ABRAXANE 5mg / ml powder for infusion suspension medication leaflet

Abraxane 5 mg/ml powder for dispersion for infusion.

Each vial contains 100 mg of paclitaxel formulated as albumin bound nanoparticles.

Each vial contains 250 mg of paclitaxel formulated as albumin bound nanoparticles.

After reconstitution, each ml of dispersion contains 5 mg of paclitaxel formulated as albumin boundnanoparticles.

For the full list of excipients, see section 6.1.

Powder for dispersion for infusion.

The reconstituted dispersion has a pH of 6-7.5 and an osmolality of 300-360 mOsm/kg.

The powder is white to yellow.

Abraxane monotherapy is indicated for the treatment of metastatic breast cancer in adult patients whohave failed first-line treatment for metastatic disease and for whom standard, anthracycline containingtherapy is not indicated (see section 4.4).

Abraxane in combination with gemcitabine is indicated for the first-line treatment of adult patients withmetastatic adenocarcinoma of the pancreas.

Abraxane in combination with carboplatin is indicated for the first-line treatment of non-small cell lungcancer in adult patients who are not candidates for potentially curative surgery and/or radiation therapy.

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

Breast cancer

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

Dose adjustments during treatment of breast cancer

Patients who experience severe neutropenia (neutrophil count < 500 cells/mm3 for a week or longer) orsevere sensory neuropathy during Abraxane therapy should have the dose reduced to 220 mg/m2 forsubsequent courses. Following recurrence of severe neutropenia or severe sensory neuropathy, additionaldose reduction should be made to 180 mg/m2. Abraxane should not be administered until neutrophilcounts recover to >1500 cells/mm3. For Grade 3 sensory neuropathy, withhold treatment until resolutionto 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 administeredintravenously over 30 minutes on Days 1, 8 and 15 of each 28-day cycle. The concurrent recommendeddose of gemcitabine is 1000 mg/m2 administered intravenously over 30 minutes immediately after thecompletion 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 10001st dose level reduction 100 8002nd dose level reduction 75 600

If additional dose reductionrequired Discontinue treatment Discontinue treatment

Table 2: Dose modifications for neutropenia and/or thrombocytopenia at the start of a cycle orwithin 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 andfollow 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 andfollow with WBC Growth Factors

Day 15 ≥ 1000 AND ≥ 75,000 OR

Treat with same doses as Day 8

Treat with Day 8 dose levels andfollow 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 andfollow 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 followwith 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 pancreaticadenocarcinoma

Adverse Drug Reaction(ADR) Abraxane Dose Gemcitabine Dose

Febrile Neutropenia: Withhold doses until fever resolves and ANC ≥ 1500; resume at next

Grade 3 or 4 lower dose levela

Peripheral Neuropathy: Withhold dose until improves to≤ 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 leveladiarrhoea

a. See Table 1 for dose level reductions

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

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 ≥1500cells/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 withhelduntil 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

Nadir ANC <500/mm3 with neutropenic First 75 4.5fever > 38°C

OR Second 50 3.0

Delay of next cycle due to persistentneutropenia2 (Nadir ANC <1500/mm3)

OR Third Discontinue Treatment

Nadir ANC <500/mm3 for > 1 week

First 75 4.5

Nadir platelets <50,000/mm3 Second Discontinue Treatment1On 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 doseof Abraxane; reduce the dose of carboplatin in the subsequent cycle.2Maximum 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 thetoxicity improves to ≤ Grade 1, then restart treatment according to the guidelines in Table 5. For ≥ Grade3 peripheral neuropathy, withhold treatment until resolution to ≤ Grade 1. Treatment may be resumed atthe next lower dose level in subsequent cycles according to the guidelines in Table 5. For any other Grade3 or 4 non-haematologic toxicity, interrupt treatment until the toxicity improves to ≤ Grade 2, then restarttreatment 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

Any other Grade 3 or 4 non- Third Discontinue Treatmenthaematologic toxicity

Grade 4 cutaneous toxicity, diarrhoea, or First Discontinue Treatmentmucositis1On 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 doseof Abraxane; reduce the dose of carboplatin in the subsequent cycle.

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

For metastatic breast cancer patients and non-small cell lung cancer patients with moderate to severehepatic impairment (total bilirubin > 1.5 to ≤ 5 x ULN and AST ≤ 10 x ULN), a 20% reduction in dose isrecommended. The reduced dose may be escalated to the dose for patients with normal hepatic function ifthe 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 hepaticimpairment, 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 permitdosage recommendations regardless of indication (see sections 4.4 and 5.2).

Adjustment of the starting Abraxane dose is not required for patients with mild to moderate renalimpairment (estimated creatinine clearance ≥30 to <90 ml/min). There are insufficient data available torecommend dose modifications of Abraxane in patients with severe renal impairment or end stage renaldisease (estimated creatinine clearance <30 ml/min) (see section 5.2).

No additional dosage reductions, other than those for all patients, are recommended for patients 65 yearsand 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 morefrequently among patients at least 65 years of age who received Abraxane. However, a subsequentanalysis 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 incombination with gemcitabine, 41% were 65 years and older and 10% were 75 years and older. In patientsaged 75 years and older who received Abraxane and gemcitabine, there was a higher incidence of seriousadverse reactions and adverse reactions that led to treatment discontinuation (see section 4.4). Patientswith pancreatic adenocarcinoma aged 75 years and older should be carefully assessed before treatment isconsidered (see section 4.4).

