AFINITOR - PACKAGE LEAFLET - LEAFLETS

Home / leaflets / 2021

Afinitor - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Everolimus

Afinitor 2.5 mg tablets
Afinitor 5 mg tablets
Afinitor 10 mg tablets

Indications Why is Afinitor used? What is it for?

Afinitor is a cancer medicine that contains an active substance called everolimus. Everolimus reduces the blood supply to the tumor and slows the growth and spread of cancer cells.

Afinitor is used to treat adult patients with:

Advanced hormone receptor-positive advanced breast cancer in postmenopausal women in whom other treatments (referred to as "non-steroidal aromatase inhibitors") can no longer control the disease. It is given together with a type of medicine. a medicine called exemestane, a steroid aromatase inhibitor, which is used for anticancer hormone therapy.
advanced cancers called neuroendocrine tumors that originate in the stomach, intestines, lungs or pancreas. It is used if the tumors are inoperable and do not overproduce specific hormones or other related natural substances.
advanced kidney cancer (advanced kidney cancer) where other treatments (referred to as "targeted anti-VEGF therapies") have not been helpful in stopping it.

Contraindications When Afinitor should not be used

Afinitor will only be prescribed to you by a doctor who has experience in treating cancer. Follow all the doctor's instructions carefully. These instructions may differ from the general information contained in this leaflet. If you have any questions about Afinitor or why it was prescribed for you, ask your doctor.

Do not take Afinitor

if you are allergic to everolimus, to similar substances such as sirolimus or temsirolimus, or to any of the other ingredients of this medicine (listed in section 6).

If you think you are allergic, ask your doctor for advice

Precautions for use What you need to know before taking Afinitor

Talk to your doctor before taking Afinitor:

if you have liver problems or have ever had any disease which may have affected your liver. If this is the case, your doctor may need to prescribe a different dose of Afinitor.
if you have diabetes (high blood sugar levels). Afinitor can raise blood sugar levels and worsen diabetes mellitus. This may require the use of insulin and / or therapy with oral antidiabetic agents. Tell your doctor if you are excessively thirsty or have an increased frequency of urination.
if you need to take a vaccine while you are taking Afinitor.
if you have high cholesterol levels. Afinitor can raise the levels of cholesterol and / or other fats in the blood.
if you have recently had surgery, or if you have a wound that has not yet healed following surgery. Afinitor can increase the risk of problems associated with wound healing.
if you have an infection. The infection may need to be treated before starting Afinitor.
if you have previously had hepatitis B, as it can be reactivated during treatment with Afinitor (see section 4 "Possible side effects").

Afinitor can also:

weaken the immune system. Therefore, you may be exposed to the risk of getting an infection during treatment with Afinitor.
impair kidney function. Therefore, your doctor will monitor your kidney function during treatment with Afinitor.
cause shortness of breath, cough and fever.

Tell your doctor if you get these symptoms.

You will have regular blood tests during your treatment.These tests will check the amount of blood cells in your body (white blood cells, red blood cells and platelets) to see if Afinitor has an undesirable effect on these cells. You will also have blood tests to check your kidney function (creatinine level) and liver function (transaminase levels) and your blood sugar and cholesterol levels. These levels can also be affected by Afinitor.

Children and adolescents

Afinitor should not be used in children or adolescents (under 18 years of age).

Interactions Which drugs or foods may change the effect of Afinitor

Afinitor can affect the way some medicines work. If you are taking other medicines at the same time as you are taking Afinitor, your doctor may need to change the dose of Afinitor or the other medicines.

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

The following substances may increase the risk of side effects with Afinitor:

ketoconazole, itraconazole, voriconazole, or fluconazole and other antifungals used to treat fungal infections.
clarithromycin, telithromycin or erythromycin, antibiotics used to treat bacterial infections.
ritonavir and other medicines used to treat HIV / AIDS infection.
verapamil or diltiazem used to treat heart disease or high blood pressure.
dronedarone, used to help regulate the heartbeat.
cyclosporine, a medicine used to stop the body from rejecting transplanted organs.
imatinib, used to stop the growth of abnormal cells.
angiotensin converting enzyme (ACE) inhibitors (such as ramipril) used to treat high blood pressure or other cardiovascular problems.

The following substances may reduce the effectiveness of Afinitor:

rifampicin, used to treat tuberculosis (TB).
efavirenz or nevirapine, used to treat HIV / AIDS infection.
St. John's wort (Hypericum perforatum), a herbal product used to treat depression and other conditions.
dexamethasone, a corticosteroid used to treat a wide range of conditions including inflammatory or immune problems.
phenytoin, carbamazepine or phenobarbital and other anti-epileptics used to block seizures.

These medicines should be avoided during treatment with Afinitor. If you are taking any of these medicines, your doctor may prescribe you different medicines, or may change the dose of Afinitor.

Afinitor with food and drink

You must take Afinitor at the same time every day, regularly with or without food. Avoid grapefruit and grapefruit juice while being treated with Afinitor.

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

Pregnancy

Afinitor can harm an unborn baby and is not recommended during pregnancy. Tell your doctor if you are pregnant or suspect pregnancy. Your doctor will discuss with you whether you should take this medicine during pregnancy.

Women who may become pregnant should use highly effective contraception during treatment. If, despite these measures, you suspect that you are pregnant, ask your doctor for advice before taking Afinitor again.

Feeding time

Afinitor can harm the infant. You must not breast-feed during treatment. Tell your doctor if you are breastfeeding.

Female fertility

Interruptions of the menstrual cycle (amenorrhea) have been observed in some patients taking Afinitor.

Afinitor can impact female fertility. Tell your doctor if you want to have children.

Male fertility

Afinitor can affect male fertility. Talk to your doctor if you want to become a father.

Driving and using machines

If you feel unusually tired (tiredness is a very common side effect), take special care when driving or using machines.

Afinitor contains lactose

Afinitor contains lactose (milk sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Afinitor: Posology

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

The recommended dose is 10 mg, taken once a day. Your doctor will tell you how many Afinitor tablets to take.

If you have liver problems, your doctor may prescribe a lower dose of Afinitor (2.5, 5, or 7.5 mg / day).

If certain side events occur while you are taking Afinitor (see section 4), your doctor may reduce your dose or stop treatment for a short time or permanently.

Take Afinitor once a day, at about the same time each day, regularly with or without food.

Swallow the tablet (s) whole with a glass of water. Do not chew or crush the tablets.

If you forget to take Afinitor

If you forget to take a dose, just take your next dose as scheduled. Do not take a double dose to make up for a forgotten tablet.

If you stop taking Afinitor

Do not stop taking Afinitor unless your doctor tells you to. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Afinitor

If you have taken more Afinitor than you should, or if someone else has accidentally taken your tablets, contact a doctor or go to a hospital immediately. Emergency treatment may be required.

Keep the pack and this leaflet so your doctor knows what has been taken.

