Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: YES Pharmaceutical Development Services GmbH, Bahnstraße 42-46, 61381 Friedrichsdorf, Germany
Celdoxome pegylated liposomal is indicated in adults:
Celdoxome pegylated liposomal may be used as first-line systemic chemotherapy, or as second line chemotherapy in AIDS-KS patients with disease that has progressed with, or in patients intolerant to, prior combination systemic chemotherapy comprising at least two of the following agents: a vinca alkaloid, bleomycin and standard doxorubicin (or other anthracycline).
Celdoxome pegylated liposomal should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic agents.
Celdoxome pegylated liposomal exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin hydrochloride.
Celdoxome pegylated liposomal should be 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.
Celdoxome pegylated liposomal should be 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.
Celdoxome pegylated liposomal should be administered intravenously at 20 mg/m² every two-to-three weeks. Intervals shorter than 10 days should be avoided 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. Treatment should be continued as needed to maintain a therapeutic response.
If the patient experiences early symptoms or signs of infusion reaction (see sections 4.4 and 4.8), the infusion must be discontinued immediately, appropriate premedications should be given (antihistamine and/or short acting corticosteroid) and treatment restarted at a slower rate.
To manage adverse reactions such as palmar-plantar erythrodysesthesia (PPE), stomatitis or haematological toxicity, the dose may be reduced or delayed. Guidelines for Celdoxome pegylated liposomal dose modification secondary to these adverse reactions 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 provided following Table 4.
Table 1. Palmar plantar erythrodysesthesia:
| Week after prior Celdoxome pegylated liposomal dose | |||
| Toxicity grade at current assessment | Week 4 | Week 5 | Week 6 |
| Grade 1 (mild erythema, swelling, or desquamation not interfering with daily activities) | Redose unless patient has experienced a previous grade 3 or 4 skin toxicity, in which case wait an additional week | Redose unless patient has experienced a previous grade 3 or 4 skin toxicity, in which case wait an additional week | Decrease dose by 25%; return to 4-week interval |
| Grade 2 (erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter) | Wait an additional week | Wait an additional week | Decrease dose by 25%; return to 4-week interval |
| Grade 3 (blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing) | Wait an additional week | Wait an additional week | Withdraw patient |
| Grade 4 (diffuse or local process causing infectious complications, or a bedridden state or hospitalisation) | Wait an additional week | Wait an additional week | Withdraw patient |
Table 2. Stomatitis:
| Week after prior Celdoxome pegylated liposomal dose | |||
| Toxicity grade at current assessment | Week 4 | Week 5 | Week 6 |
| Grade 1 (painless ulcers, erythema, or mild soreness) | Redose unless patient has experienced a previous grade 3 or 4 stomatitis in which case wait an additional week | Redose unless patient has experienced a previous grade 3 or 4 stomatitis in which case wait an additional week | Decrease dose by 25%; return to 4-week interval or withdraw patient per physician’s assessment |
| Grade 2 (painful erythema, oedema, or ulcers, but can eat) | Wait an additional week | Wait an additional week | Decrease dose by 25%; return to 4-week interval or withdraw patient per physician’s assessment |
| Grade 3 (painful erythema, edema, or ulcers, but cannot eat) | Wait an additional week | Wait an additional week | Withdraw patient |
| Grade 4 (requires parenteral or enteral support) | Wait an additional week | Wait an additional week | Withdraw patient |
Table 3. Haematological toxicity (ANC or platelets) - management of patients with breast or ovarian cancer:
| Grade | ANC | Platelets | Modification |
| Grade 1 | 1 500 – 1 900 | 75 000 – 150 000 | Resume treatment with no dose reduction. |
| Grade 2 | 1 000 – <1 500 | 50 000 – <75 000 | Wait until ANC ≥1 500 and platelets ≥75 000; redose with no dose reduction. |
| Grade 3 | 500 – <1 000 | 25 000 – <50 000 | Wait until ANC ≥1 500 and platelets ≥75 000; redose with no dose reduction. |
| Grade 4 | <500 | <25 000 | Wait until ANC ≥1 500 and platelets ≥75 000; decrease dose by 25% or continue full dose with growth factor support. |
For multiple myeloma patients treated with Celdoxome pegylated liposomal in combination with bortezomib who experience PPE or stomatitis, the Celdoxome 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 Celdoxome pegylated liposomal and bortezomib combination therapy. For more detailed information on bortezomib dosing and dose adjustments, see the SmPC for bortezomib.