Of the 514 patients with non-small cell lung cancer in the randomized study who received Abraxane incombination 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 65years 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 tumoursindicates that patients ≥ 65 years of age may be more susceptible to development of neutropenia within thefirst treatment cycle.

The safety and efficacy of Abraxane in children and adolescents aged 0 to less than 18 years has not beenestablished. Currently available data are described in section s 4.8, 5.1 and 5.2 but no recommendation ona posology can be made. There is no relevant use of Abraxane in the paediatric population for theindication of metastatic breast cancer or pancreatic adenocarcinoma or non-small cell lung cancer.

Administer reconstituted Abraxane dispersion intravenously using an infusion set incorporating a 15 µmfilter. Following administration, it is recommended that the intravenous line be flushed with sodiumchloride 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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Lactation (see section 4.6).

Patients who have baseline neutrophil counts < 1500 cells/mm3.

Abraxane is an albumin-bound nanoparticle formulation of paclitaxel, which may have substantiallydifferent pharmacological properties compared to other formulations of paclitaxel (see sections 5.1 and5.2). It should not be substituted for or with other paclitaxel formulations.

Rare occurrences of severe hypersensitivity reactions, including very rare events of anaphylactic reactionswith fatal outcome, have been reported. If a hypersensitivity reaction occurs, the medicinal product shouldbe discontinued immediately, symptomatic treatment should be initiated, and the patient should not berechallenged with paclitaxel.

Bone marrow suppression (primarily neutropenia) occurs frequently with Abraxane. Neutropenia isdose-dependent and a dose-limiting toxicity. Frequent monitoring of blood cell counts should beperformed during Abraxane therapy. Patients should not be retreated with subsequent cycles of Abraxaneuntil neutrophils recover to >1500 cells/mm3 and platelets recover to >100,000 cells/mm3 (see section4.2).

Neuropathy

Sensory neuropathy occurs frequently with Abraxane, although development of severe symptoms is lesscommon. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose reduction.

When Abraxane is used as monotherapy, if Grade 3 sensory neuropathy develops, treatment should bewithheld until resolution to Grade 1 or 2 followed by a dose reduction for all subsequent courses of

Abraxane is recommended (see section 4.2). For combination use of Abraxane and gemcitabine, if Grade3 or higher peripheral neuropathy develops, withhold Abraxane; continue treatment with gemcitabine atthe same dose. Resume Abraxane at reduced dose when peripheral neuropathy improves to Grade 0 or 1(see section 4.2). For combination use of Abraxane and carboplatin, if Grade 3 or higher peripheralneuropathy develops, treatment should be withheld until improvement to Grade 0 or 1 followed by a dosereduction for all subsequent courses of Abraxane and carboplatin (see section 4.2).

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane incombination with gemcitabine. Complications due to the underlying pancreatic cancer, especially biliaryobstruction or presence of biliary stent, were identified as significant contributing factors. If a patientbecomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. Forfebrile neutropenia, withhold Abraxane and gemcitabine until fever resolves and ANC ≥ 1500 cells/mm3,then resume treatment at reduced dose levels (see section 4.2).

Pneumonitis

Pneumonitis occurred in 1% of patients when Abraxane was used as monotherapy and in 4% of patientswhen Abraxane was used in combination with gemcitabine. Closely monitor all patients for signs andsymptoms of pneumonitis. After ruling out infectious etiology and upon making a diagnosis ofpneumonitis, permanently discontinue treatment with Abraxane and gemcitabine and promptly initiateappropriate treatment and supportive measures (see section 4.2).

Because the toxicity of paclitaxel can be increased with hepatic impairment, administration of Abraxane inpatients with hepatic impairment should be performed with caution. Patients with hepatic impairment maybe at increased risk of toxicity, particularly from myelosuppression; such patients should be closelymonitored for development of profound myelosuppression.

Abraxane is not recommended in patients that have total bilirubin > 5 x ULN or AST > 10 x ULN. Inaddition, Abraxane is not recommended in patients with metastatic adenocarcinoma of the pancreas thathave moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and AST ≤ 10 x ULN) (seesection 5.2).

Rare reports of congestive heart failure and left ventricular dysfunction have been observed amongindividuals receiving Abraxane. Most of the individuals were previously exposed to cardiotoxic medicinalproducts such as anthracyclines or had underlying cardiac history. Thus, patients receiving Abraxaneshould be vigilantly monitored by physicians for the occurrence of cardiac events.

CNS metastases

The effectiveness and safety of Abraxane in patients with central nervous system (CNS) metastases hasnot 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 maybe treated with commonly used anti-emetics and constipating agents.

Cystoid macular oedema (CMO) has been reported in patients treated with Abraxane. Patients withimpaired vision should undergo a prompt and complete ophthalmologic examination. In case CMO isdiagnosed, Abraxane treatment should be discontinued and appropriate treatment initiated (seesection 4.8).