Side Effects What are the side effects of Afinitor

Like all medicines, this medicine can cause side effects, although not everybody gets them.

STOP treatment with Afinitor and see your doctor immediately if you experience any of the following signs of an allergic reaction:

difficulty in breathing or swallowing
swelling of the face, lips, tongue or throat
severe itching of the skin, with red rash or swelling of the skin

Serious side effects of Afinitor include:

Very common (may affect more than 1 in 10 users)

Increased temperature, chills (signs of infection)
Fever, cough, difficulty in breathing, wheezing (signs of lung inflammation, also known as pneumonia)

Common (may affect up to 1 in 10 users)

Excessive thirst, high urine output, increased appetite with weight loss, tiredness (signs of diabetes)
Bleeding (haemorrhage), for example in the intestinal wall
Severe decrease in urine production (signs of kidney failure)

Uncommon (may affect up to 1 in 100 users)

Fever, rash, joint pain and inflammation, as well as tiredness, loss of appetite, nausea, jaundice (yellowing of the skin), pain in the upper right abdomen, light colored stools, dark colored urine (may be signs of hepatitis B reactivation)
Wheezing, difficulty breathing when lying down, swelling of the feet and legs (signs of heart failure)
Swelling and / or pain in one of the legs, usually in the calf, redness or warmth of the skin in the affected area (signs of blockage 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 the lungs become blocked)
Severe decrease in urine production, swelling of the legs, feeling confused, back pain (signs of sudden kidney failure)
Skin rash, itching, hives, difficulty breathing or swallowing, dizziness (signs of severe allergic reactions, also called hypersensitivity)

Rare (may affect up to 1 in 1,000 users)

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

If you experience any of these side effects, tell your doctor immediately, as this could be life threatening.

Other possible side effects of Afinitor include:

Very common (may affect more than 1 in 10 users)

High blood sugar levels (hyperglycemia)
Loss of appetite
Altered sense of taste (dysgeusia)
Headache
Bleeding from the nose (epistaxis)
Cough
Mouth ulcers
Upset stomach including feeling sick (nausea) or diarrhea
Rash
Itching
Tiredness or weakness
Tiredness, shortness of breath, dizziness, pale skin, signs of low level of red blood cells (anemia)
Swelling of the arms, hands, feet, ankles or other parts of the body (signs of edema)
Weight loss
High levels of lipids (fats) in the blood (hypercholesterolemia)

Common (may affect up to 1 in 10 users)

Spontaneous bleeding or bruising (signs of a low platelet level, also known as thrombocytopenia)
Shortness of breath (dyspnoea)
Thirst, low urine output, dark urine, dry red skin, irritability (signs of dehydration)
Difficulty sleeping (insomnia)
Headache, dizziness (signs of high blood loss, also known as hypertension)
Fever, sore throat, mouth ulcers caused by infections (signs of low white blood cell count, leukopenia, lymphopenia and / or neutropenia)
Fever
Inflammation of the inner lining of the mouth, stomach and intestines
Dry mouth
Heartburn (dyspepsia)
Feeling sick (vomiting)
Difficulty swallowing (dysphagia)
Abdominal pain
Acne
Rash and pain on the palms of the hands or soles of the feet (hand-foot syndrome)
Redness of the skin (erythema)
Pain in the joints
Pain in the mouth
Menstruation disorders such as irregular cycles
High levels of lipids (fats) in the blood (hyperlipidaemia, increased triglycerides)
Low level of potassium in the blood (hypokalaemia)
Low level of phosphates in the blood (hypophosphataemia)
Low level of calcium in the blood (hypocalcemia)
Dryness, exfoliation and skin lesions
Nail problems, nail breaks
Mild hair loss
Altered results in blood tests for liver function (increased alanine and aspartate aminotransferase)
Altered results in blood tests for kidney function (increased creatinine)
Discharge from the eyes with itching, redness and swelling
Protein in the urine

Uncommon (may affect up to 1 in 100 users)

Weakness, spontaneous bleeding or bruising and frequent infections with signs such as fever, chills, sore throat or mouth ulcers (signs of a low level of blood cells, also known as pancytopenia)
Loss of sense of taste (ageusia)
Coughing up blood (hemoptysis)
Disturbances in menstruation such as absence of periods (amenorrhea)
Need to urinate more often during the day
Chest pain
Problems in wound healing
Flushes
Red eyes (conjunctivitis)

Rare (may affect up to 1 in 1000 users)

Tiredness, shortness of breath, dizziness, paleness (signs of a low level of red blood cells, possibly due to a type of anemia called pure red cell aplasia)
Swelling of the face, around the eyes, mouth and inside the mouth and / or throat, as well as of the tongue and difficulty in breathing or swallowing (also known as angioedema), may be signs of an allergic reaction

If these side effects get worse, please tell your doctor and / or pharmacist. most side effects are mild or moderate in intensity and usually disappear if treatment is stopped for a few days.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister. The expiry date refers to the last day of that month.
Do not store above 25 ° C.
Store in the original package to protect from light and moisture.
Open the blister only when taking the tablets.
Do not use this medicine if the packaging is damaged or has been tampered with.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Other information

What Afinitor contains

The active ingredient is everolimus.
- Each Afinitor 2.5 mg tablet contains 2.5 mg everolimus.
- Each Afinitor 5 mg tablet contains 5 mg everolimus.
- Each 10 mg Afinitor tablet contains 10 mg everolimus.
The other ingredients are butylhydroxytoluene (E321), magnesium stearate, lactose monohydrate, hypromellose, crospovidone type A and anhydrous lactose.

Description of the appearance of Afinitor and contents of the package

Afinitor 2.5 mg tablets are white to yellowish, elongated tablets. They have "LCL" stamped on one side and "NVR" on the other.

Afinitor 5 mg tablets are white to yellowish, elongated tablets. They have "5" on one side and "NVR" on the other.

Afinitor 10 mg tablets are white to yellowish, elongated tablets. They have "UHE" on one side and "NVR" on the other.

Afinitor 2.5 mg is available in packs containing 30 or 90 tablets.

Afinitor 5 mg and Afinitor 10 mg are available in packs containing 10, 30 or 90 tablets.

Not all pack sizes or strengths may be marketed in your country.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Afinitor can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

AFINITOR TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Afinitor 2.5 mg tablets

Each tablet contains 2.5 mg everolimus.

Excipient with known effects:

Each tablet contains 74 mg of lactose.

Afinitor 5 mg tablets

Each tablet contains 5 mg everolimus.

Excipient with known effects:

Each tablet contains 149 mg of lactose.

Afinitor 10 mg tablets

Each tablet contains 10 mg everolimus.

Excipient with known effects:

Each tablet contains 297 mg of lactose.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablet.

Afinitor 2.5 mg tablets

White to slightly yellow, elongated tablets with a bevelled edge and no score, debossed with "LCL" on one side and "NVR" on the other.

