Powder for suspension for infusion. The reconstituted suspension has a pH of 67.5 and an osmolality of 300360 mOsm/kg. The powder is white to yellow.

Powder

Abraxane monotherapy is indicated for the treatment of metastatic breast cancer in patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated

Abraxane should only be administered under the supervision of a qualified oncologist in units specialised in the administration of cytotoxic agents.

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

Dose adjustments during treatment:

Patients who experience severe neutropenia (neutrophil count < 0.50 x 109/l 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 >1.5 x 109/l. For grade 3 sensory neuropathy withhold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses.

Patients with hepatic impairment:

Insufficient data are currently available to recommend dose modifications in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment should not be treated with paclitaxel.

Patients with impaired renal function:

Studies in patients with impaired renal function have not been performed and insufficient data are currently available to recommend dose modifications in patients with renal impairment.

Paediatric patients:

Abraxane is not recommended for use in children below age 18 years due to insufficient data on safety and efficacy.

In the clinical studies, no toxicities occurred notably more frequently among elderly patients who received Abraxane.

Hypersensitivity to the active substance or to any of the excipients.

Lactation.

Patients who have baseline neutrophil counts < 1.5 x 109/l.

Abraxane is an albumin-bound nanoparticle formulation of paclitaxel, which may have substantially different pharmacological properties compared to other formulations of paclitaxel.

Hypersensitivity:

If hypersensitivity occurs, the medicinal product should be discontinued immediately, symptomatic treatment should be initiated, and that patient should not be rechallenged with paclitaxel.

Haematology:

Bone marrow suppression (primarily neutropenia) occurs frequently with Abraxane. Neutropenia is dosedependent and a doselimiting toxicity. Frequent monitoring of blood cell counts should be performed during Abraxane therapy. Patients should not be retreated with subsequent cycles of Abraxane until neutrophils recover to >1.5 x 109/l and platelets recover to >100 x 109/l.

Neuropathy:

Sensory neuropathy occurs frequently with Abraxane, although development of severe symptoms is less common. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose reduction. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of Abraxane is recommended.

Hepatic Impairment:

Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression, and such patients should be closely monitored for development of profound myelosuppression. The use of Abraxane has not been formally studied in patients specifically with hepatic impairment. Patients with severe hepatic impairment (bilirubin > 5 x ULN or ASL/ALT > 10 x ULN) should not be treated with Abraxane. The appropriate dose regimen in patients with less severe hepatic impairment is unknown.

Cardiotoxicity:

While cardiotoxicity unequivocally related to Abraxane has not been demonstrated, cardiac events are not uncommon in the indicated population, especially in patients who have previously received anthracyclines or have underlying cardiac or pulmonary disease. Thus patients receiving Abraxane should be vigilantly monitored by physicians for the occurrence of cardiac events.

Sexually active men and women should use effective methods of contraception during treatment and up to six months after treatment for men, and one month after treatment for women.

The effectiveness and safety of Abraxane in patients with central nervous system (CNS) metastases has not been established. CNS metastases are generally not well controlled by systemic chemotherapy.

Gastrointestinal Symptoms:

If patients experience nausea, vomiting and diarrhoea following the administration of Abraxane, they may be treated with commonly used antiemetics and constipating agents.

Excipients:

When reconstituted, Abraxane contains approximately 425 mg sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

No interaction studies have been performed.

The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Therefore, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g. erythromycin, fluoxetine, imidazole antifungals) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) either CYP2C8 or CYP3A4.

Abraxane is indicated for monotherapy. Abraxane should not be used in combination with other anticancer agents

The following are the most common and important incidences of adverse reactions related to 229 patients with metastatic breast cancer who were treated with 260 mg/m2 Abraxane once every three weeks in the pivotal phase III clinical study.

Blood and lymphatic system disorders: Neutropenia was the most notable important haematological toxicity (reported in 79% of patients), and was rapidly reversible and dose dependent; leukopenia was reported in 71% of patients. Grade 4 neutropenia (< 0.5 x 109/l) occurred in 9% of patients treated with Abraxane. Febrile neutropenia occurred in four patients on Abraxane. Anaemia (Hb < 10 g/dl) was observed in 46% of patients on Abraxane, and was severe (Hb < 8 g/dl) in three cases. Lymphopenia was observed in 45% of the patients.

Nervous system disorders: In general, the frequency and severity of neurotoxicity was dosedependent in patients receiving Abraxane. Peripheral neuropathy (mostly Grade 1 or 2 sensory neuropathy) was observed in 68% of patients on Abraxane with 10% being Grade 3, and no cases of Grade 4.

Gastrointestinal disorders: Nausea occurred in 29% of the patients and diarrhoea in 25% of the patients.

Skin and subcutaneous system disorders: Alopecia was observed in 90% of the patients treated with Abraxane.

Musculoskeletal and connective tissue disorders: Arthralgia occurred in 32% of patients on Abraxane and was severe in 6% of cases. Myalgia occurred in 24% of patients on Abraxane and was severe in 7% of cases. The symptoms were usually transient, typically occurred three days after Abraxane administration and resolved within a week.

General disorders and administration site disorders: Asthenia/Fatigue was reported in 40% of the patients.

Table 1 lists adverse reactions associated with the administration of Abraxane to patients from studies in which Abraxane has been administered as a single agent at any dose in any indication (N = 789).

The frequency of undesirable effects listed in table 1 is defined using the following convention:

Very common (1/10); common ( 1/100, <1/10); uncommon (1/1,000, <1/100); rare (1/10,000, <1/1,000); very rare (< 1/10,000).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Adverse reactions reported with Abraxane at any dose in clinical trials.

¹The frequency of hypersensitivity reactions is calculated based on one definitely related case in a population of 789 patients

Postmarketing experience

Cranial nerve palsies, vocal cord paresis, and rare reports of severe hypersensitivity reactions have been reported during postmarketing surveillance of Abraxane.

In some patients previously exposed to capecitabine, reports of palmarplantar erythrodysaesthesiae have been reported as part of the continuing surveillance of Abraxane. Because these events have been reported voluntarily during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established.

Abraxis BioScience Limited

19 March 2009