Patients 75 years and older

For patients of 75 years and older, no benefit for the combination treatment of Abraxane and gemcitabinein comparison to gemcitabine monotherapy has been demonstrated. In the very elderly (≥ 75 years) whoreceived Abraxane and gemcitabine, there was a higher incidence of serious adverse reactions and adversereactions that led to treatment discontinuation including haematologic toxicities, peripheral neuropathy,decreased appetite and dehydration. Patients with pancreatic adenocarcinoma aged 75 years and oldershould be carefully assessed for their ability to tolerate Abraxane in combination with gemcitabine withspecial consideration to performance status, co-morbidities and increased risk of infections (see section4.2 and 4.8).

Although limited data is available, no clear benefit in terms of prolonged overall survival has beendemonstrated in pancreatic adenocarcinoma patients with normal CA 19-9 levels prior to start of treatmentwith Abraxane and gemcitabine (see section 5.1).

Erlotinib should not be co-administered with Abraxane plus gemcitabine (see section 4.5).

This medicine contains less than 1 mmol sodium (23 mg) per 100 mg, that is to say essentially ‘sodiumfree’.

The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and

CYP3A4 (see section 5.2). Therefore, in the absence of a PK drug-drug interaction study, caution shouldbe exercised when administering paclitaxel concomitantly with medicines known to inhibit either

CYP2C8 or CYP3A4 (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine,gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity ofpaclitaxel may be increased due to higher paclitaxel exposure. Administering paclitaxel concomitantlywith medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin,efavirenz, nevirapine) is not recommended because efficacy may be compromised because of lowerpaclitaxel exposures.

Paclitaxel and gemcitabine do not share a common metabolic pathway. Paclitaxel clearance is primarilydetermined by CYP2C8 and CYP3A4 mediated metabolism followed by biliary excretion, whilegemcitabine is inactivated by cytidine deaminase followed by urinary excretion. Pharmacokineticinteractions between Abraxane and gemcitabine have not been evaluated in humans.

A pharmacokinetic study was conducted with Abraxane and carboplatin in non-small cell lung cancerpatients. There were no clinically relevant pharmacokinetic interactions between Abraxane andcarboplatin.

Abraxane is indicated as monotherapy for breast cancer, in combination with gemcitabine for pancreaticadenocarcinoma, or in combination with carboplatin for non-small cell lung cancer (see section 4.1).

Abraxane should not be used in combination with other anticancer agents.

Interaction studies have only been performed in adults.

Women of childbearing potential should use effective contraception during treatment and up to 1 monthafter receiving treatment with Abraxane. Male patients treated with Abraxane are advised to use effectivecontraception and to avoid fathering a child during and up to six months after treatment.

There are very limited data on the use of paclitaxel in human pregnancy. Paclitaxel is suspected to causeserious birth defects when administered during pregnancy. Studies in animals have shown reproductivetoxicity (see section 5.3). Women of childbearing potential should have a pregnancy test prior to startingtreatment with Abraxane. Abraxane should not be used in pregnancy, and in women of childbearingpotential not using effective contraception, unless the clinical condition of the mother requires treatmentwith paclitaxel.

Paclitaxel and/or its metabolites were excreted into the milk of lactating rats (see section 5.3). It is notknown if paclitaxel is excreted in human milk. Because of potential serious adverse reactions inbreast-feeding infants, Abraxane is contraindicated during lactation. Breast-feeding must be discontinuedfor the duration of therapy.

Abraxane induced infertility in male rats (see section 5.3). Based on findings in animals, male and femalefertility may be compromised. Male patients should seek advice on conservation of sperm prior totreatment because of the possibility of irreversible infertility due to therapy with Abraxane.

Abraxane has minor or moderate influence on the ability to drive and use machines. Abraxane may causeadverse reactions such as tiredness (very common) and dizziness (common) that may affect the ability todrive and use machinery. Patients should be advised not to drive and use machines if they feel tired ordizzy.

The most common clinically significant adverse reactions associated with the use of Abraxane have beenneutropenia, peripheral neuropathy, arthralgia/myalgia and gastrointestinal disorders.

Table 6 lists adverse reactions associated with Abraxane monotherapy at any dose in any indication duringclinical trials (N = 789), Abraxane in combination with gemcitabine for pancreatic adenocarcinoma fromthe phase III clinical trial (N = 421), Abraxane in combination with carboplatin for non-small cell lungcancer from the phase III clinical trial (N = 514) and from post-marketing use.

Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from theavailable data). Within each frequency grouping, adverse reactions are presented in order of decreasingseriousness.

Table 6: Adverse reactions reported with Abraxane

Monotherapy (N=789) Combination therapy Combination therapywith gemcitabine with carboplatin(N =421) (N = 514)

Infection, urinary tract infection, Sepsis, pneumonia, oral Pneumonia, bronchitis,

Common: folliculitis, upper respiratory tract candidiasis upper respiratory tractinfection, candidiasis, sinusitis infection, urinary tractinfection

Sepsis1, neutropenic sepsis1, Sepsis, oral candidiasispneumonia, oral candidiasis,nasopharyngitis, cellulitis, herpes

Uncommon: simplex, viral infection, herpeszoster, fungal infection,catheter-related infection, injectionsite infection

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon: Tumour necrosis, metastatic pain

Very Bone marrow suppression, Neutropenia, Neutropenia ,common: neutropenia, thrombocytopenia, thrombocytopenia, thrombocytopenia3,anaemia, leukopenia, lymphopenia anaemia anaemia3, leukopenia3