Afinitor 5 mg tablets

White to slightly yellow, elongated tablets with a beveled edge and no score, debossed with "5" on one side and "NVR" on the other.

Afinitor 10 mg tablets

White to slightly yellow, elongated tablets with a bevelled edge and no score, debossed with "UHE" on one side and "NVR" on the other.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Advanced breast cancer with hormone receptor positive status

Afinitor is indicated for the treatment of hormone receptor positive, HER2 / neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women with no symptomatic visceral disease after relapse or progression following treatment with an aromatase inhibitor. non-steroidal.

Neuroendocrine tumors of pancreatic origin

Afinitor is indicated for the treatment of unresectable or metastatic, well or moderately differentiated, unresectable or metastatic neuroendocrine tumors of pancreatic origin in adults.

Neuroendocrine tumors of gastrointestinal or pulmonary origin

Afinitor is indicated for the treatment of well-differentiated (Grade 1 or Grade 2), nonfunctioning, unresectable or metastatic neuroendocrine tumors of gastrointestinal or pulmonary origin in progressing disease in adults (see sections 4.4 and 5.1).

Renal cell carcinoma

Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma who have progressed during or after treatment with anti-VEGF targeted therapy.

04.2 Posology and method of administration

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

Dosage

For the different dosage regimens Afinitor is available in 2.5 mg, 5 mg and 10 mg tablets.

The recommended dose of everolimus is 10 mg once daily. Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity appears.

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

Dose adjustment due to adverse reactions

Management of suspected serious and / or intolerable adverse reactions may require a dose reduction and / or temporary discontinuation of Afinitor. For Grade 1 adverse reactions, no dose adjustment is normally required. If dose reduction is necessary, the recommended dose is 5 mg / day and should not be lower than 5 mg / day.

Table 1 summarizes the recommendations for dose adjustment for specific adverse reactions (see also section 4.4).

Table 1 Afinitor dose adjustment recommendations

Adverse reaction Severity 1 Afinitor dose adjustment Non-infectious pneumonia Grade 2 Consider discontinuing therapy until symptoms improve to Grade ≤1. Resume treatment at 5 mg daily. Discontinue treatment if there is no recovery within 4 weeks. Grade 3 Discontinue treatment until symptoms return to Grade ≤1. Consider resuming treatment at 5 mg daily. If toxicity returns to Grade 3, consider discontinuing therapy. Grade 4 Discontinue treatment. Stomatitis Grade 2 Temporary interruption of dose administration until recovery to Grade ≤1. Resume treatment at the same dose. If stomatitis returns to Grade 2, interrupt dosing until Grade ≤1 is achieved. Resume treatment at 5 mg per day. Grade 3 Temporary dose interruption until recovery to Grade ≤1. Resume treatment at 5 mg per day. Grade 4 Discontinue treatment. Other non-haematological toxicities (excluding metabolic events) Grade 2 If toxicity is tolerable, no dose adjustment is required. If toxicity becomes intolerable, temporarily interrupt the dose until recovery to Grade ≤1. Resume treatment at the same dose. If toxicity returns to Grade 2, discontinue treatment until recovery to Grade ≤1. Resume treatment at 5 mg per day. Grade 3 Temporarily interrupt the dose until recovery to Grade ≤1. Consider resuming treatment at 5 mg daily. If toxicity returns to Grade 3, consider discontinuing therapy. Grade 4 Discontinue treatment. Metabolic events (e.g. hyperglycemia, dyslipidemia) Grade 2 No dose adjustment is required. Grade 3 Temporary dose interruption. Resume treatment at 5 mg per day. Grade 4 Discontinue treatment. Thrombocytopenia Grade 2 ( Temporary dose interruption until recovery to Grade ≤1 (≥75x109 / L). Resume treatment at the same dose. Grade 3 & 4 ( Temporary dose interruption until recovery to Grade ≤1 (≥75x109 / L). Resume treatment at 5 mg daily. Neutropenia Grade 2 (≥1x109 / l) No dose adjustment is required. Grade 3 ( Temporary dose interruption until recovery to Grade ≤2 (≥1x109 / L). Resume treatment at the same dose. Grade 4 ( Temporary dose interruption until recovery to Grade ≤2 (≥1x109 / L). Resume treatment at 5 mg per day. Febrile neutropenia Grade 3 Temporary dose interruption until recovery to Grade ≤2 (≥1.25x109 / L) and absence of fever. Resume treatment at 5 mg per day. Grade 4 Discontinue treatment. 1 Classification under National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0

Particular categories of patients

Elderly patients (≥65 years of age)

No dose adjustment is necessary (see section 5.2).

Renal impairment

No dose adjustment is necessary (see section 5.2).

Hepatic impairment

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

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

- Severe hepatic impairment (Child-Pugh C) - Afinitor is only recommended if the expected benefit outweighs the risk. In this case, the dose of 2.5 mg per day should not be exceeded.

Dose adjustments should be made if the patient's liver condition changes during treatment (see also sections 4.4 and 5.2).

Pediatric population

The safety and efficacy of Afinitor in children aged 0-18 years have not been established. There are no data available.

Method of administration

Afinitor should be administered orally once daily at the same time of day, regularly with or without food (see section 5.2). Afinitor tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed.

04.3 Contraindications

Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients listed in section 6.1.

04.4 Special warnings and appropriate precautions for use

Non-infectious pneumonia

Non-infectious pneumonia is a class effect of rapamycin derivatives, including everolimus. Non-infectious pneumonia (including interstitial lung disease) has been frequently reported in patients treated with Afinitor (see section 4.8). Some cases have been serious and, on rare occasions, a fatal outcome has been reported. A diagnosis of non-infectious pneumonia should be considered in patients with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnoea for which infectious, neoplastic and other unrelated causes have been excluded after appropriate analysis. to the drug. Opportunistic infections such as pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) should be excluded in the differential diagnosis of non-infectious pneumonia (see "Infections" below). Patients should be advised to promptly report any new or worsening respiratory symptoms.

Patients who have radiological changes indicative of non-infectious pneumonia and have few or no symptoms can continue Afinitor therapy without dose adjustment. If symptoms are moderate (Grade 2) or severe (Grade 3), use of corticosteroids may be necessary until clinical symptoms resolve.

For patients requiring the use of corticosteroids for the treatment of non-infectious pneumonia, prophylaxis for pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) may be considered.

Infections

Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoal infections, including infections with opportunistic pathogens (see section 4.8). Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis, candidiasis or pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) and viral infections including reactivation of the hepatitis B virus. Some of these infections have been serious (eg leading to sepsis, respiratory or hepatic failure) and occasionally fatal.

Physicians and patients should be aware of the increased risk of infections with Afinitor. Pre-existing infections should be treated appropriately and must be completely resolved before starting treatment with Afinitor. During treatment with Afinitor, attention should be paid to symptoms and signs of an "infection; if an infection is diagnosed, appropriate treatment should be initiated promptly and discontinuation or discontinuation of Afinitor considered.

