Naveruclif

Patient Information Leaflet

Naveruclif 5 mg/mL powder for dispersion for infusion

paclitaxel
Please read all of this leaflet carefully before you start using this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• This medicine has been prescribed for you only. Do not pass it on to other people, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse. See section 4.

Contents of this leaflet

1. What Naveruclif is and what it is used for
2. What you need to know before using Naveruclif
3. How to use Naveruclif
4. Possible side effects
5. How to store Naveruclif
6. Contents of the pack and other information

1. What Naveruclif is and what it is used for

Naveruclif contains, as its active substance, paclitaxel bound to albumin, a human protein, in the form of tiny particles known as nanoparticles. Paclitaxel belongs to a group of medicines called taxanes, which are used in cancer therapy.

• Paclitaxel is the part of the medicine that acts against cancer by stopping cancer cells from dividing, causing them to die.
• Albumin is the part of the medicine that helps paclitaxel dissolve in the blood and cross the walls of blood vessels to reach the tumour. This means that additional chemical substances, which may cause undesirable effects that could be life-threatening, are not required. Some side effects are much less frequent with Naveruclif.

What Naveruclif is used for
Naveruclif is used to treat the following types of cancer:

Breast cancer

• Breast cancer that has spread to other parts of the body (this is called “metastatic” breast cancer).
• Naveruclif is used in metastatic breast cancer when at least one other therapy has been tried but was ineffective, and in patients who are not suitable for treatments containing a group of medicines called “anthracyclines”.
• Patients with metastatic breast cancer who received Naveruclif after another therapy had failed showed a higher likelihood of tumour shrinkage and lived longer compared to patients who received an alternative therapy.

Pancreatic cancer

• In metastatic pancreatic cancer, Naveruclif is used in combination with a medicine called gemcitabine. In a clinical study, patients with metastatic pancreatic cancer (pancreatic cancer that has spread to other parts of the body) treated with Naveruclif and gemcitabine lived longer than those who received gemcitabine alone.

Lung cancer

• Naveruclif is used in combination with a medicine called carboplatin for the treatment of the most common type of lung cancer, known as “non-small cell lung cancer”.
• Naveruclif is used in non-small cell lung cancer when surgery or radiotherapy are not suitable options for treating the disease.

2. What you need to know before using Naveruclif

Do not use Naveruclif

• if you are allergic to paclitaxel or to any of the other ingredients of this medicine (listed in section 6);

• if you are breastfeeding;

• if you have a low white blood cell count (baseline neutrophil count <1,500 cells/mm³ – your doctor will provide information on this). Warnings and precautions
  Talk to your doctor or nurse before using Naveruclif

• if you have reduced kidney function;

• if you have severe liver problems;

• if you have heart disorders.
  Consult your doctor or nurse if you develop any of the following conditions during treatment with Naveruclif; your doctor may decide to stop treatment or reduce the dose:

• unusual bruising, bleeding, or signs of infection such as sore throat or fever;

• numbness, tingling, burning sensations, increased sensitivity to touch, or muscle weakness;

• breathing problems, such as shortness of breath or dry cough.

Children and adolescents
Naveruclif is intended for adults only and must not be used in children and adolescents under 18 years of age.
Other medicines and Naveruclif
Tell your doctor if you are taking, have recently taken, or might take any other medicines, including over-the-counter medicines and herbal products. This is because Naveruclif may affect the action of other medicines, and other medicines may affect the action of Naveruclif.
Be cautious and consult your doctor when taking Naveruclif together with any of the following:

• medicines used to treat infections (i.e., antibiotics such as erythromycin, rifampicin, etc.; ask your doctor, nurse, or pharmacist if you are unsure whether your medicine is an antibiotic), including medicines used to treat fungal infections (e.g., ketoconazole);
• medicines used to stabilize mood, sometimes also called antidepressants (e.g., fluoxetine);
• medicines used to treat epileptic seizures (epilepsy) (e.g., carbamazepine, phenytoin);
• medicines used to lower lipid levels in the blood (e.g., gemfibrozil);
• medicines used for heartburn or stomach ulcers (e.g., cimetidine);
• medicines used to treat HIV and AIDS (e.g., ritonavir, saquinavir, indinavir, nelfinavir, efavirenz, nevirapine);
• a medicine called clopidogrel, used to prevent blood clots.