Common: Febrile neutropenia Pancytopenia Febrile neutropenia,lymphopenia

Thrombotic Pancytopenia

Uncommon: thrombocytopenicpurpura

Rare: Pancytopenia

Monotherapy (N=789) Combination therapy Combination therapywith gemcitabine with carboplatin(N =421) (N = 514)

Uncommon: Hypersensitivity Drug hypersensitivity,hypersensitivity

Rare: Severe hypersensitivity1

Very Anorexia Dehydration, decreased Decreased appetitecommon: appetite, hypokalaemia

Common: Dehydration, decreased appetite, Dehydrationhypokalaemia

Hypophosphataemia, fluid retention,

Uncommon: hypoalbuminaemia, polydipsia,hyperglycaemia, hypocalcaemia,hypoglycaemia, hyponatraemia

Not known: Tumour lysis syndrome1

Very Depression, insomniacommon:

Common: Depression, insomnia, anxiety Anxiety Insomnia

Uncommon: Restlessness

Very Peripheral neuropathy, neuropathy, Peripheral neuropathy, Peripheral neuropathycommon: hypoaesthesia, paraesthesia dizziness, headache,dysgeusia

Peripheral sensory neuropathy, Dizziness, headache,dizziness, peripheral motor dysgeusia

Common: neuropathy, ataxia, headache,sensory disturbance, somnolence,dysgeusia

Polyneuropathy, areflexia, syncope, VIIth nerve paralysis

Uncommon: postural dizziness, dyskinesia,hyporeflexia, neuralgia, neuropathicpain, tremor, sensory loss

Not known: Cranial nerve palsies multiple 1

Vision blurred, lacrimation Lacrimation increased Vision blurred

Common: increased, dry eye,keratoconjunctivitis sicca, madarosis

Reduced visual acuity, abnormal Cystoid macular

Uncommon: vision, eye irritation, eye pain, oedemaconjunctivitis, visual disturbance,eye pruritus, keratitis

Rare: Cystoid macular oedema1

Ear and labyrinth disorders

Common: Vertigo

Uncommon: Tinnitus, ear pain

Common: Arrhythmia, tachycardia, Cardiac failuresupraventricular tachycardia congestive, tachycardia

Monotherapy (N=789) Combination therapy Combination therapywith gemcitabine with carboplatin(N =421) (N = 514)

Cardiac arrest, cardiac failure

Rare: congestive, left ventriculardysfunction, atrioventricular block1,bradycardia

Common: Hypertension, lymphoedema, Hypotension, Hypotension,flushing, hot flushes hypertension hypertension

Uncommon: Hypotension, orthostatic Flushing Flushinghypotension, peripheral coldness

Rare: Thrombosis

Very Dyspnoea, epistaxis, Dyspnoeacommon: cough

Interstitial pneumonitis2, dyspnoea, Pneumonitis, nasal Haemoptysis, epistaxis,

Common: epistaxis, pharyngolaryngeal pain, congestion coughcough, rhinitis, rhinorrhoea

Pulmonary emboli, pulmonary Dry throat, nasal Pneumonitisthromboembolism, pleural effusion, drynessexertional dyspnoea, sinus

Uncommon: congestion, decreased breath sounds,productive cough, allergic rhinitis,hoarseness, nasal congestion, nasaldryness, wheezing

Not known: Vocal cord paresis1

Diarrhoea, vomiting, nausea, Diarrhoea, vomiting, Diarrhoea, vomiting,

Very constipation, stomatitis nausea, constipation, nausea, constipationcommon: abdominal pain,abdominal pain upper

Gastrooesophageal reflux disease, Intestinal obstruction, Stomatitis, dyspepsia,

Common: dyspepsia, abdominal pain, colitis, stomatitis, dry dysphagia, abdominalabdominal distension, abdominal mouth painpain upper, oral hypoaesthesia

Rectal haemorrhage, dysphagia,flatulence, glossodynia, dry mouth,

Uncommon: gingival pain, loose stools,oesophagitis, abdominal pain lower,mouth ulceration, oral pain

Common: Cholangitis Hyperbilirubinaemia

Uncommon: Hepatomegaly

Very Alopecia, rash Alopecia, rash Alopecia, rashcommon:

Pruritus, dry skin, nail disorder, Pruritus, dry skin, nail Pruritus, nail disordererythema, nail disorder

Common: pigmentation/discolouration, skinhyperpigmentation, onycholysis, nailchanges

Monotherapy (N=789) Combination therapy Combination therapywith gemcitabine with carboplatin(N =421) (N = 514)

Photosensitivity reaction, urticaria, Skin exfoliation,skin pain, generalised pruritus, dermatitis allergic,pruritic rash, skin disorder, urticariapigmentation disorder,hyperhidrosis, onychomadesis,

Uncommon: erythematous rash, generalised rash,dermatitis, night sweats,maculo-papular rash, vitiligo,hypotrichosis, nail bed tenderness,nail discomfort, macular rash,papular rash, skin lesion, swollenface

Very rare: Stevens-Johnson syndrome1, toxicepidermal necrolysis1

Not known: Palmar-plantar erythrodysaesthesiaesyndrome1, 4, scleroderma1

Very Arthralgia, myalgia Arthralgia, myalgia, Arthralgia, myalgiacommon: pain in extremity

