. If co-administration of a moderate CYP3A4 and/or PgP

inhibitor or inducer cannot be avoided, dose adjustments of Afinitor for oncology patients can be taken

into consideration based on predicted AUC, dose adjustments of Afinitor for TSC patients may also be

required (see section 4.5).

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Concomitant treatment with potent CYP3A4 inhibitors result in dramatically increased blood

concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing

recommendations in this situation. Hence, concomitant treatment of Afinitor and potent inhibitors is

not recommended.

Caution should be exercised when Afinitor is taken in combination with orally administered CYP3A4

substrates with a narrow therapeutic index due to the potential for drug interactions. If Afinitor is taken

with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide,

terfenadine, astemizole, cisapride, quinidine, ergot alkaloid derivatives or carbamazepine), the patient

should be monitored for undesirable effects described in the product information of the orally

administered CYP3A4 substrate (see section 4.5).

Hepatic impairment

Oncology patients:

Exposure to everolimus was increased in patients with mild (Child-Pugh A), moderate (Child-Pugh B),

and severe (Child-Pugh C) hepatic impairment (see section

5.2 .

Afinitor is only recommended for use in patients with severe hepatic impairment (Child-Pugh C) if the

potential benefit outweighs the risk (see sections 4.2 and 5.2).

No clinical safety or efficacy data are currently available to support dose adjustment recommendations

for the management of adverse reactions in oncology patients with hepatic impairment.

TSC patients:

Afinitor is not recommended for use in patients:

≥18 years of age

and concomitant severe hepatic impairment (Child-Pugh C) unless the

potential benefit outweighs the risk (see sections 4.2 and 5.2).

<18 years of age with SEGA

and concomitant hepatic impairment (Child-Pugh A, B and C)

(see sections 4.2 and 5.2).

Vaccinations

The use of live vaccines should be avoided during treatment with Afinitor (see section 4.5).

For pediatric patients with SEGA who do not require immediate treatment, completion of the

recommended childhood series of live virus vaccinations is advised prior to the start of therapy according

to local treatment guidelines.

Wound healing complications

Impaired wound healing is a class effect of rapamycin derivatives, including Afinitor. Caution should

therefore be exercised with the use of Afinitor in the peri-surgical period.

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-

galactose malabsorption should not take this medicinal product.

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4.5

Interaction with other medicinal products and other forms of interaction

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore,

absorption and subsequent elimination of everolimus may be influenced by products that affect

CYP3A4 and/or PgP.

In vitro

, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor

of CYP2D6.

Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP are

listed in Table 2 below.

CYP3A4 and PgP inhibitors increasing everolimus concentrations

Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by

decreasing metabolism or the efflux of everolimus from intestinal cells.

CYP3A4 and PgP inducers decreasing everolimus concentrations

Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by

increasing metabolism or the efflux of everolimus from intestinal cells.

Table 2

Effects of other active substances on everolimus

Active substance by

interaction

Interaction – Change in

Everolimus AUC/C

max

Geometric mean ratio

(observed range)

Recommendations concerning

co-administration

Potent CYP3A4/PgP inhibitors

Ketoconazole

AUC ↑15.3-fold

(range 11.2-22.5)

↑4.1-fold

(range 2.6-7.0)

Concomitant treatment of Afinitor

and potent inhibitors is not

recommended.

Itraconazole,

posaconazole,

voriconazole

Not studied. Large increase in

everolimus concentration is

expected.

Telithromycin,

clarithromycin

Nefazodone

Ritonavir, atazanavir,

saquinavir, darunavir,

indinavir, nelfinavir

Moderate CYP3A4/PgP inhibitors

Erythromycin

AUC ↑4.4-fold

(range 2.0-12.6)

↑2.0-fold

(range 0.9-3.5)

Use caution when co-administration of

moderate CYP3A4 inhibitors or PgP

inhibitors cannot be avoided.

Imatinib

AUC ↑ 3.7-fold

↑ 2.2-fold

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Verapamil

AUC ↑3.5-fold

(range 2.2-6.3)

↑2.3-fold

(range1.3-3.8)

Oncology patient and patients with

renal angiomyolipoma associated with

TSC:

If patients require co-administration of

a moderate CYP3A4 or PgP inhibitor,

dose reduction to 5 mg daily or 2.5 mg

daily may be considered.

However, there are no clinical data

with this dose adjustment. Due to

between subject variability the

recommended dose adjustments may

not be optimal in all individuals,

therefore close monitoring of side

effects is recommended.

If the

moderate inhibitor is discontinued,

consider a washout period of at least 2

to 3 days (average elimination time for

most commonly used moderate

inhibitors) before the Afinitor dose is

returned to the dose used prior to

initiation of the co-administration.

(see also Therapeutic drug monitoring

in section 4.2).

For patients with SEGA associated

with TSC:

If patients require co-administration of

a moderate CYP3A4 or PgP inhibitor,

reduce the daily dose by approximately

50%. Further dose reduction may be

required to manage adverse reactions

(see sections 4.2 and 4.4). Everolimus

trough concentrations should be

assessed approximately 2 weeks after

the addition of a moderate CYP3A4 or

PgP inhibitor. If the moderate inhibitor

is discontinued, consider a washout

period of at least 2 to 3 days (average

elimination time for most commonly

used moderate inhibitors) before the

Afinitor dose is returned to the dose

used prior to initiation of the co-

administration. The everolimus trough

concentration should be assessed

approximately 2 weeks after any

change in dose (see sections 4.2 and

4.4)

Ciclosporin oral

AUC ↑2.7-fold

(range 1.5-4.7)

↑1.8-fold

(range 1.3-2.6)

Fluconazole

Not studied. Increased

exposure expected.

Diltiazem

Dronedarone

Not studied. Increased

exposure expected.

Amprenavir,

fosamprenavir

Not studied. Increased

exposure expected.

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Grapefruit juice or

other food affecting

CYP3A4/PgP

Not studied. Increased

exposure expected (the effect

varies widely).

Combination should be avoided.

Potent and moderate CYP3A4 inducers

Rifampicin

AUC ↓63%

(range 0-80%)

↓58%

(range 10-70%)

Avoid the use of concomitant potent

CYP3A4 inducers.

For oncology patients and patients

with renal angiomyolipoma

associated with TSC:

If patients require co-administration

of a potent CYP3A4 inducer, an

Afinitor dose increase from 10 mg

daily up to 20 mg daily should be

considered using 5 mg increments or

less applied on Day 4 and 8

following start of the inducer. This

dose of Afinitor is predicted to adjust

the AUC to the range observed

without inducers. However, there are

no clinical data with this dose

adjustment. If treatment with the

inducer is discontinued, consider a

washout period of at least 3 to 5 days

(reasonable time for significant

enzyme de-induction) before the

Afinitor dose is returned to the dose

used prior to initiation of the

co-administration (see also

Therapeutic drug monitoring in

section 4.2).

For patients with SEGA associated

with TSC:

Patients receiving concomitant

potent CYP3A4 inducers may

require an increased Afinitor dose to

achieve the same exposure as

patients not taking potent inducers.

Dosing should be titrated to attain

trough concentrations of 5 to

15 ng/ml. If concentrations are below

5 ng/ml, the daily dose may be

increased by 2.5 mg every 2 weeks,

checking the trough level and

assessing tolerability before

increasing the dose.

Dexamethasone

Not studied. Decreased

exposure expected.

Antiepileptics (e.g.

carbamazepine,

phenobarbital,

phenytoin)

Not studied. Decreased

exposure expected.

Efavirenz, nevirapine

Not studied. Decreased

exposure expected.

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The addition of another concomitant

strong CYP3A4 inducer may not

require additional dose adjustment.

Assess the everolimus trough level

2 weeks after initiating the additional

inducer. Adjust the dose by

increments of 2.5 mg as necessary to

maintain the target trough

concentration.

Discontinuation of one of multiple

strong CYP3A4 inducers may not

require additional dose adjustment.

Assess the everolimus trough level

2 weeks after discontinuation of one

of multiple strong CYP3A4 inducers.

If all potent inducers are

discontinued, consider a washout

period of at least 3 to 5 days

(reasonable time for significant

enzyme de-induction) before the

Afinitor dose is returned to the dose

used prior to initiation of the

co-administration. The everolimus

trough concentrations should be

assessed approximately 2 weeks after

any change in dose (see sections 4.2

and 4.4).

St John’s Wort

(Hypericum perforatum)

Not studied. Large decrease in

exposure expected.

Preparations containing St John’s

Wort should not be used during

treatment with everolimus

Agents whose plasma concentration may be altered by everolimus

Based on

in vitro

results, the systemic concentrations obtained after oral daily doses of 10 mg make

inhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the gut

cannot be excluded. An interaction study in healthy subjects demonstrated that co-administration of an

oral dose of midazolam, a sensitive CYP3A substrate probe, with everolimus resulted in a 25%

increase in midazolam C

and a 30% increase in midazolam AUC

(0-inf)

. The effect is likely to be due

to inhibition of intestinal CYP3A4 by everolimus. Hence everolimus may affect the bioavailability of

orally co-administered CYP3A4 substrates. However, a clinically relevant effect on the exposure of

systemically administered CYP3A4 substrates is not expected (see section 4.4).