If an invasive systemic fungal infection is diagnosed, treatment with Afinitor must be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy.

Cases of pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome, have been reported in patients receiving everolimus. PJP / PCP may be associated with concomitant use of corticosteroids or other immunosuppressive agents. PJP / PCP prophylaxis should be considered when concomitant use of corticosteroids or other immunosuppressive agents is required.

Hypersensitivity reactions

Hypersensitivity reactions which have occurred with symptoms including, but not limited to, anaphylaxis, dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the respiratory tract or tongue, with or without respiratory compromise) have been observed with everolimus ( see section 4.3).

Concomitant use with angiotensin converting enzyme (ACE) inhibitors

Patients taking ACE inhibitors as concomitant therapy (e.g. ramipril) may have an increased risk of angioedema (e.g. swelling of the respiratory tract or tongue, with or without respiratory compromise) (see section 4.5).

Ulcerations of the oral cavity

Mouth ulcers, stomatitis and oral mucositis have been observed in patients treated with Afinitor (see section 4.8). Topical treatments are recommended in these cases, but the use of mouthwashes containing alcohol, peroxides, iodized products and thyme derivatives should be avoided because they can worsen the condition. Antifungal agents should not be used unless a fungal infection has been diagnosed ( see section 4.5).

Events of renal failure

Cases of renal failure (including acute renal failure), some with fatal outcome, have been observed in patients treated with Afinitor (see section 4.8). Renal function should be monitored particularly when patients have additional risk factors that may further impair renal function.

Laboratory analysis and monitoring

Kidney function

Increases in serum creatinine, usually mild, and in proteinuria have been reported (see section 4.8). It is recommended that renal function be monitored, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine levels prior to initiating therapy with Afinitor and periodically during therapy.

Glycemia

Cases of hyperglycaemia have been reported (see section 4.8). It is recommended that fasting blood glucose be monitored before initiating therapy with Afinitor and periodically during therapy. More frequent monitoring is recommended when Afinitor is co-administered with other medicinal products that can induce hyperglycaemia. Whenever possible, optimal blood glucose control should be achieved before treating a patient with Afinitor.

Lipids

Cases of dyslipidaemia (including hypercholesterolaemia and hypertriglyceridaemia) have been reported. A check of blood cholesterol and triglycerides is recommended before the start of therapy with Afinitor and periodically thereafter, as well as management with appropriate drug therapy.

Hematological parameters

Decreases in hemoglobin, lymphocytes, neutrophils and platelets have been reported (see section 4.8). It is recommended that complete blood counts be monitored before initiating therapy with Afinitor and periodically during therapy.

Functioning carcinoid tumors

In a multicentre, randomized, double-blind study in patients with functional carcinoid tumors, Afinitor plus slow-release octreotide was compared with placebo plus slow-release octreotide. The study did not meet the primary efficacy endpoint (progression-free survival (PFS)) and the interim overall survival (OS) analysis was numerically favorable for the placebo plus treatment arm. slow-release octreotide. Therefore the safety and efficacy of Afinitor in patients with functioning carcinoid tumors has not been established.

Prognostic factors in neuroendocrine tumors of gastrointestinal or pulmonary origin

In patients with nonfunctioning gastrointestinal or pulmonary neuroendocrine tumors and with good prognostic factors at baseline, e.g. ileus as primary tumor site and normal chromogranin A values or without bone involvement, an individual benefit-risk assessment should be performed before initiation of Afinitor therapy. Limited evidence of PFS benefit has been reported in the subgroup of patients with ileus as the primary tumor site (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 the co-administration of a moderate inhibitor or inducer of CYP3A4 and / or PgP cannot be avoided, dose adjustment of Afinitor based on expected AUC may be considered (see section 4.5).

Concomitant treatment with powerful CYP3A4 inhibitors dramatically increases everolimus plasma concentrations (see section 4.5). There are currently insufficient data to allow dose recommendations in this situation. Hence, concomitant treatment of Afinitor with powerful inhibitors is not recommended.

Caution should be exercised when Afinitor is taken in combination with CYP3A4 substrates with a narrow therapeutic index administered orally 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 or ergot alkaloid derivatives), the patient should be monitored for side effects described in the package leaflet. of orally administered CYP3A4 substrate (see section 4.5).

Hepatic impairment

Everolimus exposure 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 recommended in patients with severe hepatic impairment (Child-Pugh C) only if the potential benefit outweighs the risk (see sections 4.2 and 5.2).

No clinical efficacy and safety data are currently available to support dose adjustment for the management of adverse reactions in patients with hepatic impairment.

Vaccinations

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

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Complications in wound healing

Slowed wound healing is a class effect of rapamycin derivatives, including everolimus. Therefore Afinitor should be used with caution in the peri-surgical period.

04.5 Interactions with other medicinal products and other forms of interaction

Everolimus is a substrate of CYP3A4, as well as a substrate and moderate inhibitor of PgP. Therefore the absorption and subsequent elimination of everolimus may be affected by substances that interfere with 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 CYP3A4 and PgP inhibitors and inducers are listed in Table 2 below.

CYP3A4 and PgP inhibitors that increase everolimus concentrations

Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by decreasing the metabolism or efflux of everolimus from intestinal cells.

Inducers of CYP3A4 and PgP which decrease everolimus concentrations

Substances that are inducers of CYP3A4 or PgP may decrease the blood concentrations of everolimus by increasing the metabolism or efflux of everolimus from intestinal cells.