Back pain, pain in extremity, bone Muscular weakness, Back pain, pain in

Common: pain, muscle cramps, limb pain bone pain extremity,musculoskeletal pain

Chest wall pain, muscular weakness,neck pain, groin pain, muscle

Uncommon: spasms, musculoskeletal pain, flankpain, limb discomfort, muscleweakness

Common: Acute renal failure

Haematuria, dysuria, pollakiuria, Haemolytic uraemic

Uncommon: nocturia, polyuria, urinary syndromeincontinence

Uncommon: Breast pain

Very Fatigue, asthenia, pyrexia Fatigue, asthenia, Fatigue, asthenia,common: pyrexia, oedema oedema peripheralperipheral, chills

Malaise, lethargy, weakness, Infusion site reaction Pyrexia, chest painperipheral oedema, mucosal

Common: inflammation, pain, rigors, oedema,decreased performance status, chestpain, influenza-like illness,hyperpyrexia

Chest discomfort, abnormal gait, Mucosal inflammation,swelling, injection site reaction infusion site

Uncommon: extravasation, infusionsite inflammation,infusion site rash

Monotherapy (N=789) Combination therapy Combination therapywith gemcitabine with carboplatin(N =421) (N = 514)

Rare: Extravasation

Weight decreased,

Very alaninecommon: aminotransferaseincreased

Decreased weight, increased alanine Aspartate Weight decreased,aminotransferase, increased aspartate aminotransferase alanineaminotransferase, decreased increased, blood aminotransferase

Common: haematocrit, decreased red blood cell bilirubin increased, increased, aspartatecount, increased body temperature, blood creatinine aminotransferaseincreased increased increased, bloodgamma-glutamyltransferase, alkaline phosphataseincreased blood alkaline phosphatase increased

Increased blood pressure, increasedweight, increased blood lactatedehydrogenase, increased blood

Uncommon: creatinine, increased blood glucose,increased blood phosphorus,decreased blood potassium,increased bilirubin

Uncommon: Contusion

Rare: Radiation recall phenomenon,radiation pneumonitis1 As reported in the post-marketing surveillance of Abraxane.2 The frequency of pneumonitis is calculated based on pooled data in 1310 patients in clinical trials receiving Abraxane monotherapy for breastcancer and for other indications.3 Based on laboratory assessments: maximal degree of myelosuppression (treated population).4 In some patients previously exposed to capecitabine.

This section contains the most common and clinically relevant adverse reactions related to Abraxane.

Adverse reactions were assessed in 229 patients with metastatic breast cancer who were treated with260 mg/m2 Abraxane once every three weeks in the pivotal phase III clinical study (Abraxanemonotherapy).

Adverse reactions were assessed in 421 patients with metastatic pancreatic cancer who were treated with

Abraxane in combination with gemcitabine (125 mg/m2 Abraxane in combination with gemcitabine at adose of 1000 mg/m2 given on Days 1, 8 and 15 of each 28-day cycle) and 402 gemcitabinemonotherapy-treated patients receiving first-line systemic treatment for metastatic adenocarcinoma of thepancreas (Abraxane/gemcitabine).

Adverse reactions were assessed in 514 patients with non-small cell lung cancer who were treated with

Abraxane in combination with carboplatin (100mg/m2 Abraxane given on Days 1, 8 and 15 of each 21-daycycle in combination with carboplatin given on Day 1 of each cycle) in the phase III randomized,controlled clinical trial (Abraxane/carboplatin). Patient-reported taxane toxicity was assessed using the 4subscales of the Functional Assessment of Cancer Therapy (FACT)-Taxane questionnaire. Using repeatedmeasure analysis, 3 of the 4 subscales (peripheral neuropathy, pain hands/feet and hearing) favored

Abraxane and carboplatin (p ≤ 0.002). For the other subscale (oedema), there was no difference in thetreatment arms.

Abraxane/gemcitabine

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane incombination with gemcitabine during the conduct of a trial in pancreatic adenocarcinoma. Of the 22 casesof sepsis reported in patients treated with Abraxane in combination with gemcitabine, 5 had a fataloutcome. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presenceof biliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardlessof neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold

Abraxane and gemcitabine until fever resolves and ANC ≥ 1500 cells/mm3, then resume treatment atreduced dose levels (see section 4.2).

Abraxane monotherapy-metastatic breast cancer

In patients with metastatic breast cancer, neutropenia was the most notable important haematologicaltoxicity (reported in 79% of patients) and was rapidly reversible and dose-dependent; leukopenia wasreported in 71% of patients. Grade 4 neutropenia (< 500 cells/mm3) occurred in 9% of patients treatedwith Abraxane. Febrile neutropenia occurred in four patients on Abraxane. Anaemia (Hb < 10 g/dl) wasobserved in 46% of patients on Abraxane and was severe (Hb < 8 g/dl) in three cases. Lymphopenia wasobserved in 45% of the patients.

Abraxane/gemcitabine

Table 7 provides the frequency and severity of haematologic laboratory-detected abnormalities forpatients treated with Abraxane in combination with gemcitabine or with gemcitabine.