Pregnancy, breastfeeding, and fertility
Paclitaxel can cause severe birth defects and therefore must not be used during pregnancy. Your doctor will perform a pregnancy test before starting treatment with Naveruclif.
Women of childbearing potential must use effective contraception during treatment with Naveruclif and for at least 6 months after stopping treatment.
Do not breastfeed during treatment with Naveruclif, as it is unknown whether the active substance paclitaxel passes into breast milk.
Male patients are advised to use effective contraception and to avoid fathering a child during treatment and for at least 3 months after stopping treatment. You should also discuss sperm preservation with your doctor before starting treatment, as treatment with Naveruclif may lead to permanent infertility.
Ask your doctor for advice before taking this medicine.
Driving and using machines
After administration of Naveruclif, some people may experience fatigue or dizziness. If this occurs, do not drive or operate tools or machinery.
If other medicines are prescribed as part of your treatment, consult your doctor regarding your ability to drive and use machines.
Naveruclif contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per 100 mg, i.e., essentially 'sodium-free'.

3. How to use Naveruclif

Naveruclif will be administered into a vein through an intravenous infusion by a doctor or nurse. The amount given depends on body surface area and blood test results. The usual dose for breast cancer is 260 mg/m² of body surface area, administered over 30 minutes. The usual dose for advanced pancreatic cancer is 125 mg/m² of body surface area, administered over 30 minutes. The usual dose for non-small cell lung cancer is 100 mg/m² of body surface area, administered over 30 minutes.

How often is Naveruclif administered?
For the treatment of metastatic breast cancer, Naveruclif is usually given once every three weeks (on day 1 of a 21-day cycle).

For the treatment of advanced pancreatic cancer, Naveruclif is administered on days 1, 8, and 15 of each 28-day treatment cycle, with gemcitabine given shortly after Naveruclif.

For the treatment of non-small cell lung cancer, Naveruclif is administered once a week (i.e., on days 1, 8, and 15 of a 21-day cycle), with carboplatin given once every three weeks (i.e., only on day 1 of each 21-day cycle), immediately after administration of the Naveruclif dose.

If you have any doubts about how to use this medicine, consult your doctor or nurse.

4. Possible side effects

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

Very common side effects (may affect more than 1 in 10 people):

• Hair loss (most cases of hair loss occurred within less than one month after starting treatment with Naveruclif. When it occurs, hair loss is severe (more than 50%) in most patients)
• Rash
• Abnormally low levels of certain types of white blood cells (neutrophils, lymphocytes or leukocytes) in the blood
• Anaemia (deficiency of red blood cells)
• Reduced platelet count in the blood
• Effects on peripheral nerves (pain, numbness, tingling or loss of sensation)
• Pain in one or more joints
• Muscle pain
• Nausea, diarrhoea, constipation, sore mouth, loss of appetite
• Vomiting
• Weakness and fatigue, fever
• Dehydration, taste disturbance, weight loss
• Low blood potassium levels
• Depression, sleep problems
• Headache
• Chills
• Difficulty breathing
• Dizziness
• Swelling of mucous membranes and soft tissues
• Increased liver function test values
• Pain in the extremities
• Cough
• Abdominal pain
• Nosebleed

Common side effects (may affect up to 1 in 10 people):

• Itching, dry skin, nail disorders
• Infection, fever with reduced number of a type of white blood cells (neutrophils) in the blood, redness, candidiasis, severe blood infection which may be caused by reduced white blood cell count
• Reduced count of all types of blood cells
• Chest pain or sore throat
• Indigestion, abdominal discomfort
• Nasal congestion
• Back pain, bone pain
• Reduced muscle coordination or difficulty reading, increased or decreased tear production, eyelash loss
• Changes in heart rate or rhythm, heart failure
• Decreased or increased blood pressure
• Redness or swelling at the injection site
• Anxiety
• Lung infection
• Urinary tract infection
• Intestinal obstruction, inflammation of the large intestine, inflammation of the bile duct
• Acute kidney failure
• Increased bilirubin in the blood
• Coughing up blood
• Dry mouth, difficulty swallowing
• Muscle weakness
• Blurred vision

Uncommon side effects (may affect up to 1 in 100 people):