Table 2 Effects of other active substances on everolimus

Active substances by type of interaction Interaction - Change in everolimus AUC / Cmax Geometric Mean Ratio (Observed Range) Recommendations regarding co-administration Powerful CYP3A4 / PgP inhibitors Ketoconazole Increase in AUC by a factor of 15.3 (range 11.2-22.5) Concomitant treatment of Afinitor with potent inhibitors is not recommended. Increase in Cmax by a factor of 4.1 (range 2.6-7.0) Itraconazole, posaconazole, voriconazole Not studied. Strong increase in everolimus concentration expected. Telithromycin, clarithromycin Nefazodone Ritonavir, atazanavir, saquinavir, darunavir, indinavir, nelfinavir Moderate CYP3A4 / PgP inhibitors Erythromycin Increase in AUC by a factor of 4.4 (range 2.0-12.6) Use caution when co-administration of moderate CYP3A4 or PgP inhibitors cannot be avoided. If patients require co-administration of a moderate CYP3A4 or PgP inhibitor, a dose reduction to 5 mg / day or 2.5 mg / day may be considered.However, there are no clinical data to support this dose adjustment. Due to inter-subject variability, recommended dose adjustments may not be optimal in all individuals, therefore close monitoring for adverse reactions is recommended. If the moderate inhibitor is discontinued, a washout period of at least 2-3 days (mean elimination time for the most common moderate inhibitors) should be considered before returning to the Afinitor dose used prior to co-administration. Increase in Cmax by a factor of 2.0 (range 0.9-3.5) Imatinib Increase in AUC by a factor of 3.7 Increase in Cmax by a factor of 2.2 Verapamil Increase in AUC by a factor of 3.5 (range 2.2-6.3) Increase in Cmax by a factor of 2.3 (range 1.3-3.8) Oral cyclosporine Increase in AUC by a factor of 2.7 (range 1.5-4.7) Increase in Cmax by a factor of 1.8 (range 1.3-2.6) Fluconazole Not studied. An increase in exposure is expected. Diltiazem Dronedarone Not studied. An increase in exposure is expected. Amprenavir, fosamprenavir Not studied. An increase in exposure is expected. Grapefruit juice or other foods that affect CYP3A4 / PgP Not studied. Increased exposure expected (effect varies greatly). Powerful and moderate inducers of CYP3A4 Rifampicin Reduction in AUC by 63% (range 0-80%) Avoid concomitant use with potent CYP3A4 inducers. If patients require co-administration of a potent CYP3A4 inducer, a dose increase of Afinitor from 10 mg / day up to 20 mg / day should be considered, using increments of 5 mg or less applied on days 4 and 8 after initiation of inducer treatment. This dose of Afinitor is estimated to adjust AUC to the range observed in the absence of inducers. However, there are no supporting clinical data. of this dose adjustment. If inducer treatment is discontinued, a washout period of at least 3-5 days (reasonable time for significant enzyme de-induction) should be considered before returning to the used Afinitor dose. prior to co-administration. Reduction in Cmax by 58% (range 10-70%) Dexamethasone Not studied. Expected reduction of exposure. Carbamazepine, phenobarbital, phenytoin Not studied. Expected reduction of exposure. Efavirenz, nevirapine Not studied. Expected reduction of exposure. St. John's wort (Hypericum Perforatum) Not studied. A strong reduction of the exposure is 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 results in vitro, it is unlikely that systemic concentrations obtained after oral daily doses of 10 mg will result in an inhibition of PgP, CYP3A4 and CYP2D6. However, an inhibition of CYP3A4 and PgP in the intestine cannot be excluded. An interaction study in healthy subjects demonstrated that co-administration of an oral dose of midazolam, a validated sensitive CYP3A substrate, and everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in AUC (0-inf) of midazolam. The effect is likely to be caused by the inhibition of intestinal CYP3A4 by everolimus. Therefore everolimus may affect the bioavailability of orally co-administered CYP3A4 substrates. However, a clinically relevant effect on the exposure of orally administered CYP3A4 substrates is not expected (see section 4.4).

Co-administration of everolimus and slow-release octreotide increased octreotide Cmin with a geometric mean ratio (everolimus / placebo) of 1.47. It was not possible to establish a clinically significant effect on the efficacy response to everolimus in patients with advanced neuroendocrine tumors.

Co-administration of everolimus and exemestane increased the Cmin and C2h of exemestane by 45% and 64%, respectively. However, the corresponding steady state levels of estradiol

(4 weeks) were no different in the two treatment arms. No increase in exemestane-related adverse events was observed in patients with advanced hormone receptor positive breast cancer receiving the combination. Increased levels of exemestane are unlikely to have an impact on efficacy or safety.

Concomitant use with angiotensin converting enzyme (ACE) inhibitors

Patients taking ACE inhibitors as concomitant therapy (e.g. ramipril) may have an increased risk of angioedema (see section 4.4).

Vaccinations

Afinitor may affect the immune response to vaccinations and, therefore, vaccinations carried out during treatment with Afinitor may be less effective. The use of live vaccines should be avoided during treatment with Afinitor (see section 4.4). Examples of live vaccines are as follows: intranasal influenza, measles, mumps, rubella, oral polio, BCG (Bacillus

Calmette-Guérin), yellow fever, chicken pox, and typhoid TY21a.

04.6 Pregnancy and breastfeeding

Women of childbearing potential / Contraception in men and women

Women of childbearing potential must use a highly effective method of contraception (e.g. hormonal birth control method not containing oral estrogen, injection or implantation, progesterone-based contraceptives, hysterectomy, tubal ligation, complete abstinence, barrier methods, intrauterine device [IUD], and / or female / male sterilization) while using everolimus, and up to 8 weeks after the end of treatment. Male patients should not be prohibited from conceiving children.

Pregnancy

There are no adequate data from the use of everolimus in pregnant women. Studies in animals have shown reproductive toxicity effects including embryotoxicity and foetotoxicity (see section 5.3). The potential risk for humans is unknown.

Everolimus is not recommended during pregnancy and in women of childbearing potential who are not using contraceptives.

Feeding time

It is unknown whether everolimus is excreted in human milk. However, in rats, everolimus and / or its metabolites rapidly pass into milk (see section 5.3). Therefore, women on everolimus treatment should not breastfeed.

Fertility

The potential for everolimus to cause infertility in male and female patients is unknown, however amenorrhea (secondary amenorrhea and other menstrual irregularities) associated with luteinizing hormone (LH) / follicle-stimulating hormone imbalance has been observed in female patients ( FSH). Male and female fertility, based on non-clinical findings, may be impaired by treatment with everolimus (see section 5.3).

04.7 Effects on ability to drive and use machines

Afinitor may mildly or moderately affect the ability to drive or use machines. Patients should be advised to be cautious when driving or operating machinery if they experience fatigue during treatment with Afinitor.

04.8 Undesirable effects

Summary of the safety profile

The safety profile is based on pooled data from 2,672 patients treated with Afinitor in ten clinical trials, including five randomized, double-blind, placebo-controlled phase III studies and five open-label phase I and phase II studies. in the approved indications.

From the safety data set the most common adverse reactions (incidence ≥1 / 10) were (in decreasing order): stomatitis, rash, fatigue, diarrhea, infections, nausea, decreased appetite, anemia, dysgeusia, pneumonia, peripheral edema, hyperglycemia, asthenia, pruritus, weight reduction, hypercholesterolemia, epistaxis, cough and headache.

The most frequent Grade 3-4 adverse reactions (incidence ≥1 / 100 to haemorrhage, hypophosphataemia, rash, hypertension, pneumonia, increased alanine aminotransferase (ALT) increased aspartate aminotransferase (AST) and diabetes mellitus. degrees follows the version 3.0 and 4.03 of the CTCAE.

