Apexelsin

Patient Information Leaflet

Apexelsin 5 mg/mL powder for infusion dispersion

paclitaxel
Please read all of this leaflet carefully before receiving this medicine because 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.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or nurse. See section 4.

Contents of this leaflet

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

1. What Apexelsin is and what it is used for

What Apexelsin is
Apexelsin 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 component of the medicine that acts against cancer by inhibiting the division of tumor cells, causing them to die.
• Albumin is the component that helps paclitaxel dissolve in the blood and cross the walls of blood vessels to reach the tumor. This means that additional chemical substances, which could cause life-threatening side effects, are not required. Some adverse reactions are much less frequent with Apexelsin.

What Apexelsin is used for
Apexelsin 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).
  • Apexelsin is used in metastatic breast cancer after at least one other therapy has been attempted but proved ineffective, and when the patient is not suitable for treatments containing a group of medicines called “anthracyclines”.
  • Patients with metastatic breast cancer who received paclitaxel bound to the human protein albumin, in cases where another therapy had failed, showed a higher probability of tumor shrinkage and lived longer compared to patients receiving alternative therapy.
• Pancreatic cancer
  • Apexelsin is used in combination with a medicine called gemcitabine for metastatic pancreatic cancer. In a clinical study, patients with metastatic pancreatic cancer (pancreatic cancer that has spread to other parts of the body) treated with paclitaxel bound to the human protein albumin and gemcitabine lived longer than those who received gemcitabine alone.
• Lung cancer
  • Apexelsin 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”.
  • Apexelsin is used in non-small cell lung cancer when surgery or radiotherapy are not suitable treatment options for the disease.

2. What you need to know before receiving Apexelsin

Apexelsin must not be administered

• 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 less than 1,500 cells/mm³ – your doctor will provide information on this).

Warnings and precautions
Talk to your doctor or nurse before receiving Apexelsin

• if you have reduced kidney function;
• if you have severe liver problems;
• if you have heart disorders.

Consult your doctor or nurse if you experience any of the following conditions during treatment with Apexelsin; your doctor may decide to interrupt 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
This medicine is intended for adults only and must not be administered to children and adolescents under 18 years of age.
Other medicines and Apexelsin
Inform your doctor if you are taking or have recently taken any other medicines, including those obtained without a prescription and herbal medicines. This is because Apexelsin may affect the action of other medicines and other medicines may affect the action of Apexelsin.
Be cautious and consult your doctor when taking Apexelsin together with any of the following:

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

Pregnancy, breastfeeding, and fertility
Paclitaxel may cause severe birth defects (present at birth) and therefore must not be used during pregnancy. Your doctor will perform a pregnancy test before starting treatment with this medicine.
Women of childbearing potential must use effective contraceptive methods during treatment with Apexelsin and for at least 6 months after stopping treatment.
Do not breastfeed during treatment with this medicine, as it is not known whether the active substance paclitaxel passes into breast milk.
Male patients are advised to use effective contraception and to avoid fathering children during treatment and for at least 3 months after stopping treatment. You should also discuss sperm preservation before starting treatment, due to the possibility that treatment with this medicine may cause permanent infertility.
Ask your doctor for advice before taking this medicine.
Driving and using machines
Some people may experience fatigue or dizziness after administration of this medicine. 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.
Apexelsin contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e. essentially 'sodium-free'.

3. How Apexelsin is administered

This medicine will be administered intravenously as an intravenous infusion by a doctor or nurse.
The dose administered 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 Apexelsin administered?

• For the treatment of metastatic breast cancer, Apexelsin is usually given once every three weeks (on day 1 of a 21-day cycle).
• For the treatment of advanced pancreatic cancer, Apexelsin is administered on days 1, 8, and 15 of each 28-day treatment cycle, with gemcitabine given immediately after Apexelsin.
• For the treatment of non-small cell lung cancer, Apexelsin 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 the administration of Apexelsin.

