Posology : מינונים

4.2    Posology and method of administration

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


Posology

Breast cancer
The recommended dose of Abraxane is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.

Dose adjustments during treatment of breast cancer
Patients who experience severe neutropenia (neutrophil count < 500 cells/mm3 for a week or longer) or severe sensory neuropathy during Abraxane therapy should have the dose reduced to 220 mg/m2 for subsequent courses. Following recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. Abraxane should not be administered until neutrophil counts recover to >1500 cells/mm3. For Grade 3 sensory neuropathy, withhold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses.

Pancreatic adenocarcinoma
The recommended dose of Abraxane in combination with gemcitabine is 125 mg/m2 administered intravenously over 30 minutes on Days 1, 8 and 15 of each 28-day cycle. The concurrent recommended dose of gemcitabine is 1000 mg/m2 administered intravenously over 30 minutes immediately after the completion of Abraxane administration on Days 1, 8 and 15 of each 28-day cycle.

Dose adjustments during treatment of pancreatic adenocarcinoma
Table 1: Dose level reductions for patients with pancreatic adenocarcinoma Dose Level                              Abraxane Dose (mg/m2)           Gemcitabine Dose (mg/m2) Full dose                                        125                             1000 1st dose level reduction                         100                              800 2nd dose level reduction                         75                               600
If additional dose reduction
Discontinue treatment            Discontinue treatment required

Table 2: Dose modifications for neutropenia and/or thrombocytopenia at the start of a cycle or within a cycle for patients with pancreatic adenocarcinoma
Cycle         ANC count                     Platelet count           Abraxane          Gemcitabine Day           (cells/mm3)                    (cells/mm3)               Dose               Dose Day 1     < 1500                 OR    < 100,000                      Delay doses until recovery Day 8     ≥ 500 but < 1000       OR    ≥ 50,000 but < 75,000          Reduce doses 1 dose level < 500                  OR    < 50,000                            Withhold doses Day 15: If Day 8 doses were given without modification:
Treat with Day 8 dose level and follow with WBC Growth Factors
Day 15    ≥ 500 but < 1000       OR    ≥ 50,000 but < 75,000                    OR Reduce doses 1 dose level from
Day 8 doses
< 500                  OR    < 50,000                            Withhold doses Day 15: If Day 8 doses were reduced:
Return to the Day 1 dose levels and
Day 15    ≥ 1000                 AND   ≥ 75,000                   follow with WBC Growth Factors OR
Treat with same doses as Day 8
Treat with Day 8 dose levels and follow with WBC Growth Factors
≥ 500 but < 1000        OR     ≥ 50,000 but < 75,000                    OR Reduce doses 1 dose level from
Day 8 doses
< 500                   OR     < 50,000                           Withhold doses Day 15: IF Day 8 doses were withheld:
Return to Day 1 dose levels and follow with WBC Growth Factors
Day 15    ≥ 1000                 AND     ≥ 75,000                                OR Reduce doses 1 dose level from
Day 1 doses
Reduce 1 dose level and follow with WBC Growth Factors
≥ 500 but < 1000        OR     ≥ 50,000 but < 75,000                  OR Reduce doses 2 dose levels from
Day 1 doses
< 500                   OR     < 50,000                           Withhold doses Abbreviations: ANC=Absolute Neutrophil Count; WBC=white blood cell

Table 3: Dose modifications for other adverse drug reactions in patients with pancreatic adenocarcinoma
Adverse Drug Reaction
Abraxane Dose                    Gemcitabine Dose
(ADR)
Febrile Neutropenia:          Withhold doses until fever resolves and ANC ≥ 1500; resume at next Grade 3 or 4                                     lower dose levela
Withhold dose until improves to
Peripheral Neuropathy:
≤ Grade 1;                     Treat with same dose
Grade 3 or 4 resume at next lower dose levela
Cutaneous Toxicity:                            Reduce to next lower dose levela; Grade 2 or 3                            discontinue treatment if ADR persists Gastrointestinal
Toxicity:                        Withhold doses until improves to ≤ Grade 1; Grade 3 mucositis or                       resume at next lower dose levela diarrhoea a
See Table 1 for dose level reductions

Non-small cell lung cancer:
The recommended dose of Abraxane is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8 and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC = 6 mg•min/mL on Day 1 only of each 21-day cycle, beginning immediately after the end of Abraxane administration.

Dose adjustments during treatment of non-small cell lung cancer:
Abraxane should not be administered on Day 1 of a cycle until absolute neutrophil count (ANC) is ≥1500 cells/mm3 and platelet count is ≥100,000 cells/mm3. For each subsequent weekly dose of Abraxane, patients must have an ANC ≥500 cells/mm3 and platelets >50,000 cells/mm3 or the dose is to be withheld until counts recover. When counts recover, resume dosing the following week according to the criteria in Table 4. Reduce subsequent dose only if criteria in Table 4 are met.
Table 4: Dose reductions for haematologic toxicities in patients with non-small cell lung cancer Haematologic Toxicity                       Occurrence Dose of Abraxane Dose of carboplatin (mg/m2)1         (AUC mg•min/mL)1
3
Nadir ANC <500/mm with neutropenic              First              75                      4.5 fever > 38°C
OR                         Second               50                      3.0 Delay of next cycle due to persistent neutropenia2 (Nadir ANC <1500/mm3)
OR                          Third                 Discontinue Treatment 3
Nadir ANC <500/mm for > 1 week
First              75                      4.5
Nadir platelets <50,000/mm3
Second                 Discontinue Treatment
1
On Day 1 of the 21-day cycle reduce the dose of Abraxane and carboplatin simultaneously. On Days 8 or 15 of the 21-day cycle reduce the dose of Abraxane; reduce the dose of carboplatin in the subsequent cycle.
2
Maximum of 7 days post scheduled Day 1 dose of next cycle.