Table of adverse reactions

Table 3 lists the frequency category of adverse reactions reported in the pooled analysis for safety data. Adverse reactions are listed by MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1 / 10); common (≥1 / 100,

Table 3 Adverse reactions reported in clinical studies

Infections and infestations Very common Infections a, * Disorders of the blood and lymphatic system Very common Anemia common Thrombocytopenia, neutropenia, leukopenia, lymphopenia Uncommon Pancytopenia Rare Pure red cell aplasia Disorders of the immune system Uncommon Hypersensitivity Metabolism and nutrition disorders Very common Decreased appetite, hyperglycemia, hypercholesterolemia common Hypertriglyceridaemia, hypophosphataemia, diabetes mellitus, hyperlipidemia, hypokalaemia, dehydration, hypocalcaemia Psychiatric disorders common Insomnia Nervous system disorders Very common Dysgeusia, headache Uncommon Ageusia Eye disorders common Edema of the eyelids Uncommon Conjunctivitis Cardiac pathologies Uncommon Congestive heart failure Vascular pathologies common Hemorrhage b, hypertension Uncommon Flushing, deep vein thrombosis Respiratory, thoracic and mediastinal disorders Very common Pneumonia c, epistaxis, cough common Dyspnea Uncommon Hemoptysis, pulmonary embolism Rare Acute respiratory distress syndrome Gastrointestinal disorders Very common Stomatitis d, diarrhea, nausea common Vomiting, dry mouth, abdominal pain, mucosal inflammation, oral pain, dyspepsia, dysphagia Hepatobiliary disorders common Increased aspartate aminotransferase, increased alanine aminotransferase Skin and subcutaneous tissue disorders Very common Rash, itching 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, kidney failure * Uncommon Increased urination during the day, acute renal failure Diseases of the reproductive system and breast common Irregular menstruation Uncommon Amerorreae General disorders and administration site conditions Very common Fatigue, asthenia, peripheral edema common Pyrexia Uncommon Non-cardiac chest pain, slowed wound healing Diagnostic tests Very common Weight reduction * See also subsection "Description of selected adverse reactions" a 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. . aspergillosis, candidiasis, pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) and hepatitis B (see also section 4.4)] and (rare) viral myocarditis b Includes various bleeding events from different sites not listed individually c Includes (common) pneumonia, interstitial lung disease, pulmonary infiltration and (rare) pulmonary alveolar haemorrhage, pulmonary toxicity, and alveolitis d Includes (very common) stomatitis, (common) aphthous stomatitis, mouth and tongue ulcerations and (uncommon) glossodynia and glossitis e Frequency based on the number of women 10 to 55 years of age in the pooled data

Description of selected adverse reactions

In clinical trials and post-marketing spontaneous reports, everolimus has been associated with severe cases of hepatitis B reactivation, including fatal outcomes. Reactivation of an infection is an expected event during periods of immunosuppression.

In clinical studies and in post-marketing spontaneous reports, everolimus has been associated with events of renal failure (including fatal cases) and proteinuria. Monitoring of renal function is recommended (see section 4.4).

In clinical trials and post-marketing spontaneous reports, everolimus has been associated with cases of amenorrhea (secondary amenorrhea and other menstrual irregularities).

In clinical trials and post-marketing spontaneous reports, everolimus has been associated with cases of pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome (see section 4.4).

In clinical studies and in post-marketing spontaneous reports, angioedema has been reported with or without concomitant use of ACE inhibitors (see section 4.4).

Elderly patients

In the safety data set, 37% of patients treated with Afinitor were ≥65 years of age. The number of patients with an adverse reaction leading to drug discontinuation was higher in patients ≥65 years of age ( 20% vs 13%) The most common adverse reactions leading to drug discontinuation were pneumonia (including interstitial lung disease), stomatitis, fatigue and dyspnoea.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.

04.9 Overdose

The experience of overdose in humans is very limited. Single doses up to 70 mg have been administered with acceptable acute tolerability. In all cases of overdose, general supportive measures should be taken.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, protein kinase inhibitors.

ATC code: L01XE10.

Mechanism of action

Everolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). mTOR is a key serine-threonine kinase whose activity is known to be upregulated in numerous human cancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits the activity of mTOR complex-1 (mTORC1). Inhibition of the mTORC1 signaling pathway interferes with protein translation and synthesis by reducing the activity of ribosomal protein kinase S6 (S6K1) and eukaryotic translation elongation factor 4E binding protein (4EBP-1) which regulate proteins involved in cell cycle, angiogenesis and glycolysis. S6K1 is believed to phosphorylate functional domain 1 of estrogen receptor activation, which is responsible for ligand-independent activation of the receptor. Everolimus reduces the levels of vascular endothelial growth factor (VEGF), which potentiates tumor angiogenic processes. Everolimus is a potent inhibitor of the growth and proliferation of cancer cells, endothelial cells, fibroblasts and smooth muscle cells associated with blood vessels and has been shown to reduce glycolysis in solid tumors. in vitro And in vivo.

Clinical efficacy and safety

Advanced breast cancer with hormone receptor positive status

The BOLERO-2 (CRAD001Y2301), randomized, double-blind, multicenter Phase III study of Afinitor + exemestane versus placebo + exemestane, was conducted in postmenopausal women with hormone receptor positive, HER2 / neu negative breast cancer in advanced stage with relapse or progression after previous letrozole or anastrozole therapy. Randomization was stratified by documented sensitivity to prior hormone therapy and by the presence of visceral metastases. Sensitivity to prior hormone therapy was defined as documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥24 weeks) to at least one prior hormone therapy in the advanced setting or at least 24 months of adjuvant hormone therapy prior of the onset of relapse.

The primary end point for the study was progression-free survival (PFS) as assessed by RECIST (Response Evaluation Criteria in Solid Tumors), based on investigator assessment (local radiological assessment). Supportive analyzes for PFS were based on independent centralized radiological review.

Secondary endpoints included overall survival (OS), objective response rate, clinical benefit rate, safety profile, change in quality of life (QoL), and time to worsening of Eastern Cooperative Oncology (ECOG PS). Group performance status).

A total of 724 patients were randomized in a 2: 1 ratio to everolimus (10 mg daily) + exemestane (25 mg daily) (n = 485) or to placebo + exemestane (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). Median duration of exemestane treatment was 29.5 weeks (1.0-199.1) longer in the everolimus + exemestane group compared to 14.1 weeks (1.0-156.0) in the placebo + exemestane group. .

Efficacy results for the primary endpoint were obtained from the final PFS analysis (see Table 4).Patients in the placebo + exemestane arm did not cross over to everolimus at the time of progression.

Table 4 BOLERO-2 efficacy results

Analyses Afinitora n = 485 Placeboa n = 239 Hazard ratio p value Median progression-free survival (months) (95% CI) Investigator radiological review 7,8 (6,9 - 8,5) 3,2 (2,8 - 4,1) 0,45 (0,38 - 0,54) Independent radiological review 11,0 (9,7 - 15,0) 4,1 (2,9 - 5,6) 0,38 (0,31 - 0,48) 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 b 12,6% (9,8 - 15,9) 1,7% (0,5 - 4,2) n / ad Clinical benefit rate c 51,3% (46,8 - 55,9) 26,4% (20,9 - 32,4) n / ad to More exemestane b Objective response rate = proportion of patients with complete or partial response c Clinical benefit rate = proportion of patients with complete or partial response or stable disease ≥24 weeks d Not applicable and p value is obtained with the exact Cochran-Mantel-Haenszel test using a layered version of the Cochran-Armitage permutation test.