In EXIST-3 (Study CRAD001M2304), everolimus increased pre-dose concentrations of the

antiepileptics carbamazepine, clobazam, and the clobazam metabolite N-desmethylclobazam by about

10%. The increase in the pre-dose concentrations of these antiepileptics may not be clinically

significant but dose adjustments for antiepileptics with a narrow therapeutic index, e.g carbamazepine,

may be considered. Everolimus had no impact on pre-dose concentrations of antiepileptics that are

substrates of CYP3A4 (clonazepam, diazepam, felbamate and zonisamide).

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Co-administration of everolimus and depot octreotide increased octreotide C

with a geometric mean

ratio (everolimus/placebo) of 1.47. A clinically significant effect on the efficacy response to

everolimus in patients with advanced neuroendocrine tumours could not be established.

Co-administration of everolimus and exemestane increased exemestane C

and C

by 45% and 64%,

respectively. However, the corresponding oestradiol levels at steady state (4 weeks) were not different

between the two treatment arms. No increase in adverse reactions related to exemestane was observed

in patients with hormone receptor-positive advanced breast cancer receiving the combination. The

increase in exemestane levels is unlikely to have an impact on efficacy or safety.

Concomitant use of ACE inhibitors

Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for

angioedema (see section 4.4).

Vaccinations

The immune response to vaccination may be affected and, therefore, vaccination may be less effective

during treatment with Afinitor. The use of live vaccines should be avoided during treatment with Afinitor

(see section 4.4). Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral

polio, BCG (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a typhoid vaccines.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential/

Contraception in males and females

Women of childbearing potential must use a highly effective method of contraception (e.g. oral,

injected, or implanted non-oestrogen-containing hormonal method of birth control, progesterone-based

contraceptives, hysterectomy, tubal ligation, complete abstinence, barrier methods, intrauterine device

[IUD], and/or female/male sterilisation) while receiving Afinitor, and for up to 8 weeks after ending

treatment.

Male patients should not be prohibited from attempting to father children.

Pregnancy

There are no adequate data from the use of everolimus in pregnant women. Studies in animals have

shown reproductive toxicity effects including embryo-toxicity and feto-toxicity (see section 5.3). The

potential risk for humans is unknown.

Everolimus is not recommended during pregnancy and in women of childbearing potential not using

contraception.

Breast-feeding

It is not known whether everolimus is excreted in human breast milk. However, in rats, everolimus

and/or its metabolites readily pass into the milk (see section 5.3). Therefore women taking Afinitor

should not breast-feed during treatment and for 2 weeks after the last dose.

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Fertility

The potential for everolimus to cause infertility in male and female patients is unknown, however

amenorrhoea (secondary amenorrhoea and other menstrual irregularities) and associated luteinising

hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed in female patients.

Based on non-clinical findings, male and female fertility may be compromised by treatment with

Afinitor (see section 5.3).

4.7

Effects on ability to drive and use machines

Afinitor has a minor or moderate influence on the ability to drive and use machines. Patients should

be advised to be cautious when driving or using machines if they experience fatigue during treatment

with Afinitor.

4.8

Undesirable effects

Oncology patients

Summary of safety profile

The safety profile is based on pooled data from 2,879 patients treated with Afinitor in eleven clinical

studies consisting of five randomized, double-blind, placebo controlled phase III studies and six open-

label phase 1 and phase II studies related to the approved indications in oncology.

The most common adverse reactions (incidence ≥1/10) from the pooled safety data were (in decreasing

order): stomatitis, rash, fatigue, diarrhoea, infections, nausea, decreased appetite, anemia, dysgeusia,

pneumonitis, oedema peripheral, hyperglycemia, asthenia, pruritus, weight decreased,

hypercholesterolemia, epistaxis, cough and headache.

The most frequent Grade 3-4 adverse reactions (incidence ≥ 1

/100 to <1/10) were stomatitis, anemia,

hyperglycemia, infections, fatigue, diarrhea, pneumonitis, asthenia, thrombocytopenia, neutropenia,

dyspnea, proteinuria, lymphopenia, hemorrhage, hypophosphatemia, rash, hypertension, pneumonia,

alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and diabetes

mellitus. The grades follow CTCAE Version 3.0 and 4.03.

Tabulated list of adverse reactions in oncology

Table 3 presents the frequency category of adverse reactions reported in the pooled analysis

considered for the safety pooling.

Adverse reactions are listed according to MedDRA system

organ class and frequency category. Frequency categories are defined using the following

convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to

<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency

grouping, adverse reactions are presented in order of decreasing seriousness.

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Table 3

Adverse reactions reported in oncology clinical studies

Infections and infestations

Very common

Infections

Blood and lymphatic system disorders

Very common

Anemia

Common

Thrombocytopenia, neutropenia, leukopenia, lymphopenia

Uncommon

Pancytopenia

Rare

Pure red cell aplasia

Immune system disorders

Uncommon

Hypersensitivity

Metabolism and nutrition disorders

Very common

Decreased appetite, hyperglycemia, hypercholesterolemia

Common

Hypertriglyceridemia, hypophosphatemia, diabetes mellitus, hyperlipidemia,

hypokalemia, dehydration, hypocalcaemia

Psychiatric disorders

Common

Insomnia

Nervous system disorders

Very common

Dysgeusia, headache

Uncommon

Ageusia

Eye disorders

Common

uncommon

eyelid oedema

Conjunctivitis

Cardiac disorders

Uncommon

Congestive cardiac failure

Vascular disorders

Common

Hemorrhage

, hypertension

Uncommon

Flushing, deep vein thrombosis

Respiratory, thoracic and mediastinal disorders

Very common

Pneumonitis

, epistaxis, cough

Common

Dyspnea

Uncommon

Hemoptysis, pulmonary embolism

Rare

Acute respiratory distress syndrome

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Gastrointestinal disorders

Very common

Stomatitis

, diarrhea, nausea

Common

Vomiting, dry mouth, abdominal pain, mucosal inflammation, oral pain, dyspepsia,

dysphagia

Hepatobiliary disorders

Common

Aspartate aminotransferase increased, alanine aminotransferase increased

Skin and subcutaneous tissue disorders

Very common

Rash, pruritus

Common

Dry skin, nail disorder, mild alopecia, acne, erythema, onychoclasis, palmar-

plantar erythrodysaesthesia syndrome, skin exfoliation, skin lesion

Rare

Angioedema*

Musculoskeletal and connective tissue disorders

Common

Arthralgia

Renal and urinary disorders

Common

Proteinuria*, blood creatinine increased* renal failure*

Uncommon

Increased daytime urination, acute renal failure*

Reproductive system and breast disorders

Common

Menstruation irregular

Uncommon

Amenorrhea

General disorders and administration site conditions

Very common

Fatigue, asthenia, oedema peripheral

Common

Pyrexia

Uncommon

Non-cardiac chest pain, impaired wound healing

Investigations

Very common

Weight decreased

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See also subsection “Description of selected adverse reactions”

Includes all reactions within the ‘infections and infestations’ system organ class including

(common) pneumonia, urinary tract infection; (uncommon) bronchitis, herpes zoster, sepsis,

abscess, and isolated cases of opportunistic infections [e.g. aspergillosis, candidiasis, PJP/PCP)

and hepatitis B (see also section 4.4)] and (rare) viral myocarditis

Includes different bleeding events from different sites not listed individually

Includes (very common) pneumonitis, (common) interstitial lung disease, lung infiltration and

(rare) pulmonary alveolar haemorrhage, pulmonary toxicity, and alveolitis

Includes (very common) stomatitis, (common) aphthous stomatitis, mouth and tongue ulceration

and (uncommon) glossodynia, glossitis

Frequency based upon number of women from 10 to 55 years of age in the pooled data

Tuberous sclerosis complex (TSC)

Summary of the safety profile

Three randomised, double-blind, placebo-controlled pivotal phase III studies , including double-blind

and open label treatment periods and a non-randomised, open-label, single-arm phase II study

contribute to the safety profile of Afinitor (n=612, including 409 patients <18 years of age; median

duration of exposure 36.8 months [range 0.5 to 83.2]).

EXIST-3 (CRAD001M2304): This was a randomised, double-blind, controlled, phase III trial

comparing adjunctive treatment of low and high everolimus exposure (low trough [LT] range of

3-7 ng/ml [n=117] and high trough [HT] range of 9-15 ng/ml [n=130]) versus placebo (n=119),

in patients with TSC and refractory partial-onset seizures receiving 1 to 3 antiepileptics. The

median duration of the double-blind period was 18 weeks. The cumulative median duration

exposure to Afinitor (361 patients who took at least one dose of everolimus) was 30.4 months

(range 0.5 to

48.8).