• Weight gain, increased lactate dehydrogenase (an enzyme) in the blood, reduced kidney function, increased blood sugar, increased blood phosphorus
• Decreased or absent reflexes, involuntary movements, neuralgia, fainting, dizziness upon standing, tremor, facial nerve paralysis
• Eye irritation, eye pain, red eyes, itchy eyes, double vision, reduced vision or seeing flashing lights, blurred vision due to swelling of the retina (cystoid macular edema)
• Ear pain, ringing in the ears
• Cough with mucus, shortness of breath when walking or climbing stairs, runny or dry nose, decreased breath sounds, fluid in the lungs, loss of voice, blood clot in the lung, dry throat
• Flatulence (intestinal gas), stomach cramps, gum pain, rectal bleeding
• Painful urination, frequent urination, blood in urine, urinary incontinence
• Hand nail pain, hand nail discomfort, hand nail loss, hives, skin pain, sun-induced skin redness, skin colour changes, increased sweating, night sweats, white spots on the skin, ulcers, facial swelling
• Decreased blood phosphorus, fluid retention, low blood albumin levels, increased thirst, decreased blood calcium, decreased blood sugar, decreased blood sodium
• Nasal pain and swelling, skin infections, catheter-related infection
• Bruising
• Pain at tumour site, tumour necrosis
• Decreased blood pressure when standing, cold sensation in hands and feet
• Difficulty walking, swelling
• Allergic reaction
• Decreased liver function, enlarged liver
• Breast pain
• Restlessness
• Small areas of bleeding under the skin due to blood clots
• A condition involving destruction of red blood cells and acute kidney failure

Rare side effects (may affect up to 1 in 1,000 people):

• Skin reaction to another agent or radiation-induced lung inflammation
• Blood clots
• Very slow pulse, heart attack
• Leakage of medicine from the vein
• A disorder of the heart's electrical conduction system (atrioventricular block)

Very rare side effects (may affect up to 1 in 10,000 people):

• Severe skin and mucosal inflammation/rash (Stevens-Johnson syndrome, toxic epidermal necrolysis)

Side effects not known (frequency cannot be estimated from the available data):

• Skin hardening/thickening (scleroderma)

Reporting of side effects

If you get any side effects, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the national reporting system referred to in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Naveruclif

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 vial after
Exp./EXP. The expiry date refers to the last day of that month.
Closed vials: keep the vial in the outer packaging to protect the medicine from light.
After first reconstitution, the dispersion should be used immediately. If not used immediately, the dispersion can be stored in a refrigerator (2 °C - 8 °C) for up to 24 hours in the vial kept in the outer packaging which protects the medicine from light.
The reconstituted dispersion for intravenous infusion can be stored in a refrigerator (2 °C - 8 °C) for up to 24 hours, protected from light.
Chemical and physical in-use stability for 24 hours at 2°C-8°C when protected from light, followed by up to 4 hours at 25°C when not protected from light.
The doctor or pharmacist is responsible for the proper disposal of unused Naveruclif.

6. Package contents and other information

What Naveruclif contains
The active substance is paclitaxel.

• Each vial contains 100 mg of paclitaxel bound to albumin formulated as nanoparticles. After reconstitution, each mL of dispersion contains 5 mg of paclitaxel bound to albumin formulated as nanoparticles.
• The other component is albumin (human) (containing sodium caprylate and N-acetyl-L-tryptophan), see section 2 “Naveruclif contains sodium”.

Description of the appearance of Naveruclif and contents of the pack
Naveruclif is a white to yellow lyophilized powder or tablet for dispersion for infusion. Naveruclif is available in glass vials containing 100 mg of paclitaxel bound to albumin formulated as nanoparticles. Each pack contains 1 vial.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder
Accord Healthcare S.L.U.
World Trade Center, Moll De Barcelona s/n,
Edifici Est, 6a Planta,
Barcelona, 08039,
Spain

Manufacturer
Accord Healthcare Polska Sp.z o.o.
ul. Lutomierska 50,
95-200 Pabianice, Poland
Or
Laboratori Fundació Dau
C/ C, 12-14 Pol. Ind.
Zona Franca, Barcelona, 08040,
Spain
Or
Accord Healthcare Single Member S.A.
64 Km National Road, Athens,
Lamia, Schimatari, 32009, Greece

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
AT / BE / BG / CY / CZ / DE / DK / EE / ES / FI / FR / HR / HU / IE / IS / IT / LT / LV / LU / MT /
NL / NO / PL / PT / RO / SE / SI / SK
Accord Healthcare S.L.U.
Tel: +34 93 301 00 64
EL
Win Medica Α.Ε.
Tel: +30 210 74 88 821

More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

For physicians or healthcare professionals
The following information is intended exclusively for physicians or healthcare professionals:

Instructions for use, handling and disposal
Precautions for preparation and administration
Paclitaxel is a cytotoxic antineoplastic medicinal product; as with other potentially toxic compounds, certain precautions should be taken when handling Naveruclif. Gloves, goggles, and protective clothing must be worn. If the dispersion comes into contact with the skin, wash the skin immediately and thoroughly with soap and water. If contact occurs with mucous membranes, they must be rinsed thoroughly with abundant water. Naveruclif must be prepared and administered only by personnel adequately trained in handling cytotoxic agents. Naveruclif must not be handled by pregnant women.