The estimated effect of treatment on PFS was supported by a planned subgroup analysis of PFS based on investigator assessment. A positive effect of treatment with everolimus + exemestane versus placebo + exemestane with an estimated hazard ratio ranging from 0.25 to 0.60.

No differences were observed in the two arms over time to ≥5% worsening of the global and functional domain scores QLQ-C30.

Advanced neuroendocrine tumors of pancreatic origin (pNET)

Phase III, multicentre, randomized, double-blind, RADIANT-3 (CRAD001C2324) 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 compared to placebo with 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

RADIANT-3 enrolled patients with well or moderately differentiated advanced neuroendocrine tumors of pancreatic origin (pNET) whose disease had progressed within the previous 12 months. Treatment with somatostatin analogues was permitted as part of the BSC.

The primary endpoint of the study was PFS assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Following radiologically documented progression, the physician could open the patient randomization code. Patients on placebo could then be treated with Afinitor in open label.

Secondary endpoints included the safety profile, objective response rate, duration of response, and overall survival (OS).

In total, 410 patients were randomized, in a 1: 1 ratio, to receive Afinitor 10 mg / day (n = 207) or placebo (n = 203). Demographics were well balanced (median age 58, 55% male, 78.5% Caucasian). Fifty-eight percent of patients in both arms had received prior systemic therapies. The median duration of blinded treatment in the study 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 who received placebo.

Following disease progression or opening the study blind, 172 of 203 patients (84.7%) initially randomized to placebo switched to open-label treatment with Afinitor. The median duration of open-label treatment was 47. 7 weeks among all patients; 67.1 weeks in 53 patients randomized to everolimus who switched to open-label everolimus and 44.1 weeks in 172 patients randomized to placebo who switched to open-label everolimus.

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) Independent radiological review 13,67 (11,17 - 18,79) 5,68 (5,39 - 8,31) 0,38 (0,28 - 0,51) Median overall survival (months) (95% CI) Median overall survival 44,02 37,68 0,94 0,300

Neuroendocrine tumors of gastrointestinal or pulmonary origin

The Phase III, multicentre, randomized, double-blind RADIANT-4 study (study CRAD001T2302) of Afinitor plus best supportive care (BSC) versus placebo plus BSC was conducted in patients with neuroendocrine tumors of origin gastrointestinal or pulmonary, well differentiated (Grade 1 or Grade 2) nonfunctioning, inoperable or metastatic with no past or active symptoms related to carcinoid syndrome.

The primary end point of the study was progression free survival (PFS) as assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, based on an independent radiological review. A "supportive analysis of PFS was based on the radiological review of the local investigator. Secondary endpoints included overall survival (OS), overall response rate, disease control rate, safety, change in quality of life (FACT-G), and time to deterioration in WHO PS ( World Health Organization performance status).

In total, 302 patients were randomized 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 22-86], 76% Caucasian, use of a previous somatostatin analogue [SSA]). The median duration of blinded treatment was 40.4 weeks for patients who received Afinitor and 19.6 weeks for those who received placebo. Patients in the placebo arm did not switch to everolimus at the time of progression.

Efficacy results for the primary endpoint were obtained from the final PFS analysis (see Table 6).

Table 6 RADIANT-4 - Progression-free survival results

Population Afinitor n = 205 Placebo n = 97 Hazard ratio (95% CI) p valuea Median progression-free survival (months) (95% CI) Independent radiological review 11,01 3,91 0,48 Investigator radiological review 13,96 5,45 0,39 a one-sided p value of the stratified log-rank test

In supportive analyzes, the positive treatment effect was observed in all subgroups with the exception of the subgroup of patients with ileus as the primary site of origin (ileus: HR = 1.22 [95% CI: 0.56-2.65]; non-ileus: HR = 0.34 [95% CI: 0.22-0.54]; lung: HR = 0.43 [95% CI: 0.24-0.79 ]).

The pre-planned interim analysis of OS after 101 deaths (out of 191 needed for the final analysis) and 33 months of follow-up favored the everolimus arm; however, no statistically significant difference was observed in OS. (HR = 0.73 [95% CI: 0.48-1.11; p = 0.071]).

No differences were observed in the two arms between time to definitive deterioration in WHO PS (≥1 point) and time to definitive deterioration in quality of life (FACT-G total score ≥7 points).

Advanced renal cell carcinoma

The RECORD-1 study (CRAD001C2240), phase III, international, multicentre, randomized, double-blind, to compare everolimus at a dose of 10 mg / day versus placebo, both treatments in combination with best supportive care, was conducted in patients with metastatic renal cell carcinoma who had progressed during or after therapy with VEGFR-TKIs (vascular endothelial growth factor receptor tyrosine kinase inhibitors: sunitinib, sorafenib, or both). Previous therapy with bevacizumab and interferon-alpha was also allowed. Patients were stratified according to Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic criteria (favorable risk groups vs. intermediate vs. unfavorable) and previous anticancer therapy (1 vs. 2 previous VEGFR-TKIs).

The primary endpoint was progression-free survival, documented using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria and assessed by a blinded independent centralized review. Secondary endpoints included safety profile, objective tumor response rate , overall survival, disease-related symptoms and quality of life. Following radiologically documented progression, the physician could open the patient randomization code: patients on placebo could then be treated with everolimus 10 mg / day in open. L "Independent Data Monitoring Committee (Independent Data Control Board) recommended that the study be discontinued at the time of the second interim analysis because the primary endpoint had been met.

In total, 416 patients were randomized, in a 2: 1 ratio, 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 treatment in the study was 141 days (range 19-451) for patients who received everolimus and 60 days (range 21-295) for those who received placebo.

Afinitor was superior to placebo over the primary endpoint of progression-free survival, with a statistically significant 67% reduction in the risk of progression or death (see Table 7).

Table 7 RECORD-1 - Progression-free survival results

Population n Afinitor n = 277 Placebo n = 139 Hazard ratio (95% CI) P. Median progression-free survival (months) (95% CI) Primary analysis All (blinded independent centralized review) 416 4,9 (4,0-5,5) 1,9 (1,8-1,9) 0,33 (0,25-0,43) Supportive / sensitivity analysis All (local investigator review) 416 5,5 (4,6-5,8) 1,9 (1,8-2,2) 0,32 (0,25-0,41) MSKCC Prognostic Risk Criteria (Blinded Independent Central Review) Favorable risk 120 5,8 (4,0-7,4) 1,9 (1,9-2,8) 0,31 (0,19-0,50) Intermediate risk 235 4,5 (3,8-5,5) 1,8 (1,8-1,9) 0,32 (0,22-0,44) Unfavorable risk 61 3,6 (1,9-4,6) 1,8 (1,8-3,6) 0,44 (0,22-0,85) 0,007 a stratified log-rank test

The 6-month PFS rate was 36% for Afinitor versus 9% for placebo.

