ZOLSKETIL Concentrate for dispersion for infusion Ref.[50039] Active ingredients: Doxorubicin

ZOLSKETIL pegylated liposomal should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic agents.

ZOLSKETIL pegylated liposomal exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin hydrochloride.

Posology

Breast cancer/Ovarian cancer

ZOLSKETIL pegylated liposomal is administered intravenously at a dose of 50 mg/m² once every 4 weeks for as long as the disease does not progress and the patient continues to tolerate treatment.

Multiple myeloma

ZOLSKETIL pegylated liposomal is administered at 30 mg/m² on day 4 of the bortezomib 3 week regimen as a 1 hour infusion administered immediately after the bortezomib infusion. The bortezomib regimen consists of 1.3 mg/m² on days 1, 4, 8, and 11 every 3 weeks. The dose should be repeated as long as patients respond satisfactorily and tolerate treatment. Day 4 dosing of both medicinal products may be delayed up to 48 hours as medically necessary. Doses of bortezomib should be at least 72 hours apart.

AIDS-related KS

ZOLSKETIL pegylated liposomal is administered intravenously at 20 mg/m² every two-to-three weeks. Avoid intervals shorter than 10 days as medicinal product accumulation and increased toxicity cannot be ruled out. Treatment of patients for two-to-three months is recommended to achieve a therapeutic response. Continue treatment as needed to maintain a therapeutic response.

For all patients

If the patient experiences early symptoms or signs of infusion reaction (see sections 4.4 and 4.8), immediately discontinue the infusion, give appropriate premedications (antihistamine and/or short acting corticosteroid) and restart at a slower rate.

Guidelines for ZOLSKETIL pegylated liposomal dose modification

To manage adverse reaction such as palmar-plantar erythrodysesthesia (PPE), stomatitis or haematological toxicity, the dose may be reduced or delayed. Guidelines for ZOLSKETIL pegylated liposomal dose modification secondary to these adverse effects are provided in the tables below. The toxicity grading in these tables is based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC).

The tables for PPE (Table 1) and stomatitis (Table 2) provide the schedule followed for dose modification in clinical trials in the treatment of breast or ovarian cancer (modification of the recommended 4 week treatment cycle): if these toxicities occur in patients with AIDS-related KS, the recommended 2 to 3 week treatment cycle can be modified in a similar manner.

The table for haematological toxicity (Table 3) provides the schedule followed for dose modification in clinical trials in the treatment of patients with breast or ovarian cancer only. Dose modification in patients with AIDS-KS is addressed in section 4.8.

Table 1. Palmar-Plantar erythrodysesthesia:

Table 2. Stomatitis:

Table 3. Haematological toxicity (ANC or platelets) - Management of patients with breast or ovarian cancer:

For multiple myeloma patients treated with doxorubicin pegylated liposomal in combination with bortezomib who experience PPE or stomatitis, the doxorubicin pegylated liposomal dose should be modified as described in Table 1 and 2 above respectively. Table 4, below provides the schedule followed for other dose modifications in the clinical trial in the treatment of patients with multiple myeloma receiving doxorubicin pegylated liposomal and bortezomib combination therapy. For more detailed information on bortezomib dosing and dosage adjustments, see the SmPC for bortezomib.

Table 4. Dosage adjustments for doxorubicin pegylated liposomal + bortezomib combination therapy – patients with multiple myeloma:

^* for more information on bortezomib dosing and dosage adjustment, see the SmPC for bortezomib

For AIDS-KS patients treated with ZOLSKETIL pegylated liposomal, haematological toxicity may require dose reduction or suspension or delay of therapy. Temporarily suspend ZOLSKETIL pegylated liposomal treatment in patients when the ANC count is <1,000/mm³ and/or the platelet count is <50,000/mm³. G-CSF (or GM-CSF) may be given as concomitant therapy to support the blood count when the ANC count is <1,000/mm³ in subsequent cycles.

Special populations

Hepatic impairment

Doxorubicin pegylated liposomal pharmacokinetics determined in a small number of patients with elevated total bilirubin levels do not differ from patients with normal total bilirubin; however, until further experience is gained, the doxorubicin pegylated liposomal dosage in patients with impaired hepatic function should be reduced based on the experience from the breast and ovarian clinical trial programs as follows: at initiation of therapy, if the bilirubin is between 1.2-3.0 mg/dl, the first dose is reduced by 25%. If the bilirubin is > 3.0 mg/dl, the first dose is reduced by 50%. If the patient tolerates the first dose without an increase in serum bilirubin or liver enzymes, the dose for cycle 2 can be increased to the next dose level, i.e., if reduced by 25% for the first dose, increase to full dose for cycle 2; if reduced by 50% for the first dose, increase to 75% of full dose for cycle 2. The dosage can be increased to full dose for subsequent cycles if tolerated. Doxorubicin pegylated liposomal can be administered to patients with liver metastases with concurrent elevation of bilirubin and liver enzymes up to 4 x the upper limit of the normal range. Prior to doxorubicin pegylated liposomal administration, evaluate hepatic function using conventional clinical laboratory tests such as ALT/AST, alkaline phosphatase, and bilirubin.