EXIST-2 (CRAD001M2302): This was a randomised, double-blind, controlled, phase III trial of

everolimus (n=79) versus placebo (n=39) in patients with either TSC plus renal

angiomyolipoma (n=113) or sporadic lymphangioleiomyomatosis (LAM) plus renal

angiomyolipoma (n=5). The median duration of blinded study treatment was 48.1 weeks (range

2 to 115) for patients receiving Afinitor and 45.0 weeks (range 9 to 115) for those receiving

placebo. The cumulative median duration of exposure to Afinitor (112 patients who took at least

one dose of everolimus) was 46.9 months (range 0.5 to 63.9).

EXIST-1 (CRAD001M2301): This was a randomised, double-blind, controlled, phase III trial of

everolimus (n=78) versus placebo (n=39) in patients with TSC who have SEGA, irrespective of

age. The median duration of blinded study treatment was 52.2 weeks (range 24 to 89) for

patients receiving Afinitor and 46.6 weeks (range 14 to 88) for those receiving placebo. The

cumulative median duration of exposure to Afinitor (111 patients who took at least one dose of

everolimus) was 47.1 months (range 1.9 to 58.3).

CRAD001C2485: This was a prospective, open-label, single-arm phase II study of everolimus

in patients with SEGA (n=28). The median duration of exposure was 67.8 months (range 4.7 to

83.2).

The adverse events considered to be associated with the use of Afinitor (adverse reactions), based

upon the review and medical assessment of all adverse events reported in the above studies, are

described below.

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The most frequent adverse reactions (incidence ≥1/10) from the pooled safety data are (in decreasing

order): stomatitis, pyrexia, nasopharyngitis, diarrhoea, upper respiratory tract infection, vomiting,

cough, rash, headache, amenorrhoea, acne, pneumonia, urinary tract infection, sinusitis, menstruation

irregular, pharyngitis, decreased appetite, fatigue, hypercholesterolaemia

and hypertension.

The most frequent grade 3-4 adverse reactions (incidence ≥1%) were, pneumonia, stomatitis,

amenorrhoea, neutropenia, pyrexia, menstruation irregular, hypophosphataemia, diarrhoea and

cellulitis. The grades follow CTCAE Version 3.0 and 4.03.

Tabulated list of adverse reactions

Table 3-1 shows the incidence of adverse reactions based on pooled data of patients receiving

everolimus in the three TSC studies (including both the double-blind and open-label extension phase,

where applicable). Adverse reactions are listed according to MedDRA system organ class. Frequency

categories are defined using the following convention: very common (≥1/10); common (≥1/100 to

<1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not

known (cannot be estimated from the available data). Within each frequency grouping, adverse

reactions are presented in order of decreasing seriousness.

Table 3-1

Adverse reactions reported in TSC studies

Infections and infestations

Very common

Nasopharyngitis, upper respiratory tract infection, pneumonia

, urinary tract infection,

sinusitis, pharyngitis

Common

Otitis media, cellulitis, pharyngitis streptococcal, gastroenteritis viral, gingivitis

Uncommon

Herpes zoster, sepsis, bronchitis viral

Blood and lymphatic system disorders

Common

Anaemia, neutropenia, leucopenia, thrombocytopenia, lymphopenia

Immune system disorders

Common

Hypersensitivity

Metabolism and nutrition disorders

Very common

Decreased appetite, hypercholesterolaemia

Common

Hypertriglyceridaemia, hyperlipidaemia, hypophosphataemia, hyperglycemia

Psychiatric disorders

Common

Insomnia, aggression, irritability

Nervous system disorders

Very common Headache

Uncommon

Dysgeusia

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Vascular disorders

Very common

Hypertension

Common

Lymphoedema

Respiratory, thoracic and mediastinal disorders

Very common Cough

Common

Epistaxis, pneumonitis

Gastrointestinal disorders

Very common

Stomatitis

,diarrhoea, vomiting

Common

Constipation, nausea, abdominal pain, flatulence, oral pain, gastritis

Skin and subcutaneous tissue disorders

Very common

Rash

, acne

Common

Dry skin, acneiform dermatitis, pruritus, alopecia

Uncommon

Angioedema

Musculoskeletal and connective tissue disorders

Uncommon

Rhabdomyolysis

Renal and urinary disorders

Common

Proteinuria

Reproductive system and breast disorders

Very common

Amenorrhea

, menstruation irregular

Common

Uncommon

Menorrhagia, ovarian cyst, vaginal hemorrhage

Menstruation delayed

General disorders and administration site conditions

Very common

Pyrexia, fatigue

Investigations

Common

Blood lactate dehydrogenase increased, blood luteinizing hormone increased, weight

decreased

Uncommon

Blood follicle stimulating hormone increased

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Includes pneumocystis jirovecii (carinii) pneumonia (PJP, PCP)

Includes (very common) stomatitis, mouth ulceration, aphthous ulcer; (common) tongue ulceration, lip

ulceration and (uncommon) gingival pain, glossitis

Includes (very common) rash; (common) rash erythematous, erythema and (uncommon) rash

generalized, rash maculo-papular, rash macular

Frequency is based upon number of women from 10 to 55 years of age while on treatment in the pooled

data

Description of selected adverse reactions

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with

serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infection is an

expected reaction during periods of immunosuppression.

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with renal

failure events (including fatal outcome), proteinuria and increased serum creatinine. Monitoring of

renal function is recommended (see section 4.4).

In clinical studies for TSC indications, everolimus has been associated with haemorrhage events. On

rare occasions, fatal outcomes were observed in the oncology setting (see section 4.4). No serious

cases of renal haemorrhage were reported in the TSC setting.

In clinical studies for oncology indications and post-marketing spontaneous reports, everolimus has

been associated with cases of amenorrhoea (secondary amenorrhoea and other menstrual

irregularities).

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with cases

of PJP/PCP, some with fatal outcome (see section 4.4).

Additional adverse reactions of relevance observed in oncology clinical studies and post-marketing

spontaneous reports, were cardiac failure, pulmonary embolism, deep vein thrombosis, impaired

wound healing and hyperglycaemia.

In clinical studies and post-marketing spontaneous reports, angioedema has been reported with and

without concomitant use of ACE inhibitors (see section 4.4).

Paediatric population

In the pivotal phase II study, 22 of the 28 SEGA patients studied were below the age of 18 years and in

the pivotal phase III study, 101 of the 117 SEGA patients studied were below the age of 18 years. In

the pivotal phase III study in patients with TSC and refractory seizures, 299 of the 366 patients studied

were below the age of 18 years. The overall type, frequency and severity of adverse reactions observed

in children and adolescents have been generally consistent with those observed in adults,

with the

exception of infections which were reported at a higher frequency and severity in children below the

age of 6 years. A total of 49 out of 137 patients (36%) aged <6 years had Grade 3/4 infections,

compared to 53 out of 272 patients (19%) aged 6 to <18 years and 27 out of 203 patients (13%) aged

≥18 years. Two fatal cases due to infection were reported in 409 patients aged <18 years receiving

everolimus.

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Elderly

In the oncology safety pooling, 37% of the patients treated with everolimus were ≥65 years of age.

The number of oncology patients with an adverse reaction leading to discontinuation of everolimus

was higher in patients≥65 years of age (20% versus 13%). The most common adverse reactions

leading to discontinuation were pneumonitis (including interstitial lung disease), fatigue, dyspnoea,

and stomatitis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

https://sideeffects.health.gov.il/

4.9 Overdose

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been

given with acceptable acute tolerability.

It is essential to assess everolimus blood levels in cases of suspected overdose. General supportive

measures should be initiated in all cases of overdose. Everolimus is not considered dialysable to any

relevant degree (less than 10% was removed within 6 hours of haemodialysis).

Paediatric population

A limited number of TSC paediatric patients

have been exposed to doses higher than 10 mg/m

/day.

No signs of acute toxicity have been reported in these cases.

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group

:

Antineoplastic agents, other antineoplastic agents, protein kinase

inhibitors, ATC code: L01XE10

Mechanism of action

Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-

threonine kinase, the activity of which is known to be upregulated in a number of human cancers.

Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR

complex-1 (mTORC1) activity.

Inhibition of the mTORC1

signalling pathway interferes with the

translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1) and

eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in the cell

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cycle, angiogenesis and glycolysis. S6K1is thought to phosphorylate the activation function domain 1

of the oestrogen receptor, which is responsible for ligand-independent receptor activation.

