APEALEA Powder for solution for infusion Ref.[49913] Active ingredients: Paclitaxel

Apealea should only be administered under the supervision of a qualified oncologist in units specialised in the administration of cytotoxic agents. It should not be interchanged with other paclitaxel formulations.

Posology

The recommended dose of Apealea is 250 mg/m² body surface area (BSA) given as an intravenous infusion over 1 hour followed by carboplatin every three weeks for six cycles. The recommended dose of carboplatin is AUC = 5–6 mg/mL×min.

Dose adjustments and delays during treatment

Patients who experience neutropenia (neutrophil count <1.5 × 10⁹/L), febrile neutropenia or thrombocytopenia (platelet count <100 × 10⁹/L) during treatment should have the next treatment cycle delayed until neutrophil counts recover to ≥1.5 × 10⁹/L and platelets recover to ≥100 × 10⁹/L. For Apealea, dose reductions of initially 50 mg/m² and additionally 25 mg/m² should be considered for subsequent courses (see Table 1).

In the case of febrile neutropenia or low platelet count (<75 × 10⁹/L), the dose of carboplatin should be reduced by 1 AUC unit in the treatment cycles following recovery. For appropriate use of carboplatin, the prescriber is advised to consult the prescribing information for carboplatin as well.

Dose reductions or/and delays should be considered as a result of any clinically significant adverse reaction as presented in Table 1.

Table 1. Treatment delay and dose level reductions for adverse drug reactions:

^a Grade of the adverse reaction is defined according to Common Terminology Criteria for Adverse Events (CTCAE).
^b The dose of carboplatin should be reduced by 1 AUC unit for treatment cycles following the occurrence of febrile neutropenia or low platelet count (<75 × 10⁹/L).

Special populations

Hepatic impairment

Patients with mild hepatic impairment (total bilirubin >1 to ≤1.5 × upper limit of normal (ULN) and aspartate aminotransferase (AST) ≤10 × ULN) may be treated with the same doses as patients with normal hepatic function.

For patients with moderate to severe impairment (total bilirubin >1.5 to ≤5 × ULN and AST ≤10 × ULN), a 20% reduction in dose is recommended. The reduced dose may be escalated to the dose for patients with normal hepatic function if the patient is tolerating the treatment for at least two cycles (see sections 4.4 and 5.2).

For patients with total bilirubin >5 × ULN or AST >10 × ULN, there are insufficient data to permit dosage recommendations (see sections 4.4 and 5.2).

Renal impairment

Patients with mildly or moderately impaired renal function (glomerular filtration rate (GFR) 89−60 mL/min or GFR 59−30 mL/min, respectively) may be treated with Apealea without a dose modification. Patients with severe renal impairment (GFR <30 mL/min) should not be treated with paclitaxel (see section 5.2).

Elderly

No additional dosage reductions, other than those for all patients, are recommended for patients 65 years and older.

Of the 391 patients with ovarian cancer in the randomised study who received Apealea in combination with carboplatin, 13% were between 65 and 74 years old. In this limited number of patients, anorexia, fatigue, myalgia, arthralgia, peripheral sensory neuropathy, and diarrhoea were observed more frequently compared to patients younger than 65 years. Limited data are available on use in patients ≥75 years (2% of the patients in the study).

Non-Caucasian patients

There are limited data of Apealea in non-Caucasian patients and current data is insufficient to recommend additional dose adjustments (see section 4.4). If neuropathy is observed, follow dose reduction recommendations in Table 1.

Paediatric population

There is no relevant use of paclitaxel in the paediatric population for the indications of epithelial ovarian cancer, primary peritoneal cancer and fallopian tube cancer. The safety and efficacy of Apealea in children and adolescents aged 0−17 years has not been established.

Method of administration

Apealea is for intravenous use.

After reconstitution of the powder, the solution for infusion is a clear, greenish-yellow solution. The solution should be administered by an intravenous infusion over approximately one hour (120−140 drops/min). Administration sets containing a 15 µm polyamide fluid filter should be used. It is important to flush the infusion set and catheter/cannula before and after the administration using the solution for reconstitution in order to avoid accidental administration into the surrounding tissue and to ensure administration of the complete dose.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

There is no known antidote for paclitaxel overdose. In the event of an overdose, the patient should be closely monitored. Treatment should be directed at the major anticipated toxicities, which are nausea, vomiting, diarrhoea, myelosuppression, peripheral sensory neuropathy and peripheral neuropathy.