Table 7: Haematologic laboratory-detected abnormalities in pancreatic adenocarcinoma trial

Abraxane (125 mg/m2)/

Gemcitabine Gemcitabine

Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4(%) (%) (%) (%)

Anaemiaa,b 97 13 96 12

Neutropenia a,b 73 38 58 27

Thrombocytopeniab,c 74 13 70 9a 405 patients assessed in Abraxane/gemcitabine-treated groupb 388 patients assessed in gemcitabine-treated groupc 404 patients assessed in Abraxane/gemcitabine-treated group

Abraxane/carboplatin

Anaemia and thrombocytopenia were more commonly reported in the Abraxane and carboplatin arm thanin the Taxol and carboplatin arm (54% versus 28% and 45% versus 27% respectively).

Abraxane monotherapy-metastatic breast cancer

In general, the frequency and severity of neurotoxicity was dose-dependent in patients receiving

Abraxane. Peripheral neuropathy (mostly Grade 1 or 2 sensory neuropathy) was observed in 68% ofpatients on Abraxane with 10% being Grade 3, and no cases of Grade 4.

Abraxane/gemcitabine

For patients treated with Abraxane in combination with gemcitabine, the median time to first occurrenceof Grade 3 peripheral neuropathy was 140 days. The median time to improvement by at least 1 grade was21 days, and the median time to improvement from Grade 3 peripheral neuropathy to Grade 0 or 1 was 29days. Of the patients with treatment interrupted due to peripheral neuropathy, 44% (31/70 patients) wereable to resume Abraxane at a reduced dose. No patients treated with Abraxane in combination withgemcitabine had Grade 4 peripheral neuropathy.

Abraxane/carboplatin

For non-small cell lung cancer patients treated with Abraxane and carboplatin, the median time to firstoccurrence of Grade 3 treatment-related peripheral neuropathy was 121 days, and the median time toimprovement from Grade 3 treatment related peripheral neuropathy to Grade 1 was 38 days. No patientstreated with Abraxane and carboplatin experienced Grade 4 peripheral neuropathy.

There have been rare reports during post-marketing surveillance of reduced visual acuity due to cystoidmacular oedema during treatment with Abraxane (see section 4.4).

Abraxane/gemcitabine

Pneumonitis has been reported at a rate of 4% with the use of Abraxane in combination with gemcitabine.

Of the 17 cases of pneumonitis reported in patients treated with Abraxane in combination withgemcitabine, 2 had a fatal outcome. Monitor patients closely for signs and symptoms of pneumonitis.

After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinuetreatment with Abraxane and gemcitabine and promptly initiate appropriate treatment and supportivemeasures (see section 4.2).

Abraxane monotherapy-metastatic breast cancer

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

Abraxane monotherapy-metastatic breast cancer

Alopecia was observed in >80% of the patients treated with Abraxane. The majority of alopecia eventsoccurred less than one month after initiation of Abraxane. Pronounced hair loss ≥ 50% is expected for themajority of patients who experience alopecia.

Abraxane monotherapy-metastatic breast cancer

Arthralgia occurred in 32% of patients on Abraxane and was severe in 6% of cases. Myalgia occurred in24% 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.

Abraxane monotherapy-metastatic breast cancer

Asthenia/Fatigue was reported in 40% of the patients.

The study consisted of 106 patients, 104 of whom were paediatric patients aged from 6 months to less than18 years (see section 5.1). Every patient experienced at least 1 adverse reaction. The most frequentlyreported adverse reactions were neutropenia, anaemia, leukopenia and pyrexia. Serious adverse reactionsreported in more than 2 patients were pyrexia, back pain, peripheral oedema and vomiting. No new safetysignals were identified in the limited number of paediatric patients treated with Abraxane and the safetyprofile was similar to that of the adult population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

There is no known antidote for paclitaxel overdose. In the event of an overdose, the patient should beclosely monitored. Treatment should be directed at the major anticipated toxicities, which are bonemarrow suppression, mucositis and peripheral neuropathy.

Pharmacotherapeutic group: Antineoplastic agents, plant alkaloids and other natural products, taxanes,

ATC Code: L01CD01

Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers andstabilises microtubules by preventing depolymerisation. This stability results in the inhibition of thenormal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitoticcellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubulesthroughout the cell cycle and multiple asters of microtubules during mitosis.

Abraxane contains human serum albumin-paclitaxel nanoparticles of approximately 130 nm in size, wherethe paclitaxel is present in a non-crystalline, amorphous state. Upon intravenous administration, thenanoparticles dissociate rapidly into soluble, albumin bound paclitaxel complexes of approximately 10 nmin size. Albumin is known to mediate endothelial caveolar transcytosis of plasma constituents, and in vitrostudies demonstrated that the presence of albumin in Abraxane enhances transport of paclitaxel acrossendothelial cells. It is hypothesised that this enhanced transendothelial caveolar transport is mediated bythe gp-60 albumin receptor, and that there is enhanced accumulation of paclitaxel in the area of tumourdue to the albumin-binding protein Secreted Protein Acidic Rich in Cysteine (SPARC).

Breast cancer

Data from 106 patients accrued in two single-arm open-label studies and from 454 patients treated in arandomised Phase III comparative study are available to support the use of Abraxane in metastatic breastcancer. This information is presented below.