Everolimus reduces levels of vascular endothelial growth factor (VEGF), which potentiates tumour

angiogenic processes. In patients with TSC, treatment with everolimus increases VEGF-A and decreases

VEGF-D levels. Everolimus is a potent inhibitor of the growth and proliferation of tumour cells,

endothelial cells, fibroblasts and blood-vessel-associated smooth muscle cells and has been shown to

reduce glycolysis in solid tumours

in vitro

in vivo

Two primary regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis

complexes 1 & 2 (TSC1, TSC2). Loss of either TSC1 or TSC2 leads to elevated rheb-GTP levels, a ras

family GTPase, which interacts with the mTORC1 complex to cause its activation. mTORC1

activation leads to a downstream kinase signaling cascade, including activation of the S6 kinase. In

TSC syndrome, inactivating mutations in the TSC1 or the TSC2 gene lead to hamartoma formation

throughout the body.

Clinical efficacy and safety in oncology

Hormone receptor-positive advanced breast cancer

BOLERO-2 (study CRAD001Y2301), a randomised, double-blind, multicentre phase III study of

Afinitor + exemestane versus placebo + exemestane, was conducted in postmenopausal women with

oestrogen receptor-positive, HER2/neu negative advanced breast cancer with recurrence or progression

following prior therapy with letrozole or anastrozole. Randomisation was stratified by documented

sensitivity to prior hormonal therapy and by the presence of visceral metastasis. Sensitivity to prior

hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial

response [PR], stable disease ≥24 weeks) from at least one prior hormonal therapy in the advanced

setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence.

The primary endpoint for the study was progression-free survival (PFS) evaluated by RECIST

(Response Evaluation Criteria in Solid Tumors), based on the investigator’s assessment (local

radiology). Supportive PFS analyses were based on an independent central radiology review.

Secondary endpoints included overall survival (OS), objective response rate, clinical benefit rate,

safety, change in quality of life (QoL) and time to ECOG PS (Eastern Cooperative Oncology Group

performance status) deterioration.

A total of 724 patients were randomised in a 2:1 ratio to the combination everolimus (10 mg daily) +

exemestane (25 mg daily) (n=485) or to the placebo + exemestane arm (25 mg daily) (n=239). At the

time of the final OS analysis, the median duration of everolimus treatment was 24.0 weeks (range

1.0-199.1 weeks). The median duration of exemestane treatment was longer in the everolimus +

exemestane group at 29.5 weeks (1.0-199.1) compared to 14.1 weeks (1.0-156.0) in the placebo +

exemestane group.

The efficacy results for the primary endpoint were obtained from the final PFS analysis (see Table 4

and Figure 1). Patients in the placebo + exemestane arm did not cross over to everolimus at the time of

progression.

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Table 4

BOLERO-2 efficacy results

Analysis

Afinitor

a

n=485

Placebo

a

n=239

Hazard ratio

p value

Median progression-free survival (months) (95% CI)

Investigator radiological review

(6.9 to 8.5)

(2.8 to 4.1)

0.45

(0.38 to 0.54)

<0.0001

Independent radiological review

11. 0

(9.7 to 15.0)

(2.9 to 5.6)

0.38

(0.31 to 0.48)

<0.0001

Median overall survival (months) (95% CI)

Median overall survival

31.0

(28.0 – 34.6)

26.6

(22.6 – 33.1)

0.89

(0.73 – 1.10)

0.1426

Best overall response (%) (95% CI)

Objective response rate

12.6%

(9.8 to 15.9)

1.7%

(0.5 to 4.2)

<0.0001

Clinical benefit rate

51.3%

(46.8 to 55.9)

26.4%

(20.9 to 32.4)

<0.0001

Plus exemestane

Objective response rate = proportion of patients with complete or partial response

Clinical benefit rate = proportion of patients with complete or partial response or stable disease

≥24 weeks

Not applicable

p value is obtained from the exact Cochran-Mantel-Haenszel test using a stratified version of the

Cochran-Armitage permutation test.

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Figure 1

BOLERO-2 Kaplan-Meier progression-free survival curves (investigator

radiological review)

The estimated PFS treatment effect was supported by planned subgroup analysis of PFS per

investigator assessment. For all analysed subgroups (age, sensitivity to prior hormonal therapy,

number of organs involved, status of bone-only lesions at baseline and presence of visceral metastasis,

and across major demographic and prognostic subgroups) a positive treatment effect was seen with

everolimus + exemestane with an estimated hazard ratio (HR) versus placebo + exemestane ranging

from 0.25 to 0.60

No differences in the time to ≥5% deterioration in the global and functional domain scores of

QLQ-C30 were observed in the two arms.

BOLERO-6 (Study CRAD001Y2201), a three-arm, randomised, open-label, phase II study of

everolimus in combination with exemestane versus everolimus alone versus capecitabine in the

treatment of postmenopausal women with oestrogen receptor-positive, HER2/neu negative, locally

advanced, recurrent, or metastatic breast cancer after recurrence or progression on prior letrozole or

anastrozole.

Proba

bility

(%) of

event

Time (weeks)

Everolimus

Placebo

Number of Patients still at Risk

Time(weeks)

Hazard Ratio = 0.45

95% CI [0.38, 0.54]

Everolimus 10 mg + exemestane: 7.82 months

Placebo + exemestane: 3.19 months

Kaplan-Meier medians

Everolimus 10 mg + exemestane (n/N = 310/485)

Placebo + exemestane (n/N = 200/239)

Censoring Times

Log-rank p value: <0.0001

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The primary objective of the study was to estimate the HR of PFS for everolimus + exemestane versus

everolimus alone. The key secondary objective was to estimate the HR of PFS for everolimus +

exemestane versus capecitabine.

Other secondary objectives included the evaluation of OS, objective response rate, clinical benefit rate,

safety, time to ECOG performance deterioration, time to QoL deterioration, and treatment satisfaction

(TSQM). No formal statistical comparisons were planned.

A total of 309 patients were randomised in a 1:1:1 ratio to the combination of everolimus (10 mg

daily) + exemestane (25 mg daily) (n=104), everolimus alone (10 mg daily) (n=103), or capecitabine

(1250 mg/m

dose twice daily for 2 weeks followed by one week rest, 3-week cycle) (n=102). At the

time of data cut-off, the median duration of treatment was 27.5 weeks (range 2.0-165.7) in the

everolimus + exemestane arm, 20 weeks (1.3-145.0) in the everolimus arm, and 26.7 weeks

(1.4-177.1) in the capecitabine arm.

The result of the final PFS analysis with 154 PFS events observed based on local investigator

assessment showed an estimated HR of 0.74 (90% CI: 0.57, 0.97) in favour of the everolimus +

exemestane arm relative to everolimus arm. The median PFS was 8.4 months (90% CI: 6.6, 9.7) and

6.8 months (90% CI: 5.5, 7.2), respectively.

Figure 2

BOLERO-6 Kaplan-Meier progression-free survival curves (investigator

radiological review)

For the key secondary endpoint PFS the estimated HR was 1.26 (90% CI: 0.96, 1.66) in favour of

capecitabine over the everolimus + exemestane combination arm based on a total of 148 PFS events

observed.

Hazard Ratio = 0.74

90% CI [0.57;0.97]

Kaplan-Meier medians

Everolimus/Exemestane: 36.57 [28.71;42.29] weeks

Everolimus: 29.43 [24.00;31.29] weeks

Time (Weeks)

Probability (%) of event

No of patients still at risk

Time (weeks)

Everolimus/Exemestane

Everolimus

Censoring Times

Everolimus/Exemestane (n/N=80/104)

Everolimus (n/N=74/103)

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Results of the secondary endpoint OS were not consistent with the primary endpoint PFS, with a trend

observed favouring the everolimus alone arm. The estimated HR was 1.27 (90% CI: 0.95, 1.70) for the

comparison of OS in the everolimus alone arm relative to the everolimus + exemestane arm. The

estimated HR for the comparison of OS in the everolimus + exemestane combination arm relative to

capecitabine arm was 1.33 (90% CI: 0.99, 1.79).

Advanced neuroendocrine tumours of pancreatic origin (pNET)

RADIANT-3 (study CRAD001C2324), a phase III, multicentre, randomised, double-blind study of

Afinitor plus best supportive care (BSC) versus placebo plus BSC in patients with advanced pNET),

demonstrated a statistically significant clinical benefit of Afinitor over placebo by a 2.4-fold

prolongation of median progression-free-survival (PFS) (11.04 months versus 4.6 months), (HR 0.35;

95% CI: 0.27, 0.45; p<0.0001) (see Table 5 and Figure 3).

RADIANT-3 involved patients with well- and moderately-differentiated advanced pNET whose

disease had progressed within the prior 12 months. Treatment with somatostatin analogues was

allowed as part of BSC.

The primary endpoint for the study was PFS evaluated by RECIST (Response Evaluation Criteria in

Solid Tumors) Following documented radiological progression, patients could be unblinded by the

investigator. Those randomised to placebo were then able to receive open-label Afinitor.

Secondary endpoints included safety, objective response rate), response duration and overall survival

(OS).

In total, 410 patients were randomised 1:1 to receive either Afinitor 10 mg/day (n=207) or placebo

(n=203). Demographics were well balanced (median age 58 years, 55% male, 78.5% Caucasian).