If you have any doubts about the use of 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: may affect more than 1 in 10 people

• Hair loss (most cases of hair loss occurred within less than one month from the start of paclitaxel treatment. When it occurs, hair loss is marked (over 50%) in most patients)
• Skin rash
• Abnormally low levels of certain types of white blood cells (neutrophils, lymphocytes or leukocytes) in the blood
• Deficiency of red blood cells (erythrocytes)
• Reduced number of platelets 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, mouth irritation, loss of appetite
• Vomiting
• Weakness and fatigue, fever
• Dehydration, altered taste, weight loss
• Low levels of potassium in the blood
• Depression, sleep disorders
• Headache
• Chills
• Difficulty breathing
• Dizziness
• Swelling of mucous membranes and soft tissues
• Increased liver function test values
• Pain in extremities
• Cough
• Abdominal pain
• Nosebleed

Common: may affect up to 1 in 10 people

• Itching, dry skin, nail changes
• Infection, fever with reduced number of a type of white blood cells (neutrophils) in the blood, hot flushes, oral candidiasis, severe blood infection that may be caused by reduced white blood cells
• Reduced number of all types of blood cells
• Chest pain or sore throat
• Indigestion, abdominal problems
• Stuffy nose
• Back pain, bone pain
• Reduced muscle coordination or reading difficulty, increased or decreased tear production, loss of eyelashes
• 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: may affect up to 1 in 100 people

• Weight gain, increased lactate dehydrogenase (an enzyme) in the blood, decreased kidney function, increased blood sugar, increased phosphorus in the blood
• Decreased or absent reflexes, involuntary movements, neuralgia, fainting, dizziness upon standing, tremor, facial nerve paralysis
• Eye irritation, eye pain, eye redness, itchy eyes, double vision, reduced visual acuity or perception of 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, hoarseness, blood clot in the lung, dry throat
• Flatulence (intestinal gas), stomach cramps, gum pain, rectal bleeding
• Painful urination, frequent urination, blood in the urine, urinary incontinence
• Nail pain, painful sensitivity of nails, nail loss, hives, skin pain, photosensitivity reaction, pigmentation disorders, increased sweating, night sweats, white spots on the skin, skin lesions, facial swelling
• Decreased phosphorus in the blood, fluid retention, low albumin levels in the blood, increased thirst, decreased calcium in the blood, low blood sugar, low sodium in the blood
• Nasal pain and congestion, skin infections, catheter-related infection
• Bruising
• Pain at the site of the tumour, tumour necrosis
• Decreased blood pressure when standing, cold extremities (hands and feet)
• Difficulty walking, swelling
• Allergic reaction
• Decreased liver function, enlarged liver
• Chest pain
• Restlessness
• Small bleeding spots under the skin due to blood clots
• A condition involving destruction of red blood cells and acute kidney failure

Rare: may affect up to 1 in 1,000 people

• Skin reaction to another agent or radiation-induced lung inflammation
• Formation of 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: may affect up to 1 in 10,000 people

• Severe inflammation/rash of the skin and mucous membranes (Stevens-Johnson syndrome, toxic epidermal necrolysis)

Not known: frequency cannot be estimated from the available data

• Hardening/thickening of the skin (scleroderma)

Reporting of side effects
If you experience 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 detailed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Apexelsin

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and on the 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 the first reconstitution, the dispersion must be used immediately. If not used immediately,
the dispersion may 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 may be stored in a refrigerator (2 °C – 8 °C)
for up to 24 hours, protected from light.
The total storage time of the reconstituted medicine 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.
The doctor or pharmacist is responsible for the proper disposal of unused Apexelsin.

6. Package Contents and Other Information

What Apexelsin 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 human albumin solution (containing sodium caprylate and N-acetyl-L-tryptophan); see section 2, “Apexelsin contains sodium”.

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

Marketing Authorization Holder
WhiteOak Pharmaceutical B.V.
Teleportboulevard 130,
Amsterdam, 1043 EJ,
The Netherlands

Manufacturer
SciencePharma Sp. z o.o.
Chełmska 30/34
00-725 Warsaw
Poland

For further information about this medicinal product, please contact the local representative of the Marketing Authorization Holder:

België/Belgique/Belgien Lietuva
WhiteOak Pharmaceutical B.V. Zentiva, k.s.
Tél/Tel: +31 202255118 Tel: +370 52152025

България Luxembourg/Luxemburg
Zentiva, k.s. WhiteOak Pharmaceutical B.V.
Тел: +359 24417136 Tél/Tel: +31 202255118