Single-arm open-label studies

In one study, Abraxane was administered as a 30-minute infusion at a dose of 175 mg/m2 to 43 patientswith metastatic breast cancer. The second trial utilised a dose of 300 mg/m2 as a 30-minute infusion in 63patients with metastatic breast cancer. Patients were treated without steroid pre-treatment or planned

G-CSF support. Cycles were administered at 3-week intervals. The response rates in all patients were39.5% (95% CI: 24.9%-54.2%) and 47.6% (95% CI: 35.3%-60.0%), respectively. The median time todisease progression was 5.3 months (175 mg/m2; 95% CI: 4.6-6.2 months) and 6.1 months (300 mg/m2;95% CI: 4.2-9.8 months).

Randomised comparative study

This multi-centre trial was conducted in patients with metastatic breast cancer, who were treated every 3weeks with single-agent paclitaxel, either as solvent-based paclitaxel 175 mg/m2 given as a 3-hourinfusion with premedication to prevent hypersensitivity (N = 225), or as Abraxane 260 mg/m2 given as a30 minute infusion without premedication (N = 229).

Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% hadvisceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not receivedprior chemotherapy; 27% had received chemotherapy in the adjuvant setting only, 40% in the metastaticsetting only, and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study medicinalproduct as second or greater than second-line therapy. Seventy-seven percent of the patients had beenpreviously exposed to anthracyclines.

Results for overall response rate and time to disease progression, and progression-free survival andsurvival for patients receiving > 1st-line therapy, are shown below.

Table 8: Results for overall response rate, median time to disease progression, andprogression-free survival as assessed by the investigator

Efficacy variable Abraxane Solvent-based paclitaxel(260 mg/m2) (175 mg/m2) p-value

Response rate [95% CI] (%)> 1st-line therapy 26.5 [18.98, 34.05] (n = 132) 13.2 [7.54, 18.93] (n = 136) 0.006a

*Median time to disease progression [95% CI] (weeks)> 1st-line therapy 20.9 [15.7, 25.9] (n = 131) 16.1 [15.0, 19.3] (n = 135) 0.011b

*Median progression free survival [95% CI] (weeks)> 1st-line therapy 20.6 [15.6, 25.9] (n = 131) 16.1 [15.0, 18.3] (n = 135) 0.010b

*Survival [95% CI] (weeks)> 1st-line therapy 56.4 [45.1, 76.9] (n = 131) 46.7 [39.0, 55.3] (n = 136) 0.020b

*This data is based on Clinical Study Report: CA012-0 Addendum dated Final (23 March-2005)a Chi-squared testb Log-rank test

Two hundred and twenty nine patients treated with Abraxane in the randomized, controlled clinical trialwere evaluated for safety. Neurotoxicity to paclitaxel was evaluated through improvement by one gradefor patients experiencing Grade 3 peripheral neuropathy at any time during therapy. The natural course ofperipheral neuropathy to resolution to baseline due to cumulative toxicity of Abraxane after > 6 courses oftreatment was not evaluated and remains unknown.

Pancreatic adenocarcinoma

A multicenter, multinational, randomized, open-label study was conducted in 861 patients to compare

Abraxane/gemcitabine versus gemcitabine monotherapy as first-line treatment in patients with metastaticadenocarcinoma of the pancreas. Abraxane was administered to patients (N = 431) as an intravenousinfusion over 30-40 minutes at a dose of 125 mg/m2 followed by gemcitabine as an intravenous infusionover 30-40 minutes at a dose of 1000 mg/m2 given on Days 1, 8 and 15 of each 28-day cycle. In thecomparator treatment arm, gemcitabine monotherapy was administered to patients (N = 430) inaccordance with the recommended dose and regimen. Treatment was administered until diseaseprogression or development of an unacceptable toxicity. Of the 431 patients with pancreaticadenocarcinoma who were randomized to receive Abraxane in combination with gemcitabine, themajority (93%) were white, 4% were black and 2% were Asian. 16% had a Karnofsky Performance Statusof 100; 42% had a KPS of 90; 35% had a KPS of 80; 7% had a KPS of 70; and <1% of patients had a KPSof below 70. Patients with high cardiovascular risk, history of peripheral artery disease and/or ofconnective tissue disorders and/or interstitial lung disease were excluded from the study.

Patients received a median treatment duration of 3.9 months in the Abraxane/gemcitabine arm and 2.8months in the gemcitabine arm. 32% of patients in the Abraxane/gemcitabine arm compared with 15% ofpatients in the gemcitabine arm received 6 or more months of treatment. For the treated population, themedian relative dose intensity for gemcitabine was 75% in the Abraxane/gemcitabine arm and 85% in thegemcitabine arm. The median relative dose intensity of Abraxane was 81%. A higher median cumulativedose of gemcitabine was delivered in the Abraxane/gemcitabine arm (11400 mg/m2) when compared withthe gemcitabine arm (9000 mg/m2).

The primary efficacy endpoint was overall survival (OS). The key secondary endpoints were progression-free survival (PFS) and overall response rate (ORR), both assessed by independent, central, blindedradiological review using RECIST guidelines (Version 1.0).