Fifty-eight percent of the patients in both arms received prior systemic therapy. The median duration

of blinded study treatment was 37.8 weeks (range 1.1-129.9 weeks) for patients receiving everolimus

and 16.1 weeks (range 0.4-147.0 weeks) for those receiving placebo.

Following disease progression or after study unblinding, 172 of the 203 patients (84.7%) initially

randomised to placebo crossed over to open-label Afinitor. The median duration of open-label

treatment was 47.7 weeks among all patients; 67.1 weeks in the 53 patients randomised to everolimus

who switched to open-label everolimus and 44.1 weeks in the 172 patients randomised to placebo who

switched to open-label everolimus.

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Table 5

RADIANT-3 – efficacy results

Population

Afinitor

n=207

Placebo

n=203

Hazard ratio

(95% CI)

p-value

Median progression-free survival (months) (95% CI)

Investigator radiological

review

11.04

(8.41, 13.86)

4.60

(3.06, 5.39)

0.35

(0.27, 0.45)

<0.0001

Independent radiological

review

13.67

(11.17, 18.79)

5.68

(5.39, 8.31)

0.38

(0.28, 0.51)

<0.0001

Median overall survival (months) (95% CI)

Median overall survival

44.02

(35.61, 51.75)

37.68

(29.14, 45.77)

0.94

(0.73, 1.20)

0.300

Figure 3

RADIANT-3 – Kaplan-Meier progression-free survival curves (investigator

radiological review)

Hazard Ratio = 0.35

95% CI [0.27, 0.45]

Log-rank p value = <0.001

Kaplan-Meier medians

Afinitor : 11.04 months

Placebo : 4.60 months

Censoring times

Afinitor (n=207)

Placebo (n=203)

Probability (%)

No. of patients still at risk

Afinitor

Placebo

Time (months)

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Advanced neuroendocrine tumours of gastrointestinal or lung origin

RADIANT-4 (study CRAD001T2302), a randomised, double-blind, multicentre, phase III study of

Afinitor plus best supportive care (BSC) versus placebo plus BSC was conducted in patients with

advanced, well-differentiated (Grade 1 or Grade 2) non-functional neuroendocrine tumours of

gastrointestinal or lung origin without a history of and no active symptoms related to carcinoid

syndrome.

The primary endpoint for the study was progression-free survival (PFS) evaluated by Response

Evaluation Criteria in Solid Tumors (RECIST), based on independent radiology assessment.

Supportive PFS analysis was based on local investigator review. Secondary endpoints included overall

survival (OS), overall response rate, disease control rate, safety, change in quality of life (FACT-G)

and time to World Health Organisation performance status (WHO PS) deterioration.

A total of 302 patients were randomised in a 2:1 ratio to receive either everolimus (10 mg daily)

(n=205) or placebo (n=97). Demographics and disease characteristics were generally balanced (median

age 63 years [range 22 to 86], 76% Caucasian, history of prior somatostatin analogue [SSA] use). The

median duration of blinded treatment was 40.4 weeks for patients receiving Afinitor and 19.6 weeks

for those receiving placebo. Patients in the placebo arm did not cross-over to everolimus at the time of

progression.

The efficacy results for the primary endpoint were obtained from the final PFS analysis (see Table 6

and Figure 4).

Table 6

RADIANT-4 – Progression-free survival results

Population

Afinitor

n=205

Placebo

n=97

Hazard ratio

(95% CI)

p-value

a

Median progression-free survival (months) (95% CI)

Independent radiological

review

11.01

(9.2, 13.3)

3.91

(3.6, 7.4)

0.48

(0.35, 0.67)

<0.0001

Investigator radiological

review

13.96

(11.2, 17.7)

5.45

(3.7, 7.4)

0.39

(0.28, 0.54)

<0.0001

One-sided p-value from a stratified log-rank test

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Figure 4

RADIANT-4 – Kaplan-Meier progression-free survival curves (independent

radiological review)

In supportive analyses, positive treatment effect has been observed in all subgroups with the exception

of the subgroup of patients with ileum as primary site of tumour origin [Ileum: HR=1.22 (95% CI:

0.56 to 2.65); Non-ileum: HR=0.34 (95% CI: 0.22 to 0.54); Lung: HR=0.43 (95% CI: 0.24 to 0.79)]

(see Figure 5).

0 2 4 6 8 10 12 15 18 21 24 27 30

205 168 145 124 101 81 65 52 26 10 3 0 0

97 65 39 30 24 21 17 15 11 6 5 1 0

Time (months)

Hazard Ratio = 0.48

95% CI [0.35, 0.67]

Log-rank p value = <0.001

Kaplan-Meier medians

Everolimus + BSC: 11.01

[9.23;13.31] months

Placebo + BSC: 3.91 [3.58;7.43] months

Censoring times

Everolimus + BSC (n/N = 113/205)

Placebo + BSC (n/N = 65/97)

Number of Patients still at Risk

Time(months)

Everolimus

Placebo

Probability (%) of event

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Figure 5

RADIANT-4 – Progression free survival results by pre-specified patient subgroup

(independent radiological review)

The pre-planned OS interim analysis after 101 deaths (out of 191 required for final analysis) and

33 months follow-up favoured the everolimus arm; however, no statistically significant difference in

OS was noted (HR= 0.73 [95% CI: 0.48 to 1.11; p=0.071]).

No difference in the time to definitive deterioration of WHO PS (≥1 point) and time to definitive

deterioration in quality of life (FACT-G total score ≥7 points) was observed between the two arms.

Advanced renal cell carcinoma

RECORD-1 (study CRAD001C2240), a phase III, international, multicentre, randomised, double-blind

study comparing everolimus 10 mg/day and placebo, both in conjunction with best supportive care,

was conducted in patients with metastatic renal cell carcinoma whose disease had progressed on or

after treatment with VEGFR-TKI (vascular endothelial growth factor receptor tyrosine kinase

inhibitor) therapy (sunitinib, sorafenib, or both sunitinib and sorafenib). Prior therapy with

bevacizumab and interferon-α was also permitted. Patients were stratified according to Memorial

All (N=302)

<65 years (N=159)

≥65 years (N=143)

0 (N=216)

1 (N=86)

Yes (N=157)

No (N=145)

Yes (N=77)

No (N=225)

Lung (N=90)

Ileum (N=71)

Non-ileum* (N=141)

Grade 1 (N=194)

Grade 2 (N=107)

≤10% (N=228)

>10% (N=72)

>2xULN (N=139)

≤2xULN (N=138)

>ULN (N=87)

≤ULN (N=188)

Everolimus + BSC

Placebo + BSC

In favour of

WHO PS

Prior SSA

Prior

chemotherapy

Primary tumour

origin

Tumour grading

Liver tumour

burden

Baseline CgA

Baseline NSE

*Non-ileum: stomach, colon, rectum, appendix, caecum, duodenum, jejunum, carcinoma of unknown primary

origin and other gastrointestinal origin

ULN: Upper limit of normal

CgA: Chromogranin A

NSE: Neuron specific enolase

Hazard ratio (95% CI) from stratified Cox model

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Sloan-Kettering Cancer Center (MSKCC) prognostic score (favourable-

vs.

intermediate-

vs.

poor-risk

groups) and prior anticancer therapy (1

vs.

2 prior VEGFR-TKIs).

Progression-free survival, documented using RECIST (Response Evaluation Criteria in Solid

Tumours) and assessed via a blinded, independent central review, was the primary endpoint.

Secondary endpoints included safety, objective tumour response rate, overall survival, disease-related

symptoms, and quality of life. After documented radiological progression, patients could be unblinded

by the investigator: those randomised to placebo were then able to receive open-label everolimus

10 mg/day. The Independent Data Monitoring Committee recommended termination of this trial at the

time of the second interim analysis as the primary endpoint had been met.

In total, 416 patients were randomised 2:1 to receive Afinitor (n=277) or placebo (n=139).

Demographics were well balanced (pooled median age [61 years; range 27-85], 78% male, 88%

Caucasian, number of prior VEGFR-TKI therapies [1-74%, 2-26%]). The median duration of blinded

study treatment was 141 days (range 19-451 days) for patients receiving everolimus and 60 days

(range 21-295 days) for those receiving placebo.

Afinitor was superior to placebo for the primary endpoint of progression-free survival, with a

statistically significant 67% reduction in the risk of progression or death (see Table 7 and Figure 6).