Due to the possibility of extravasation, the infusion site should be closely monitored for signs of infiltration during administration of the medicinal product. Limiting the infusion of Naveruclif to 30 minutes, as indicated, reduces the likelihood of infusion-related reactions.

Reconstitution and administration of the medicinal product
Naveruclif must be administered under the supervision of a qualified oncologist in specialized units for the administration of cytotoxic agents.

Naveruclif is supplied as a sterile lyophilized powder and must be reconstituted before use. After reconstitution, each mL of dispersion contains 5 mg of paclitaxel bound to albumin formulated as nanoparticles. The reconstituted dispersion of Naveruclif is administered intravenously using an infusion set equipped with a 15-micron filter.

Using a sterile syringe, slowly inject 20 mL of sodium chloride 9 mg/mL (0.9%) solution for infusion into the Naveruclif vial over at least 1 minute.
The solution should be directed toward the inner wall of the vial. The solution must not be injected directly onto the powder, as this may cause foaming.
After completing the addition of solution, allow the vial to stand for at least 5 minutes to ensure complete wetting of the powder. Then gently and slowly rotate and/or invert the vial for at least 2 minutes until the powder is completely redispersed. Foaming must be avoided. If foam or clumps form, allow the dispersion to stand for at least 15 minutes until the foam disappears.

The reconstituted dispersion should appear milky and homogeneous, without visible precipitate. Deposits may occur in the reconstituted dispersion. If precipitates or deposits are visible, gently invert the vial again to ensure complete redispersion before use.

Examine the dispersion in the vial to check for the presence of precipitate. Do not administer the reconstituted dispersion if precipitates are observed in the vial.

The exact total volume of the 5 mg/mL dispersion required for the patient must be calculated, and the appropriate amount of reconstituted Naveruclif must be injected into an empty, sterile intravenous infusion bag made of PVC or other material.

The use of medical devices containing silicone oil as a lubricant (e.g., syringes and IV bags) for reconstituting and administering Naveruclif may cause the formation of protein filaments. Administer Naveruclif using an infusion set equipped with a 15-micron filter to prevent administration of these filaments. The use of a 15-micron filter removes the filaments and does not alter the physical or chemical properties of the reconstituted product.

The use of filters with a pore diameter smaller than 15 microns may cause filter blockage.

Special containers or administration sets free of di-(2-ethylhexyl)phthalate (DEHP) are not required for the preparation and administration of Naveruclif infusions.

After administration, it is recommended to flush the infusion line with 9 mg/mL (0.9%) sodium chloride solution for injection to ensure complete delivery of the dose.

Unused medicinal product and waste materials derived from this medicinal product must be disposed of in accordance with local regulations.

Stability
Unopened vials of Naveruclif are stable until the date indicated on the packaging, provided the vial is stored in the outer packaging to protect the medicinal product from light. Freezing and refrigeration do not have negative effects on the stability of the medicinal product. This medicinal product does not require any specific storage temperature.

Stability of the reconstituted dispersion in the vial
The chemical and physical in-use stability of the product has been demonstrated for 24 hours at 2 °C – 8 °C in the original packaging, protected from light.

Stability of the reconstituted dispersion in the infusion bag
The chemical and physical in-use stability of the product has been demonstrated for 24 hours at 2°C–8°C when protected from light, followed by 4 hours at 25°C when not protected from light.

However, from a microbiological standpoint, unless the method of reconstitution and filling of infusion bags excludes the risk of microbial contamination, the product should be used immediately after reconstitution and filling of the infusion bags.
If the product is not used immediately, the times and conditions of storage during use are the responsibility of the user.

The total storage time of the reconstituted medicinal product in the vial and in the infusion bag, when refrigerated and protected from light, is 24 hours. This may be followed by storage for 4 hours in the infusion bag at temperatures below 25 °C.