Posology : מינונים

4.2 Posology and method of administration

Caelyx liposomal should only be administered under the supervision of a qualified oncologist specialized in the administration of cytotoxic agents.

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

Posology
Breast cancer/Ovarian cancer
Caelyx 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
Caelyx liposomal is administered at 30 mg/m² on day 4 of the bortezomib 3 weeks 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
Caelyx 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 Caelyx liposomal dose modification
To manage adverse events such as palmar-plantar erythrodysesthesia (PPE), stomatitis or haematological toxicity, the dose may be reduced or delayed. Guidelines for Caelyx 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 weeks treatment cycle): if these toxicities occur in patients with AIDS-related KS, the recommended 2 to 3 weeks 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.
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Table 1. PALMAR–PLANTAR ERYTHRODYSESTHESIA
Week after prior Caelyx liposomal dose
Toxicity grade at                       Week 4                         Week 5                                   Week 6 current assessment
Grade 1                         Redose unless                       Redose unless                     Decrease dose by (mild erythema,                       patient has                         patient has                      25%; return to swelling, or                  experienced a previous              experienced a previous                4 weeks interval desquamation not                    grade 3 or 4 skin                   grade 3 or 4 skin interfering with daily             toxicity, in which case             toxicity, in which case activities)                    wait an additional                  wait an additional week                                week
Grade 2                     Wait an additional                  Wait an additional                   Decrease dose by (erythema,                            week                                week                          25%; return to desquamation, or                                                                                          4 weeks interval swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than
2 cm in diameter)
Grade 3                     Wait an additional                  Wait an additional                  Withdraw patient (blistering, ulceration,                  week                                week or swelling interfering with walking or normal daily activities; cannot wear regular clothing)
Grade 4                     Wait an additional                  Wait an additional                  Withdraw patient (diffuse or local process                  week                                week causing infectious complications, or a bedridden state or hospitalisation)
Table 2. STOMATITIS
Week after prior Caelyx liposomal dose
Toxicity grade at                       Week 4                         Week 5                                 Week 6 current assessment
Grade 1                         Redose unless                      Redose unless                    Decrease dose by (painless ulcers,              patient has experienced                   patient has                     25%; return to erythema, or mild               a previous grade 3 or 4                  experienced a                  4 weeks interval or soreness)                     stomatitis in which                previous grade 3 or 4              withdraw patient per case wait an additional               stomatitis in which                   physician’s week                       case wait an additional                 assessment week
Grade 2                      Wait an additional                 Wait an additional                  Decrease dose by (painful erythema,                      week                                week                          25%; return to oedema, or ulcers, but                                                                                    4 weeks interval or can eat)                                                                                           withdraw patient per physician’s assessment
Grade 3                      Wait an additional                 Wait an additional                 Withdraw patient (painful erythema,                      week                               week edema, or ulcers, but cannot eat)
Grade 4                      Wait an additional                 Wait an additional                  Withdraw patient (requires parenteral or                   week                               week enteral support)

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 Caelyx liposomal in combination with bortezomib who experience PPE or stomatitis, the Caelyx 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 Caelyx liposomal and bortezomib combination therapy. For more detailed information on bortezomib dosing and dosage adjustments, see the SPC for bortezomib.

Table 4. DOSAGE ADJUSTMENTS FOR CAELYX LIPOSOMAL + BORTEZOMIB COMBINATION THERAPY - PATIENTS WITH MULTIPLE MYELOMA
Patient status                       Caelyx liposomal                 Bortezomib Fever ≥ 38○C and ANC                 Do not dose this cycle if before Reduce next dose by 25%.
< 1,000/mm3                          day 4; if after day 4, reduce next dose by 25%.
On any day of medicine               Do not dose this cycle if before Do not dose; if 2 or more administration after day 1 of        day 4; if after day 4 reduce     doses are not given in a cycle, each cycle:                          next dose by 25% in the          reduce dose by 25% in 3        following  cycles  if bortezomib following cycles.
Platelet count < 25,000/mm
Hemoglobin < 8 g/dl                  is reduced  for hematologic
ANC < 500/mm3                        toxicity.*
Grade 3 or 4 non-hematologic         Do not dose until recovered to   Do not dose until recovered to medicine related toxicity            grade < 2 and reduce dose by     grade < 2 and reduce dose by 25% for all subsequent doses.                25% for all subsequent doses.
Neuropathic pain or peripheral               No dosage adjustments.                       See the SPC for bortezomib.
neuropathy
* for more information on bortezomib dosing and dosage adjustment, see the SPC for bortezomib 

For AIDS-KS patients treated with Caelyx liposomal, haematological toxicity may require dose reduction or suspension or delay of therapy. Temporarily suspend Caelyx 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.


Hepatic Impairment
Caelyx 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 Caelyx 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. Caelyx 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 Caelyx 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 Caelyx liposomal 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 Caelyx liposomal in patients who have had splenectomy, treatment with Caelyx liposomal is not recommended.

Paediatric population
The experience in children is limited. Caelyx 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 Caelyx liposomal.

Method of administration

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

Do not administer Caelyx liposomal as a bolus injection or undiluted solution. It is recommended that the Caelyx 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. Do not use with in-line filters. Caelyx liposomal must not be given by the intramuscular or subcutaneous route (see section 6.6).

For doses < 90 mg: dilute Caelyx liposomal in 250 ml 5% (50 mg/ml) glucose solution for infusion.
For doses ≥ 90 mg: dilute Caelyx liposomal in 500 ml 5% (50 mg/ml) glucose solution for infusion.

Breast cancer/Ovarian cancer/Multiple myeloma
To minimize 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 Caelyx 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 Caelyx liposomal is diluted in 250 ml 5% (50 mg/ml) glucose solution for infusion and administered by intravenous infusion over 30 minutes.