Table 7

RECORD-1 – Progression-free survival results

Population

n

Afinitor

n=277

Placebo

n=139

Hazard ratio

(95%CI)

p-value

Median progression-free

survival (months) (95% CI)

Primary analysis

All (blinded independent

central review)

(4.0-5.5)

(1.8-1.9)

0.33

(0.25-0.43)

<0.0001

Supportive/sensitivity analyses

All (local review by

investigator)

(4.6-5.8)

(1.8-2.2)

0.32

(0.25-0.41)

<0.0001

MSKCC prognostic score (blinded independent central review)

Favourable risk

(4.0-7.4)

(1.9-2.8)

0.31

(0.19-0.50)

<0.0001

Intermediate risk

(3.8-5.5)

(1.8-1.9)

0.32

(0.22-0.44)

<0.0001

Poor risk

(1.9-4.6)

(1.8-3.6)

0.44

(0.22-0.85)

0.007

Stratified log-rank test

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Figure 6

RECORD-1 – Kaplan-Meier progression-free survival curves (independent central

review)

Six-month PFS rates were 36% for Afinitor therapy compared with 9% for placebo.

Confirmed objective tumour responses were observed in 5 patients (2%) receiving Afinitor, while

none were observed in patients receiving placebo. Therefore, the progression-free survival advantage

primarily reflects the population with disease stabilisation (corresponding to 67% of the Afinitor

treatment group).

No statistically significant treatment-related difference in overall survival was noted (hazard

ratio 0.87; confidence interval: 0.65-1.17; p=0.177). Crossover to open-label Afinitor following

disease progression for patients allocated to placebo confounded the detection of any treatment-related

difference in overall survival.

Clinical efficacy and safety in Tuberous Sclerosis complex (TSC)

Renal angiomyolipoma associated with TSC

EXIST-2 (study CRAD001M2302), a randomised, controlled phase III study was conducted to evaluate

the efficacy and safety of Afinitor in patients with TSC plus renal angiomyolipoma. Presence of at least

one angiomyolipoma ≥3 cm in longest diameter using CT/MRI (based on local radiology assessment)

was required for entry.

Hazard Ratio = 0.33

95% CI [0.25, 0.43]

Kaplan-Meier medians

Everolimus: 4.90 months

Placebo: 1.87 months

Log-rank p value = <0.0001

Censoring Times

Everolimus (n/N = 155/277)

Placebo (n/N = 111/139)

Time (months)

Probability (%)

No. of patients still at risk

Time (months)

Afinitor

Placebo

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The primary efficacy endpoint was angiomyolipoma response rate based on independent central

radiology review. The analysis was stratified by use of enzyme-inducing antiepileptics at

randomisation (yes/no).

Key secondary endpoints included time to angiomyolipoma progression and skin lesion response rate.

A total of 118 patients were randomised, 79 to Afinitor 10 mg daily and 39 to placebo. Median age was

31 years (range: 18 to 61 years; 46.6% were <30 years at enrolment), 33.9% were male, and 89.0% were

Caucasian. Of the enrolled patients, 83.1% had angiomyolipomas ≥4 cm (28.8% ≥8 cm), 78.0% had

bilateral angiomyolipomas, and 39.0% had undergone prior renal embolisation/nephrectomy; 96.6% had

skin lesions at baseline and 44.1% had target SEGAs (at least one SEGA ≥1 cm in longest diameter).

Results showed that the primary objective related to best overall angiomyolipoma response was met

with best overall response rates of 41.8% (95% CI: 30.8, 53.4) for the Afinitor arm compared with 0%

(95% CI: 0.0, 9.0) for the placebo arm (p<0.0001) (Table 8).

Patients initially treated with placebo were allowed to cross over to everolimus at the time of

angiomyolipoma progression and upon recognition that treatment with everolimus was superior to

treatment with placebo. At the time of the final analysis (4 years following the last patient

randomisation), the median duration of exposure to everolimus was 204.1 weeks (range 2 to 278). The

angiomyolipoma best overall response rate had increased to 58.0% (95% CI: 48.3, 67.3), with a rate of

stable disease of 30.4% (Table 8).

Among patients treated with everolimus during the study, no cases of angiomyolipoma-related

nephrectomy and only one case of renal embolisation were reported.

Table 8

EXIST-2 - Angiomyolipoma response

Primary Analysis

3

Final

Analysis

Afinitor

Placebo

p-value

Afinitor

n=79

n=39

N=112

Primary analysis

Angiomyolipoma response rate

1,2

– %

95% CI

41.8

30.8, 53.4

0.0, 9.0

<0.0001

58.0

48.3, 67.3

Best overall angiomyolipoma response – %

Response

41.8

58.0

Stable disease

40.5

79.5

30.4

Progression

Not evaluable

16.5

15.4

10.7

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According to independent central radiology review

Angiomyolipoma responses were confirmed with a repeat scan. Response was defined

as: ≥50% reduction in the sum of angiomyolipoma volume relative to baseline, plus

absence of new angiomyolipoma ≥1.0 cm in longest diameter, plus no increase in renal

volume >20% from nadir, plus absence of grade ≥2 angiomyolipoma-related bleeding.

3 Primary analysis for double blind period

4 Final analysis includes patients who crossed over from the placebo group;

median

duration of exposure to everolimus of 204.1 weeks

Consistent treatment effects on angiomyolipoma response rate were observed across all subgroups

evaluated (i.e. enzyme-inducing antiepilepticuse versus enzyme-inducing antiepilepticnon-use, sex,

age and race) at the primary efficacy analysis.

In the final analysis, reduction in angiomyolipoma volume improved with longer term treatment with

Afinitor. At weeks 12, 96 and 192, ≥ 30% reductions in volume were observed in 75.0%, 80.6%, and

85.2% of the treated patients, respectively. Similarly, at the same timepoints, ≥ 50% reductions in

volume were observed in 44.2%, 63.3%, and 68.9% of the treated patients, respectively.

Median time to angiomyolipoma progression was 11.4 months in the placebo arm and was not reached

in the everolimus arm (HR 0.08; 95% CI: 0.02, 0.37; p<0.0001). Progressions were observed in 3.8%

of patients in the everolimus arm compared with 20.5% in the placebo arm. Estimated progression-free

rates at 6 months were 98.4% for the everolimus arm and 83.4% for the placebo arm.

At the final analysis, median time to angiomyolipoma progression was not reached. Angiomyolipoma

progressions were observed in 14.3% of the patients. The estimated angiomyolipoma progression-free

rates at 24 months and 48 months were 91.6% and 83.1%, respectively.

At the primary analysis, skin lesion response rates of 26.0% (95% CI: 16.6, 37.2) for the Afinitor arm

and 0% (95% CI: 0.0, 9.5) for the placebo arm were observed (p=0.0002). At the final analysis, the

skin lesion response rate had increased to 68.2% (95% CI: 58.5, 76.9), with one patient reporting a

confirmed complete clinical skin lesion response and no patients experiencing progressive disease as

their best response.

In an exploratory analysis of patients with TSC with angiomyolipoma who also had SEGA, the SEGA

response rate (proportion of patients with ≥50% reduction from baseline in target lesion volumes in the

absence of progression) was 10.3% in the everolimus arm in the primary analysis (versus no responses

reported in the 13 patients randomised to placebo with a SEGA lesion at baseline) and increased to

48.0% in the final analysis.

Post-hoc sub-group analysis of EXIST-2 (study CRAD001M2302) carried out at time of primary

analysis demonstrated that angiomyolipoma response rate is reduced below the threshold of 5 ng/ml

(Table 9).

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Table 9

EXIST-2 - Angiomyolipoma response rates by time-averaged C

min

category, at

primary analysis

Time-

averaged C

min

category

Number of

patients

Response rate

95% confidence interval

≤5 ng/ml

0.300

0.099, 0.501

>5 ng/ml

0.524

0.373, 0.675

Difference

-0.224

-0.475, 0.027

Difference is “≤5 ng/ml” minus “>5 ng/ml”

SEGA associated with TSC

Phase III study in SEGA patients

EXIST-1 (Study CRAD001M2301), a randomised, double-blind, multicentre phase III study of

Afinitor versus placebo, was conducted in patients with SEGA, irrespective of age. Patients were

randomised in a 2:1 ratio to receive either Afinitor or matching placebo. Presence of at least one

SEGA lesion ≥1.0 cm in longest diameter using MRI (based on local radiology assessment) was

required for entry. In addition, serial radiological evidence of SEGA growth, presence of a new SEGA

lesion ≥1 cm in longest diameter, or new or worsening hydrocephalus was required for entry.

The primary efficacy endpoint was SEGA response rate based on independent central radiology

review. The analysis was stratified by use of enzyme-inducing antiepileptics at randomisation (yes/no).

Key secondary endpoints in hierarchal order of testing included the absolute change in frequency of

total seizure events per 24-hour EEG from baseline to week 24, time to SEGA progression, and skin

lesion response rate.

A total of 117 patients were randomised, 78 to Afinitor and 39 to placebo. The two treatment arms

were generally well balanced with respect to demographic and baseline disease characteristics and

history of prior anti-SEGA therapies. In the total population, 57.3% of patients were male and 93.2%

were Caucasian. The median age for the total population was 9.5 years (age range for the Afinitor arm:

1.0 to 23.9; age range for the placebo arm: 0.8 to 26.6), 69.2% of the patients were aged 3 to <18 years

and 17.1% were <3 years at enrolment.

