Posology : מינונים

4.2 Posology and method of administration
Lipodox Liposomal should only be administered under the supervision of a qualified oncologist specialized in the administration of cytotoxic agents.
Lipodox Liposomal exhibits unique pharmacokinetic properties and must not be used interchangeably with other non-liposomal formulations of doxorubicin hydrochloride.

Posology
Breast cancer/Ovarian cancer:

Lipodox Liposomal is administered intravenously at a dose of 50 mg/m 2 once every 4 weeks for as long as the disease does not progress and the patient continues to tolerate treatment.

Multiple myeloma:
Lipodox 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:
Lipodox Liposomal is administered intravenously at 20 mg/m 2 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 Lipodox 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 Lipodox 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.

Table 1. PALMAR–PLANTAR ERYTHRODYSESTHESIA
Week after prior Lipodox Liposomal dose
Toxicity grade at current               Week 4                     Week 5                                 Week 6 assessment
Grade 1               Redose unless patient has        Redose unless patient has       Decrease dose by 25%; (mild erythema, swelling, or      experienced a previous           experienced a previous        return to 4 weeks interval desquamation not          grade 3 or 4 skin toxicity, in   grade 3 or 4 skin toxicity, in interfering with daily           which case wait an               which case wait an activities)                 additional week                  additional week 


Table 1. PALMAR–PLANTAR ERYTHRODYSESTHESIA
Week after prior Lipodox Liposomal dose
Toxicity grade at current                 Week 4                     Week 5                           Week 6 assessment
Grade 2 (erythema,           Wait an additional week       Wait an additional week       Decrease dose by 25%; desquamation, or swelling                                                                   return to 4 weeks interval interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter)
Grade 3 (blistering,          Wait an additional week       Wait an additional week       Withdraw patient ulceration, or swelling interfering with walking or normal daily activities;
cannot wear regular clothing)
Grade 4                 Wait an additional week       Wait an additional week       Withdraw patient (diffuse or local process causing infectious complications, or a bedridden state or hospitalisation)



Table 2. STOMATITIS
Week after prior Lipodox Liposomal dose
Toxicity grade at current                 Week 4                       Week 5                          Week 6 assessment
Grade 1                  Redose unless patient has     Redose unless patient has     Decrease dose by 25%; (painless ulcers, erythema,        experienced a previous        experienced a previous      return to 4 weeks interval or mild soreness)            grade 3 or 4 stomatitis in    grade 3 or 4 stomatitis in     or withdraw patient per which case wait an            which case wait an          physician’s assessment additional week               additional week
Grade 2                 Wait an additional week       Wait an additional week         Decrease dose by 25%; (painful erythema, oedema,                                                                     return to 4 weeks interval or ulcers, but can eat)                                                                       or withdraw patient per physician’s assessment
Grade 3                 Wait an additional week       Wait an additional week           Withdraw patient (painful erythema, edema,
or ulcers, but cannot eat)
Grade 4                 Wait an additional week       Wait an additional week           Withdraw patient (requires parenteral or 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.
Wait until ANC ≥ 1,500 and
Grade 2               1,000 – < 1,500    50,000 – < 75,000 platelets ≥ 75,000; redose with no dose reduction.
Wait until ANC ≥ 1,500 and
Grade 3                500 – < 1,000     25,000 – < 50,000 platelets ≥ 75,000; redose with no dose reduction.
Wait until ANC ≥ 1,500 and platelets ≥ 75,000; decrease dose
Grade 4                     < 500                      < 25,000 by 25% or continue full dose with growth factor support.


For multiple myeloma patients treated with Lipodox Liposomal in combination with bortezomib who experience PPE or stomatitis, the Lipodox 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 Lipodox 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 LIPODOX LIPOSOMAL + BORTEZOMIB COMBINATION THERAPY - PATIENTS WITH MULTIPLE MYELOMA
Patient status              Lipodox Liposomal                      Bortezomib º
Fever ≥ 38 C and ANC <      Do  not  dose this cycle if before day Reduce next dose by 25%.
1,000/mm  3                 4; if after day 4, reduce  next dose by 25%.
On any day of medicine               Do not dose this cycle if before day    Do not dose; if 2 or more doses are administration after day 1 of each   4; if after day 4 reduce next dose by   not given in a cycle, reduce dose by cycle:                               25% in the following cycles if          25% in following cycles.
Platelet count < 25,000/mm3          bortezomib is reduced for
Hemoglobin < 8 g/dl                  hematologic toxicity.*
ANC < 500/mm3
Grade 3 or 4 non-hematologic         Do not dose until recovered to grade    Do not dose until recovered to grade medicine related toxicity            < 2 and reduce dose by 25% for all      < 2 and reduce dose by 25% for all subsequent doses.                       subsequent doses.
Neuropathic pain or peripheral       No dosage adjustments.                  See the SmPC for bortezomib.
neuropathy
* for more information on bortezomib dosing and dosage adjustment, see the SPC for bortezomib 
For AIDS-KS patients treated with Lipodox Liposomal, haematological toxicity may require dose reduction or suspension or delay of therapy. Temporarily suspend Lipodox 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.


Hepatic Impairment:
Lipodox 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 Lipodox 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. Lipodox 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 Lipodox 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 Lipodox 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 Lipodox Liposomal in patients who have had splenectomy, treatment with Lipodox Liposomal is not recommended.

Paediatric population:
The experience in children is limited. Lipodox 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 Lipodox Liposomal.

Method of administration
Lipodox Liposomal is administered as an intravenous infusion. For further instructions on preparation and special precautions for handling see section 6.6.
Do not administer Lipodox Liposomal as a bolus injection or undiluted solution. It is recommended that the Lipodox 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. Lipodox Liposomal must not be given by the intramuscular or subcutaneous route (see section 6.6).

For doses < 90 mg: dilute Lipodox Liposomal in 250 ml 5% (50 mg/ml) glucose solution for infusion.
For doses ≥ 90 mg: dilute Lipodox 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 Lipodox 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 Lipodox Liposomal is diluted in 250 ml 5% (50 mg/ml) glucose solution for infusion and administered by intravenous infusion over 30 minutes.