Česká republika Magyarország
Zentiva, k.s. WhiteOak Pharmaceutical B.V.
Tel: +420 267241111 Tel: +31 202255118

Danmark Malta
FrostPharma AB WhiteOak Pharmaceutical B.V.
Tlf: +46 8243660 Tel: +31 202255118

Deutschland Nederland
WhiteOak Pharmaceutical B.V. WhiteOak Pharmaceutical B.V.
Tel.: +49 88569039983 Tel: +31 320798100

Eesti Norge
Zentiva, k.s. FrostPharma AB
Tel: +372 5270308 Tlf: +46 8243660

Ελλάδα Österreich
WhiteOak Pharmaceutical B.V. IHCS Arzneimittel Vertriebs GmbH
Τηλ: +31 202255118 Tel: +43 171728861

España Polska
Zentiva, Spain S.L.U. Zentiva Polska Sp. z o.o.
Tel: +34 671365828 Tel: +48 22 375 92 00

France Portugal
Zentiva France WhiteOak Pharmaceutical B.V.
Tél: +33 800089219 Tel: +351 300505995

Hrvatska România
WhiteOak Pharmaceutical B.V. WhiteOak Pharmaceutical B.V.
Tel: +385 17757005 Tel: +31 202255118

Ireland Slovenija
Caragen Limited WhiteOak Pharmaceutical B.V.
Tel: +353 15688566 Tel: +385 17757005

Ísland Slovenská republika
FrostPharma AB WhiteOak Pharmaceutical B.V.
Sími: +46 8243660 Tel: +421 23325144

Italia Suomi/Finland
Istituto Gentili s.r.l. FrostPharma AB
Tel: +39 0289132700 Puh/Tel: +46 8243660

Κύπρος Sverige
C.A.Papaellinas Ltd FrostPharma AB
Τηλ: +357 22741741 Tel: +46 8243660

Latvija
Zentiva, k.s.
Tel: +371 67893939

More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.
This leaflet is available in all languages of the European Union/European Economic Area on the website of the European Medicines Agency.

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 Apexelsin. Wear gloves, goggles, and protective clothing. If the Apexelsin dispersion comes into contact with the skin, wash the skin immediately and thoroughly with soap and water. If Apexelsin contacts mucous membranes, rinse them thoroughly with copious amounts of water. Apexelsin must be prepared and administered only by personnel adequately trained in handling cytotoxic agents. Apexelsin must not be handled by pregnant women.

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

Reconstitution and Administration of the Medicinal Product
Apexelsin must be administered under the supervision of a qualified oncologist in specialized units experienced in administering cytotoxic agents.

Apexelsin 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 Apexelsin dispersion 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 100 mg Apexelsin vial over at least 1 minute. The solution should be directed against the inner wall of the vial. The solution must not be injected directly onto the powder, as this may cause foaming.

After adding the 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. Avoid foaming. 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. Sediment may occur in the reconstituted dispersion. If precipitates or sediment are visible, gently invert the vial again to ensure complete redispersion before use.

Inspect the dispersion in the vial 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 Apexelsin must be transferred into an empty, sterile intravenous infusion bag made of PVC or another suitable material.

The use of medical devices containing silicone lubricant (e.g., syringes and intravenous bags) for reconstituting and administering Apexelsin may lead to the formation of proteinaceous filaments. Administer Apexelsin using an infusion set equipped with a 15-micron filter to prevent administration of these filaments. A 15-micron filter removes the filaments without altering the physical or chemical properties of the reconstituted product.

Using filters with a pore diameter smaller than 15 microns may cause filter clogging.

No special DEHP-free containers or administration sets are required for the preparation and administration of Apexelsin infusions.

After administration, the infusion line should be flushed with 9 mg/mL (0.9%) sodium chloride solution for injection to ensure complete delivery of the dose.

Unused medicinal product and waste material must be disposed of in accordance with local regulations.

Stability
Sealed Apexelsin vials 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 adversely affect 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 medicinal product has been shown to be chemically and physically stable 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 medicinal product has been shown to be chemically and physically stable for 24 hours at 2 °C – 8 °C, followed by up to 4 hours at 25 °C, protected from light.

However, from a microbiological standpoint, unless the reconstitution and filling of infusion bags are performed under conditions that exclude 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 up to 4 hours in the infusion bag at temperatures below 25 °C.