Of the enrolled patients, 79.5% had bilateral SEGAs, 42.7% had ≥2 target SEGA lesions, 25.6% had

inferior growth, 9.4% had evidence of deep parenchymal invasion, 6.8% had radiographic evidence of

hydrocephalus, and 6.8% had undergone prior SEGA-related surgery. 94.0% had skin lesions at

baseline and 37.6% had target renal angiomyolipoma lesions (at least one angiomyolipoma ≥1 cm in

longest diameter).

The median duration of blinded study treatment was 9.6 months (range: 5.5 to 18.1) for patients

receiving Afinitor and 8.3 months (range: 3.2 to 18.3) for those receiving placebo.

Results showed that Afinitor was superior to placebo for the primary endpoint of best overall SEGA

response (p<0.0001). Response rates were 34.6% (95% CI: 24.2, 46.2) for the Afinitor arm compared

with 0% (95% CI: 0.0, 9.0) for the placebo arm (Table 10). In addition, all 8 patients on the Afinitor

arm who had radiographic evidence of hydrocephalus at baseline had a decrease in ventricular volume.

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Patients initially treated with placebo were allowed to cross over to everolimus at the time of SEGA

progression and upon recognition that treatment with everolimus was superior to treatment with

placebo. All patients receiving at least one dose of everolimus were followed until

medicinal

product

discontinuation or study completion. At the time of the final analysis, the median duration of

exposure among all such patients was 204.9 weeks (range: 8.1 to 253.7). The best overall SEGA

response rate had increased to 57.7% (95% CI: 47.9, 67.0) at the final analysis.

No patient required surgical intervention for SEGA during the entire course of the study.

Table 10

EXIST-1 – SEGA response

Primary analysis

3

Final analysis

4

Afinitor

N=78

Placebo

N=39

p-value

Afinitor

N=111

SEGA response rate

- (%)

34.6

24.2, 46.2

0.0, 9.0

<0.0001

57.7

95% CI

47.9, 67.0

Best overall SEGA response - (%)

Response

34.6

57.7

Stable disease

62.8

92.3

39.6

Progression

Not evaluable

according to independent central radiology review

SEGA responses were confirmed with a repeat scan. Response was defined as:

≥50% reduction in the sum of SEGA volume relative to baseline, plus no

unequivocal worsening of non-target SEGA lesions, plus absence of new SEGA

≥1 cm in longest diameter, plus no new or worsening hydrocephalus

Primary analysis for double blind period

Final analysis includes patients who crossed over from the placebo group; median

duration of exposure to everolimus of 204.9 weeks

Consistent treatment effects were observed across all subgroups evaluated (i.e. enzyme-inducing

antiepilepticuse versus enzyme-inducing antiepilepticnon-use, sex and age) at the primary analysis.

During the double-blind period, reduction of SEGA volume was evident within the initial 12 weeks of

Afinitor treatment: 29.7% (22/74) of patients had ≥50% reductions in volume and 73.0% (54/74) had

≥30% reductions in volume. Sustained reductions were evident at week 24, 41.9% (31/74) of patients

had ≥50% reductions and 78.4% (58/74) of patients had ≥30% reductions in SEGA volume.

In the everolimus treated population (N=111) of the study, including patients who crossed over from

the placebo group, tumour response, starting as early as after 12 weeks on everolimus, was sustained at

later time points. The proportion of patients achieving at least 50% reductions in SEGA volume was

45.9% (45/98) and 62.1% (41/66) at weeks 96 and 192 after start of everolimus treatment. Similarly,

the proportion of patients achieving at least 30% reductions in SEGA volume was 71.4% (70/98) and

77.3% (51/66) at weeks 96 and 192 after start of everolimus treatment.

Analysis of the first key secondary endpoint, change in seizure frequency, was inconclusive; thus,

despite the fact that positive results were observed for the two subsequent secondary endpoints (time

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to SEGA progression and skin lesion response rate), they could not be declared formally statistically

significant.

Median time to SEGA progression based on central radiology review was not reached in either

treatment arm. Progressions were only observed in the placebo arm (15.4%; p=0.0002). Estimated

progression-free rates at 6 months were 100% for the Afinitor arm and 85.7% for the placebo arm.

The long-term follow-up of patients randomised to everolimus and patients randomised to placebo

who thereafter crossed over to everolimus demonstrated durable responses.

At the time of the primary analysis, Afinitor demonstrated clinically meaningful improvements in skin

lesion response (p=0.0004), with response rates of 41.7% (95% CI: 30.2, 53.9) for the Afinitor arm

and 10.5% (95% CI: 2.9, 24.8) for the placebo arm.

At the final analysis, the skin lesion response rate increased to 58.1% (95% CI: 48.1, 67.7).

Phase II study in patients with SEGA

A prospective, open-label, single-arm phase II study (Study CRAD001C2485) was conducted to

evaluate the safety and efficacy of Afinitor in patients with SEGA. Radiological evidence of serial

SEGA growth was required for entry.

Change in SEGA volume during the core 6-month treatment phase, as assessed via an independent

central radiology review, was the primary efficacy endpoint. After the core treatment phase, patients

could be enrolled into an extension phase where SEGA volume was assessed every 6 months.

In total, 28 patients received treatment with Afinitor; median age was 11 years (range 3 to 34), 61%

male, 86% Caucasian. Thirteen patients (46%) had a secondary smaller SEGA, including 12 in the

contralateral ventricle.

Primary SEGA volume was reduced at month 6 compared to baseline (p<0.001 [see Table 11]). No

patient developed new lesions, worsening hydrocephalus or increased intracranial pressure, and none

required surgical resection or other therapy for SEGA.

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Table 11

Change in primary SEGA volume over time

SEGA

volume

(cm

3

)

Independent central review

Baseline

n=28

Month 6

n=27

Month 12

n=26

Month 24

n=24

Month 36

n=23

Month 48

n=24

Month 60

n=23

Primary tumour volume

Mean

(standard

deviation)

2.45

(2.813)

1.33

(1.497)

1.26

(1.526)

1.19

(1.042)

1.26

(1.298)

1.16

(0.961)

1.24

(0.959)

Median

1.74

0.93

0.84

0.94

1.12

1.02

1.17

Range

0.49 -

14.23

0.31 -

7.98

0.29 - 8.18

0.20 - 4.63

0.22 -

6.52

0.18 - 4.19

0.21 - 4.39

Reduction from baseline

Mean

(standard

deviation)

1.19

(1.433)

1.07

(1.276)

1.25 (1.994)

1.41

(1.814)

1.43

(2.267)

1.44

(2.230)

Median

0.83

0.85

0.71

0.71

0.83

0.50

Range

0.06 -

6.25

0.02 - 6.05

-0.55 - 9.60

0.15 -

7.71

0.00 -

10.96

-0.74 - 9.84

Percentage reduction from baseline, n (%)

≥50%

9 (33.3)

9 (34.6)

12 (50.0)

10 (43.5)

14 (58.3)

12 (52.2)

≥30%

21 (77.8)

20 (76.9)

19 (79.2)

18 (78.3)

19 (79.2)

14 (60.9)

>0%

(100.0)

(100.0)

(95.8)

(100.0)

(95.8)

(91.3)

change

1 (4.2)

Increase

1 (4.2)

2 (8.7)

The robustness and consistency of the primary analysis were supported by the:

change in primary SEGA volume as per local investigator assessment (p<0.001), with 75.0%

and 39.3% of patients experiencing reductions of ≥30% and ≥50%, respectively

change in total SEGA volume as per independent central review (p<0.001) or local investigator

assessment (p<0.001).

One patient met the pre-specified criteria for treatment success (>75% reduction in SEGA volume) and

was temporarily taken off trial therapy; however, SEGA re-growth was evident at the next assessment

at 4.5 months and treatment was restarted.

Long-term follow-up to a median duration of 67.8 months (range: 4.7 to 83.2) demonstrated sustained

efficacy.

Other studies

Stomatitis is the most commonly reported adverse reaction in patients treated with Afinitor (see

sections 4.4 and 4.8). In a post-marketing single-arm study in postmenopausal women with advanced

breast cancer (N=92), topical treatment with dexamethasone 0.5 mg/5 ml alcohol-free oral solution

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was administered as a mouthwash (4 times daily for the initial 8 weeks of treatment) to patients at the

time of initiating treatment with Afinitor (everolimus, 10 mg/day) plus exemestane (25 mg/day) to

reduce the incidence and severity of stomatitis. The incidence of Grade ≥2 stomatitis at 8 weeks was

2.4% (n=2/85 evaluable patients) which was lower than historically reported. The incidence of Grade 1

stomatitis was 18.8% (n=16/85) and no cases of Grade 3 or 4 stomatitis were reported. The overall

safety profile in this study was consistent with that established for everolimus in the oncology and

TSC settings, with the exception of a slightly increased frequency of oral candidiasis which was

reported in 2.2% (n=2/92) of patients.