Confirmed objective tumor responses were observed in 5 patients (2%) treated with Afinitor, while no response was observed in patients treated with placebo. Therefore, the progression-free survival advantage mainly reflects the population with disease stabilization (corresponding to 67% of the Afinitor treatment group).

No statistically significant treatment-related differences were noted in relation to overall survival (hazard ratio 0.87; confidence interval: 0.65-1.17; p = 0.177). Switching patients assigned to placebo to open label Afinitor following disease progression influenced the determination of any treatment-related differences in overall survival.

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Afinitor in all subsets of the pediatric population for neuroendocrine tumors of pancreatic origin, neuroendocrine thoracic tumors and renal cell carcinoma (see section 4.2 for information on pediatric use).

05.2 Pharmacokinetic properties

Absorption

In patients with advanced solid tumors, the peak concentration (Cmax) of everolimus is reached on average 1 hour after administration of everolimus 5 and 10 mg / day fasted or with a light fat-free snack. Cmax is dose proportional between 5 and 10 mg. Everolimus is a substrate and a moderate inhibitor of PgP.

Effect of food

In healthy subjects, high-fat meals reduced everolimus 10 mg systemic exposure (measured as AUC) by 22% and peak plasma concentrations of C by 54%. Low-fat meals reduced AUC by 32%. % and Cmax of 42%. Food, however, did not have an obvious effect on the post-absorption phase concentration-time profile.

Distribution

The blood-to-plasma ratio of everolimus, which is concentration-dependent in the range of 5 to 5,000 ng / mL, ranges from 17% to 73%. In cancer patients treated with everolimus 10 mg / day approximately 20% of the everolimus concentration in whole blood is confined to plasma. Plasma protein binding is approximately 74% in healthy subjects and in patients with moderate hepatic impairment. In patients with advanced solid tumors, the Vd was 191 l in the apparent central compartment and 517 l in the apparent peripheral compartment.

Biotransformation

Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the major circulating component in human blood. Six major metabolites of everolimus have been identified in human blood, including three monohydroxylated metabolites, two products formed by hydrolytic opening of the cyclic ring, and a conjugated everolimus phosphatidylcholine. These metabolites have also been identified in animal species used in toxicity studies. and showed approximately 100 times less activity than everolimus. Everolimus is therefore considered to contribute most of the overall pharmacological activity.

Elimination

The mean oral clearance (CL / F) of everolimus following a dose of 10 mg / day in patients with advanced solid tumors was 24.5 L / h. The mean elimination half-life of everolimus is approximately 30 hours.

No specific excretion studies have been conducted in cancer patients; however, data from studies in transplant patients are available. Following administration of a single dose of radioactive everolimus in combination with cyclosporine, 80% of the radioactivity was recovered in the faeces, while 5% was excreted in the urine. The parent product was not detected in the urine and in the stool.

Steady-state pharmacokinetics

After administration of everolimus in patients with advanced solid tumors, steady-state AUC0-? Was dose proportional over the dose range of 5 to 10 mg / day. Steady state is achieved within two weeks. Cmax is dose proportional between 5 and 10 mg. Tmax is reached 1-2 hours after dosing. At steady-state, AUC0-? it is significantly correlated with trough blood levels.

Particular categories of patients

Hepatic impairment

The safety, tolerability and pharmacokinetics of everolimus were evaluated in two single oral dose studies of Afinitor tablets in 8 and 34 subjects with impaired hepatic function compared to subjects with normal hepatic function.

In the first study, the mean 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 involving 34 subjects with varying degrees of hepatic impairment, compared to subjects with normal hepatic function, there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure (AUC0 -inf) for subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively.

Multiple dose pharmacokinetic simulations support dose 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 in 170 patients with advanced solid tumors, no significant influence of creatinine clearance (25-178 ml / min) on everolimus CL / F was noted. (creatinine clearance range: 11-107 ml / min) did not affect the pharmacokinetics of everolimus in transplant patients.

Elderly patients

From an assessment of population pharmacokinetics in cancer patients, no significant influence of age (27-85 years) on the oral clearance of everolimus was noted.

Ethnicity

In Japanese and Caucasian cancer patients with similar liver function, oral clearance (CL / F) is similar. From a population pharmacokinetic analysis, CL / F is, on average, 20% higher in black transplant patients.

05.3 Preclinical safety data

The preclinical safety profile of everolimus was evaluated in mice, rats, pigs, monkeys and rabbits. The main target organs identified in various animal species were the male and female reproductive organs (testicular tubular degeneration, reduced sperm content in the epididymis and atrophy of the uterus); the lungs (increased alveolar macrophages) in rats and mice; the pancreas (degranulation and vacuolation of exocrine cells in the monkey and pig, respectively, and degeneration of islet cells in the monkey), and the eyes (opacity of the anterior lenticular suture line) only in the rat. Minor renal changes were observed in the rat (exacerbation of age-related lipofuscin in the tubular epithelium, increases in hydronephrosis) and in the mouse (exacerbation of underlying lesions). There was no indication of renal toxicity in the monkey or pig.

Spontaneously occurring background diseases (chronic myocarditis in rats, plasma and heart Coxsackie virus infection in monkeys, coccidial infestation of the gastrointestinal tract in piglets, skin lesions in mice and monkeys) appear to be exacerbated by treatment with everolimus. Such findings have usually been observed in the presence of systemic exposure levels in the therapeutic range or above, except in the rat, where, due to high tissue distribution, such findings arise below the therapeutic exposure.

In a rat male fertility study, testicular morphology was affected at doses of 0.5 mg / kg or higher and sperm motility, sperm count, and plasma testosterone levels were reduced to 5 mg / kg. , a value that leads to a reduction in male fertility. There was no evidence of reversibility.

In animal reproductivity studies, there was no change in female fertility. However, oral doses of everolimus ≥0.1 mg / kg in female rats (approximately 4% of the AUC0-24h in patients receiving the 10 mg daily dose) resulted in an increase in the loss of pre-implanted embryos.

Everolimus crosses the placenta and has been shown to be toxic to the fetus. In the rat, everolimus caused embryotoxicity and fetal toxicity, manifested as mortality and reduced fetal weight in the presence of systemic exposure below the therapeutic range. The incidence of skeletal changes and malformations at 0.3 and 0.9 mg / kg (cleft of the sternum) is increased. In rabbits, embryotoxicity was manifested by an increase in delayed resorption.

Genotoxicity studies, evaluating all major aspects of genotoxicity, did not show 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 to 3.9 and 0.2 times the expected clinical systemic exposure, respectively.