Unopened vial:

3 years.

After reconstitution:

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C in lactated and acetated Ringer’s solution and for 4 hours at 2°C to 8°C in sodium chloride 9 mg/mL (0.9%) solution when protected from light. From a microbiological point of view, unless the method of opening and reconstituting precludes the risks of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Store in a refrigerator (2°C–8°C).

Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Clear type I glass vial with a silicon coated butyl rubber stopper, an aluminium overseal and a plastic flip-off cap containing powder equivalent to 60 mg of paclitaxel.

Pack size: 1 vial.

Administration precautions

Paclitaxel is an antineoplastic medicinal product and as with other potentially toxic compounds, caution should be exercised in handling Apealea. The use of gloves, goggles and protective clothing is recommended. If the solution contacts the skin, the skin should be washed immediately and thoroughly with soap and water. If it contacts mucous membranes, the membranes should be flushed thoroughly with water. Apealea should only be prepared and administered by personnel appropriately trained in the handling of cytotoxic agents. Pregnant and breast-feeding staff should not handle Apealea. The reconstituted product should not be diluted.

Reconstitution of the medicinal product

Apealea is supplied as a sterile powder for reconstitution before use. After reconstitution, the solution contains 1 mg/mL of paclitaxel formulated as micellar nanoparticles. The reconstituted solution for infusion is a clear, greenish-yellow solution.

Protect from direct and/or bright light throughout the preparation process. The (reconstituted) product can only withstand short-term handling in absence of light protection.

Only reconstitute Apealea using one of the following commercially available solutions for reconstitution:

• sodium chloride 9 mg/mL (0.9%) solution suitable for infusion;
• lactated Ringer’s solution suitable for infusion;
• acetated Ringer’s solution suitable for infusion.

The pH of lactated or acetated Ringer’s solution must be in the range of 5.0 to 7.5, and acceptable ion concentrations of calcium and magnesium are listed below (Table 5).

Table 5. Acceptable ion concentrations for calcium and magnesium in lactated and acetated Ringer’s solutions suitable for reconstitution:

^* Solutions containing both Ca2+ and Mg2+ should have a total (combined) concentration of Ca2+ and Mg2+ within the range of 1.0 to 3.5 mmol/L.

Apealea should be reconstituted using either one of the three suitable solutions for reconstitution and according to the following steps:

a. Take the desired number of vials from the refrigerator. The powder should be greenish-yellow to yellow. In case of discolouration (orange), discard the vial. To reach room temperature, let the vials stand protected from light for approximately 15 to 20 minutes not above 25°C.

b. Due to negative pressure in the vial, pressure must be equilibrated by a needle or a spike before and during injection of the solution for reconstitution. Using a sterile syringe, inject 60 mL of solution for reconstitution per vial. The solution should be injected during approximately one minute towards the inner wall of the vial and not directly onto the powder as this will result in foaming.

c. Swirl the vial in an upright position for approximately 20 seconds. To keep the generation of foam to a minimum, do not shake the vial.

d. Protect from light and allow the vial to stand for three to five minutes.

e. Swirl the vial again in upright position for approximately 20 seconds, then gently invert it five times. Do not shake.

f. Continue to swirl the vial until the powder is completely dissolved., Alternatively, the vial may be placed on a shaker and rotated for up to 20 minutes, while being protected from light (orbital shake pattern; 200–250 rpm). Steps c and to f should not be more than 30 minutes.

g. The solution should be clear and greenish-yellow without visible particles or precipitates. If particles, precipitates, discolouration (orange) or opalescence are observed, the solution should be discarded.

h. Inject the required amount of reconstituted Apealea into an empty, sterile ethylene-vinyl acetate (EVA) bag. Ensure that the solution is clear and place a light-protective bag over the EVA infusion bag.

Compatibility with administration sets made of DEHP-free PVC (i.e. polyvinyl chloride without the plasticizer di-(2-ethylhexyl) phthalate) has been demonstrated. However, compatibility with DEHP-containing administration sets has not been demonstrated. Administration sets containing a 15 µm polyamide fluid filter should be used.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.