5.2

Pharmacokinetic properties

Absorption

In patients with advanced solid tumours, peak everolimus concentrations (C

) are reached at a

median time of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditions or

with a light fat-free snack. C

is dose-proportional between 5 and 10 mg. Everolimus is a substrate

and moderate inhibitor of PgP.

Food effect

In healthy subjects, high fat meals reduced systemic exposure to everolimus 10 mg tablets (as

measured by AUC) by 22% and the peak blood concentration C

by 54%. Light fat meals reduced

AUC by 32% and C

by 42%. Food, however, had no apparent effect on the post absorption phase

concentration-time profile 24 hours post-dose.

Relative bioavailability/bioequivalence

In a relative bioavailability study in TSC patients, AUC

0-inf

of 5 x 1 mg everolimus tablets when

administered as suspension in water was equivalent to 5 x 1 mg everolimus tablets administered as

intact tablets, and C

of 5 x 1 mg everolimus tablets in suspension was 72% of 5 x 1 mg intact

everolimus tablets.

Distribution

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to

5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is

confined to plasma of cancer patients given everolimus 10 mg/day. Plasma protein binding is

approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. In

patients with advanced solid tumours, V

was 191 l for the apparent central compartment and 517 l for

the apparent peripheral compartment.

Nonclinical studies in rats indicate:

A rapid uptake of everolimus in the brain followed by a slow efflux.

The radioactive metabolites of [3H] everolimus do not significantly cross the blood-brain

barrier.

A dose-dependent brain penetration of everolimus, which is consistent with the hypothesis of

saturation of an efflux pump present in the brain capillary endothelial cells.

The co-administration of the PgP inhibitor, cyclosporine, enhances the exposure of everolimus

in the brain cortex, which is consistent with the inhibition of PgP at the blood-brain barrier.

There are no clinical data on the distribution of everolimus in the human brain. Non-clinical studies in

rats demonstrated distribution into the brain following administration by both the intravenous and oral

routes.

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Biotransformation

Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main

circulating component in human blood. Six main metabolites of everolimus have been detected in

human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products,

and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal

species used in toxicity studies and showed approximately 100 times less activity than everolimus

itself. Hence, everolimus is considered to contribute the majority of the overall pharmacological

activity.

Elimination

Mean oral clearance CL/F of everolimus after 10 mg daily dose in patients with advanced solid

tumours was 24.5 l/h. The mean elimination half-life of everolimus is approximately 30 hours.

No specific excretion studies have been undertaken in cancer patients; however, data are available

from the studies in transplant patients. Following the administration of a single dose of radiolabelled

everolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces,

while 5% was excreted in the urine. The parent substance was not detected in urine or faeces.

Steady-state pharmacokinetics

After administration of everolimus in patients with advanced solid tumours, steady-state AUC

0-τ

dose-proportional over the range of 5 to 10 mg daily dose. . Steady-state was achieved within two weeks.

is dose-proportional between 5 and 10 mg. t

occurs at 1 to 2 hours post-dose. There was a

significant correlation between AUC

0-τ

and pre-dose trough concentration at steady-state.

Special populations

Hepatic impairment

The safety, tolerability and pharmacokinetics of Afinitor were evaluated in two single oral dose studies

of Afinitor tablets in 8 and 34 adult subjects with impaired hepatic function relative to subjects with

normal hepatic function.

In the first study, the average AUC of everolimus in 8 subjects with moderate hepatic impairment

(Child-Pugh B) was twice that found in 8 subjects with normal hepatic function.

In the second study of 34 subjects with different impaired hepatic function compared to normal

subjects, there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure (i.e. AUC

0-inf

) for subjects

with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment,

respectively.

Simulations of multiple dose pharmacokinetics support the dosing recommendations in subjects with

hepatic impairment based on their Child-Pugh status.

Based on the results of the two studies, dose adjustment is recommended for patients with hepatic

impairment (see sections 4.2 and 4.4).

Renal impairment

In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significant

influence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplant

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renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of

everolimus in transplant patients.

Paediatric population

In patients with SEGA, everolimus C

was approximately dose-proportional within the dose range

from 1.35 mg/m

to 14.4 mg/m

In patients with SEGA, the geometric mean C

values normalised to mg/m

dose in patients aged

<10 years and 10-18 years were lower by 54% and 40%, respectively, than those observed in adults

(>18 years of age), suggesting that everolimus clearance was higher in younger patients. Limited data

in TSC patients <3 years of age (n=13) indicate that BSA-normalised clearance is about two-fold

higher in patients with low BSA (BSA of 0.556 m

) than in adults. Therefore it is assumed that

steady-state could be reached earlier in TSC patients <3 years of age (see section 4.2 for dosing

recommendations).

The pharmacokinetics of everolimus have not been studied in patients younger than 1 year of age. It is

reported, however, that CYP3A4 activity is reduced at birth and increases during the first year of life,

which could affect the clearance in this patient population.

A population pharmacokinetic analysis including 111 patients with SEGA who ranged from 1.0 to

27.4 years (including 18 patients 1 to less than 3 years of age with BSA 0.42 m

to 0.74 m

) showed

that BSA-normalised clearance is in general higher in younger patients.

Elderly

In a population pharmacokinetic evaluation in cancer patients, no significant influence of age

(27-85 years) on oral clearance of everolimus was detected.

Ethnicity

Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver functions.

Based on analysis of population pharmacokinetics, oral clearance CL/F is on average 20% higher in

black transplant patients.

5.3 Preclinical safety data

The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys and rabbits.

The major target organs were male and female reproductive systems (testicular tubular degeneration,

reduced sperm content in epididymides and uterine atrophy) in several species; lungs (increased alveolar

macrophages) in rats and mice; pancreas (degranulation and vacuolation of exocrine cells in monkeys

and minipigs, respectively, and degeneration of islet cells in monkeys) and eyes (lenticular anterior

suture line opacities) in rats only. Minor kidney changes were seen in the rat (exacerbation of age-related

lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse (exacerbation of background

lesions). There was no indication of kidney toxicity in monkeys or minipigs.

Everolimus appeared to spontaneously exacerbate background diseases (chronic myocarditis in rats,

coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of the gastrointestinal

tract in minipigs, skin lesions in mice and monkeys). These findings were generally observed at systemic

exposure levels within the range of therapeutic exposure or above, with the exception of the findings in

rats, which occurred below therapeutic exposure due to a high tissue distribution.

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In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm

motility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg, which caused a

reduction in male fertility. There was evidence of reversibility.

In animal reproductive studies female fertility was not affected. However, oral doses of everolimus in

female rats at ≥0.1 mg/kg (approximately 4% the AUC

0-24h

in patients receiving the 10 mg daily dose)

resulted in increases of pre-implantation loss.

Everolimus

crossed

placenta

toxic

foetus.

rats,

everolimus

caused

embryo/fetotoxicity at systemic exposure below the therapeutic level. This was manifested as mortality

and reduced foetal weight. The incidence of skeletal variations and malformations (e.g. sternal cleft)

was increased at 0.3 and 0.9 mg/kg. In rabbits, embryotoxicity was evident in an increase in late

resorptions.

In juvenile rat toxicity studies, systemic toxicity included decreased body weight gain, food

consumption, and delayed attainment of some developmental landmarks, with full or partial recovery

after cessation of dosing. With the possible exception of the rat-specific lens finding (where young

animals appeared to be more susceptible), it appears that there is no significant difference in the

sensitivity of juvenile animals to the adverse reactions of everolimus as compared to adult animals.

Toxicity study with juvenile monkeys did not show any relevant toxicity.

Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of clastogenic or

mutagenic activity. Administration of everolimus for up to 2 years did not indicate any oncogenic

potential in mice and rats up to the highest doses, corresponding respectively to 3.9 and 0.2 times the

estimated clinical exposure.

6. PARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose anhydrous

Crospovidone

Hypromellose

Lactose monohydrate

Magnesium stearate

Butylhydroxytoluene

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

The expiry date of the product is indicated on the packaging materials.

6.4 Special precautions for storage

Do not store above 25ºC.

Store in the original package in order to protect from light and moisture.

Keep out of the reach and sight of children.

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6.5 Nature and contents of container

PA/AL/

PVC with Aluminium blister packs containing 30 tablets.

6.6 Special precautions for disposal and other handling

The extent of absorption of everolimus through topical exposure is not known. Therefore caregivers are

advised to avoid contact with suspensions of Afinitor Tablets. Hands should be washed thoroughly

before and after preparation of the suspension.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

8. REGISTRATION HOLDER AND IMPORTER AND THE ADRESS:

Novartis Israel Ltd., 7126 P.O.B, Tel-Aviv.

9. REGISTRATION NUMBERS

AFINITOR 2.5 MG 146-82-33388-00

AFINITOR 5 MG

142-86-32045-02

AFINITOR 5 MG

142-87-32046-01

Revised in October 2020.