For Grade 2 or 3 cutaneous toxicity, Grade 3 diarrhoea, or Grade 3 mucositis, interrupt treatment until the toxicity improves to ≤ Grade 1, then restart treatment according to the guidelines in Table 5. For ≥ Grade 3 peripheral neuropathy, withhold treatment until resolution to ≤ Grade 1. Treatment may be resumed at the next lower dose level in subsequent cycles according to the guidelines in Table 5. For any other Grade 3 or 4 non-haematologic toxicity, interrupt treatment until the toxicity improves to ≤ Grade 2, then restart treatment according to the guidelines in Table 5.
Table 5: Dose reductions for non-haematologic toxicities in patients with non-small cell lung cancer Non-haematologic Toxicity                   Occurrence Dose of Abraxane Dose of carboplatin (mg/m2)1         (AUC mg•min/mL)1
Grade 2 or 3 cutaneous toxicity                 First              75                      4.5 Grade 3 diarrhoea
Grade 3 mucositis                             Second               50                      3.0 ≥ Grade 3 peripheral neuropathy
Third                 Discontinue Treatment
Any other Grade 3 or 4 non- haematologic toxicity
Grade 4 cutaneous toxicity, diarrhoea, or       First                Discontinue Treatment mucositis
1
On Day 1 of the 21-day cycle reduce the dose of Abraxane and carboplatin simultaneously. On Days 8 or 15 of the 21-day cycle reduce the dose of Abraxane; reduce the dose of carboplatin in the subsequent cycle.


Special populations

Hepatic impairment
For patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x ULN and aspartate aminotransferase [AST] ≤ 10 x ULN), no dose adjustments are required, regardless of indication. Treat with same doses as patients with normal hepatic function.

For metastatic breast cancer patients and non-small cell lung cancer patients with moderate to severe hepatic impairment (total bilirubin > 1.5 to ≤ 5 x ULN and AST ≤ 10 x 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 metastatic adenocarcinoma of the pancreas that have moderate to severe hepatic impairment, there are insufficient data to permit dosage recommendations (see sections 4.4 and 5.2).

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

Renal impairment
Adjustment of the starting Abraxane dose is not required for patients with mild to moderate renal impairment (estimated creatinine clearance ≥30 to <90 ml/min). There are insufficient data available to recommend dose modifications of Abraxane in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 ml/min) (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 229 patients in the randomized study who received Abraxane monotherapy for breast cancer, 13% were at least 65 years of age and < 2% were 75 years and older. No toxicities occurred notably more frequently among patients at least 65 years of age who received Abraxane. However, a subsequent analysis in 981 patients receiving Abraxane monotherapy for metastatic breast cancer, of which 15% were ≥ 65 years old and 2% were ≥ 75 years old, showed a higher incidence of epistaxis, diarrhoea, dehydration, fatigue and peripheral oedema in patients ≥ 65 years.

Of the 421 patients with pancreatic adenocarcinoma in the randomized study who received Abraxane in combination with gemcitabine, 41% were 65 years and older and 10% were 75 years and older. In patients aged 75 years and older who received Abraxane and gemcitabine, there was a higher incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation (see section 4.4). Patients with pancreatic adenocarcinoma aged 75 years and older should be carefully assessed before treatment is considered (see section 4.4).

Of the 514 patients with non-small cell lung cancer in the randomized study who received Abraxane in combination with carboplatin, 31% were 65 years or older and 3.5% were 75 years or older.
Myelosuppression events, peripheral neuropathy events, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years of age. There is limited experience of Abraxane/carboplatin use in patients 75 years or older.

Pharmacokinetic/pharmacodynamic modelling using data from 125 patients with advanced solid tumours indicates that patients ≥ 65 years of age may be more susceptible to development of neutropenia within the first treatment cycle.

Paediatric population
Abraxane is not indicated for children and adolescents under 18 years old.
The safety and efficacy of Abraxane in children and adolescents aged 0 to less than 18 years has not been established. There is no relevant use of Abraxane in the paediatric population for the indication of metastatic breast cancer or pancreatic adenocarcinoma or non-small cell lung cancer.

Method of administration
Administer reconstituted Abraxane dispersion intravenously using an infusion set incorporating a 15 µm filter. Following administration, it is recommended that the intravenous line be flushed with sodium chloride 9 mg/ml (0.9%) solution for injection to ensure administration of the complete dose.


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