Renal impairment

As doxorubicin is metabolised by the liver and excreted in the bile, dose modification should not be required. Population pharmacokinetic data (in the range of creatinine clearance tested of 30-156 mL/min) demonstrate that doxorubicin clearance is not influenced by renal function. No pharmacokinetic data are available in patients with creatinine clearance of less than 30 mL/min.

AIDS-related KS patients with splenectomy

As there is no experience with ZOLSKETIL pegylated liposomal in patients who have had splenectomy, treatment with ZOLSKETIL pegylated liposomal is not recommended.

Paediatric population

The experience in children is limited ZOLSKETIL pegylated liposomal is not recommended in patients below 18 years of age.

Elderly

Population based analysis demonstrates that age across the range tested (21–75 years) does not significantly alter the pharmacokinetics of doxorubicin.

Method of administration

ZOLSKETIL pegylated liposomal is administered as an intravenous infusion. For further instructions on preparation and special precautions for handling see section 6.6.

Doxorubicin pegylated liposomal must not be administered as a bolus injection or undiluted solution. It is recommended that the doxorubicin pegylated liposomal infusion line be connected through the side port of an intravenous infusion of glucose 50 mg/mL (5%) solution to achieve further dilution and minimise the risk of thrombosis and extravasation. The infusion may be given through a peripheral vein. Do not use with in-line filters. Doxorubicin pegylated liposomal must not be given by the intramuscular or subcutaneous route (see section 6.6).

For doses <90 mg: dilute doxorubicin pegylated liposomal in 250 mL glucose 50 mg/mL (5%) solution for infusion.

For doses ≥90 mg: dilute doxorubicin pegylated liposomal in 500 mL glucose 50 mg/mL (5%) solution for infusion.

Breast cancer/Ovarian cancer/Multiple myeloma

To minimise the risk of infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent doxorubicin pegylated liposomal infusions may be administered over a 60-minute period.

In those patients who experience an infusion reaction, the method of infusion should be modified as follows: 5% of the total dose should be infused slowly over the first 15 minutes. If tolerated without reaction, the infusion rate may then be doubled for the next 15 minutes. If tolerated, the infusion may then be completed over the next hour for a total infusion time of 90 minutes.

AIDS-related KS

The dose of doxorubicin pegylated liposomal is diluted in 250 mL glucose 50 mg/mL (5%) solution for infusion and administered by intravenous infusion over 30 minutes.

Acute overdosing with doxorubicin hydrochloride worsens the toxic effects of mucositis, leukopaenia and thrombocytopaenia. Treatment of acute overdose of the severely myelosuppressed patient consists of hospitalisation, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of mucositis.

Unopened vial: 18 months.

After dilution:

• Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C.
• From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C.
• Partially used vials must be discarded.

Store in a refrigerator (2°C-8°C).

Do not freeze.

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

Type I glass vial with a siliconised grey bromobutyl stopper, and an aluminium seal, containing a deliverable volume of 10 mL (20 mg) or 25 mL (50 mg).

ZOLSKETIL pegylated liposomal is supplied as a single pack or packs of ten vials.

Not all pack sizes may be marketed.

Do not use material that shows evidence of precipitation or any other particulate matter.

Caution must be exercised in handling ZOLSKETIL pegylated liposomal dispersion. The use of gloves is required. If ZOLSKETIL pegylated liposomal comes into contact with skin or mucosa, wash immediately and thoroughly with soap and water. ZOLSKETIL pegylated liposomal must be handled and disposed of in a manner consistent with that of other anticancer medicinal products in accordance with local requirements.

Determine the dose of ZOLSKETIL pegylated liposomal to be administered (based upon the recommended dose and the patient’s body surface area). Take the appropriate volume of ZOLSKETIL pegylated liposomal up into a sterile syringe. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in ZOLSKETIL pegylated liposomal. The appropriate dose of ZOLSKETIL Pegylated Liposomal must be diluted in glucose 50 mg/mL (5%) solution for infusion prior to administration. For doses <90 mg, dilute ZOLSKETIL pegylated liposomal in 250 mL, and for doses ≥90 mg, dilute ZOLSKETIL pegylated liposomal in 500 mL. This can be infused over 60 or 90 minutes as detailed in 4.2.

The use of any diluent other than 50 mg/mL (5%) glucose solution for infusion, or the presence of any bacteriostatic agent such as benzyl alcohol may cause precipitation of ZOLSKETIL pegylated liposomal.

It is recommended that the ZOLSKETIL pegylated liposomal infusion line be connected through the side port of an intravenous infusion of glucose 50 mg/mL (5%). Infusion may be given through a peripheral vein. Do not use with in-line filters.