Table 4. Dose adjustments for Celdoxome pegylated liposomal + bortezomib combination therapy – patients with multiple myeloma:
| Patient status | Celdoxome pegylated liposomal | Bortezomib |
| Fever ≥38°C and ANC <1 000/mm³ | Do not dose this cycle if before Day 4; if after Day 4, reduce next dose by 25%. | Reduce next dose by 25%. |
| On any day of medicine administration after Day 1 of each cycle: Platelet count <25 000/mm³ Haemoglobin <8 g/dL ANC <500/mm³ | Do not dose this cycle if before Day 4; if after Day 4 reduce next dose by 25% in the following cycles if bortezomib is reduced for haematologic toxicity.* | Do not dose; if 2 or more doses are not given in a cycle, reduce dose by 25% in following cycles. |
| Grade 3 or 4 non-haematologic medicine related toxicity | Do not dose until recovered to grade <2 and reduce dose by 25% for all subsequent doses. | Do not dose until recovered to grade <2 and reduce dose by 25% for all subsequent doses. |
| Neuropathic pain or peripheral neuropathy | No dose adjustments. | See the SmPC for bortezomib. |
* for more information on bortezomib dosing and dose adjustment, see the SmPC for bortezomib
For AIDS-KS patients treated with Celdoxome pegylated liposomal, haematological toxicity may require dose reduction or suspension or delay of therapy. Treatment with liposomal doxorubicin should be temporarily suspended 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.
Liposomal doxorubicin 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 Celdoxome pegylated liposomal dose 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, dose can be increased to full dose for cycle 2; if reduced by 50% for the first dose, dose can be increased to 75% of full dose for cycle 2. The dose can be increased to full dose for subsequent cycles if tolerated. Celdoxome 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 Celdoxome pegylated liposomal administration, hepatic function must be evaluated using conventional clinical laboratory tests such as ALT/AST, alkaline phosphatase, and bilirubin.
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 liposomal doxorubicin clearance is not influenced by renal function. No pharmacokinetic data are available in patients with creatinine clearance of less than 30 mL/min.
As there is no experience with Celdoxome pegylated liposomal in patients who have had splenectomy, treatment with Celdoxome pegylated liposomal is not recommended.
The experience in children is limited. Celdoxome pegylated liposomal is not recommended in patients below 18 years of age.
Population based analysis demonstrates that age across the range tested (21–75 years) does not significantly alter the pharmacokinetics of Celdoxome pegylated liposomal.
Celdoxome pegylated liposomal must be administered as an intravenous infusion. For further instructions on preparation and special precautions for handling see section 6.6.
Celdoxome pegylated liposomal must not be administered as a bolus injection or undiluted dispersion. It is recommended that the Celdoxome pegylated liposomal infusion line be connected through the side port of an intravenous infusion of 5% (50 mg/mL) glucose to achieve further dilution and minimise the risk of thrombosis and extravasation. The infusion may be given through a peripheral vein. In-line filters must not be used. Celdoxome pegylated liposomal must not be given by the intramuscular or subcutaneous route (see section 6.6).
For doses <90 mg: Celdoxome pegylated liposomal must be diluted in 250 mL 5% (50 mg/mL) glucose solution for infusion.
For doses ≥90 mg: Celdoxome pegylated liposomal must be diluted in 500 mL 5% (50 mg/mL) glucose solution for infusion.
To minimise the risk of infusion reactions, the initial dose should be administered at a rate not greater than 1 mg/minute. If no infusion reaction is observed, subsequent infusions of Celdoxome pegylated liposomal 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.
The dose of Celdoxome pegylated liposomal must be diluted in 250 mL 5% (50 mg/mL) glucose 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.
Store in a refrigerator (2°C-8°C).
Do not freeze.
For storage conditions after dilution of the medicinal product, see section 6.3.
Type I glass vial with a bromobutyl rubber stopper and aluminium and PP flip-off cap containing a volume of 10 mL (20 mg) or 25 mL (50 mg).
Pack size:
1 vial
10 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 Celdoxome pegylated liposomal dispersion. The use of gloves is required. If Celdoxome pegylated liposomal comes into contact with skin or mucosa, it must be immediately and thoroughly washed with soap and water. Celdoxome pegylated liposomal must be handled and disposed of in a manner consistent with that of other anticancer medicinal products in accordance with local requirements.
The dose of Celdoxome pegylated liposomal to be administered should be determined (based upon the recommended dose and the patient’s body surface area). The appropriate volume of Celdoxome pegylated liposomal should be taken up into a sterile syringe. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in Celdoxome pegylated liposomal. The appropriate dose of Celdoxome pegylated liposomal must be diluted in 5% (50 mg/mL) glucose solution for infusion prior to administration. For doses <90 mg, Celdoxome pegylated liposomal must be diluted in 250 mL, and for doses ≥90 mg, Celdoxome pegylated liposomal must be diluted in 500 mL. This can be infused over 60 or 90 minutes as detailed in section 4.2.
The use of any diluent other than 5% (50 mg/mL) glucose solution for infusion, or the presence of any bacteriostatic agent such as benzyl alcohol may cause precipitation of Celdoxome pegylated liposomal.
It is recommended that the Celdoxome pegylated liposomal infusion line be connected through the side port of an intravenous infusion of 5% (50 mg/mL) glucose. Infusion may be given through a peripheral vein. Do not use with in-line filters. Partially used vials must be discarded.
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