Table 9: Efficacy results from randomized study in patients with pancreatic adenocarcinoma(Intent-to-treat population)

Abraxane(125 mg/m2)/gemcitabine Gemcitabine(N=431) (N=430)

Overall Survival

Number of deaths (%) 333 (77) 359 (83)

Median Overall Survival,months (95% CI) 8.5 (7.89, 9.53) 6.7 (6.01, 7.23)

HRA+G/G (95% CI)a 0.72 (0.617, 0.835)

P-valueb <0.0001

Survival Rate % (95% CI) at1 Year 35% (29.7, 39.5) 22% (18.1, 26.7)2 Year 9% (6.2, 13.1) 4% (2.3, 7.2)75th Percentile Overall

Survival (months) 14.8 11.4

Progression-free Survival

Death or progression, n (%) 277 (64) 265 (62)

Median Progression-free

Survival, months (95% CI) 5.5 (4.47, 5.95) 3.7 (3.61, 4.04)

HR a

A+G/G (95% CI) 0.69 (0.581, 0.821)

P-valueb <0.0001

Abraxane(125 mg/m2)/gemcitabine Gemcitabine(N=431) (N=430)

Overall Response Rate

Confirmed complete or partialoverall response, n (%) 99 (23) 31 (7)95% CI 19.1, 27.2 5.0, 10.1pA+G/pG (95% CI) 3.19 (2.178, pct. 4.662)

P-value (chi-square test) <0.0001

CI = confidence interval, HRA+G/G = hazard ratio of Abraxane+gemcitabine/gemcitabine, pA+G/pG=response rate ratio of

Abraxane+gemcitabine/gemcitabinea stratified Cox proportional hazard modelb stratified log-rank test, stratified by geographic region (North America versus others), KPS (70 to 80 versus 90 to 100), and presence of livermetastasis (yes versus no).

There was a statistically significant improvement in OS for patients treated with Abraxane/gemcitabineversus gemcitabine alone, with 1.8 months increase in median OS, 28% overall reduction in risk of death,59% improvement in 1-year survival, and 125% improvement in 2-year survival rates.

Figure 1: Kaplan-Meier curve of overall survival (intent-to-treat population)1.0

ABRAXANE+Gemcitabine0.9 Gemcitabine0.80.70.6

Survivalof0.50.4

Proportion0.30.20.10.0(PT at Risk )

A BX/GEM :

GEM :

Time (months)

Treatment effects on OS favoured the Abraxane/gemcitabine arm across the majority of pre-specifiedsubgroups (including gender, KPS, geographic region, primary location of pancreatic cancer, stage atdiagnosis, presence of liver metastases, presence of peritoneal carcinomatosis, prior Whipple procedure,presence of biliary stent at baseline, presence of pulmonary metastases, and number of metastatic sites).

For patients ≥ 75 years of age in the Abraxane/gemcitabine and gemcitabine arms the survival Hazard

Ratio (HR) was 1.08 (95% CI 0.653, 1. 797). For patients with normal baseline CA 19-9 levels thesurvival HR was 1.07 (95% CI 0.692, 1.661).

Proportion of Survival

There was a statistically significant improvement in PFS for patients treated with Abraxane/gemcitabineversus gemcitabine alone, with 1.8 months increase in median PFS.

A multicenter, randomized, open-label study was conducted in 1052 chemotherapy-naive patients with

Stage IIIb/IV non-small cell lung cancer. The study compared Abraxane in combination with carboplatinversus solvent-based paclitaxel in combination with carboplatin as first-line treatment in patients withadvanced non-small cell lung cancer. Over 99% of patients had an ECOG (Eastern Cooperative Oncology

Group) performance status of 0 or 1. Patients with pre-existing neuropathy of Grade ≥ 2 or seriousmedical risk factors involving any of the major organ systems were excluded. Abraxane was administeredto patients (N=521) as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8 and15 of each 21-day cycle without any steroid premedication and without granulocyte colony stimulatingfactor prophylaxis. Beginning immediately after the end of Abraxane administration, carboplatin at a doseof AUC = 6 mg*min/mL was administered intravenously on Day 1 only of each 21-day cycle. Solvent-based paclitaxel was administered to patients (N=531) at a dose of 200 mg/m2 as an intravenous infusionover 3 hours with standard premedication, immediately followed by carboplatin administeredintravenously at AUC = 6 mg*min/mL. Each drug was administered on Day 1 of each 21-day cycle. Inboth study arms treatment was administered until disease progression or development of an unacceptabletoxicity. Patients received a median of 6 cycles of treatment in both study arms.

The primary efficacy endpoint was overall response rate defined as the percentage of patients whoachieved an objective confirmed complete response or partial response based on an independent, central,blinded radiological review using RECIST (Version 1.0). Patients in the Abraxane/carboplatin arm had asignificantly higher overall response rate compared with patients in the control arm: 33% versus 25%,p = 0.005 (Table 10). There was a significant difference in overall response rate in the

Abraxane/carboplatin arm compared to the control arm in patients with non-small cell lung cancer ofsquamous histology (N=450, 41% vs. 24%, p<0.001), however this difference did not translate into adifference in PFS or OS. There was no difference in ORR between the treatment arms in patients withnon-squamous histology (N=602, 26% vs 25%, p=0.808).

Table 10: Overall response rate in randomized non-small cell lung cancer trial (intent-to-treatpopulation)

Abraxane Solvent-based paclitaxel(100 mg/m2/week) (200 mg/m2 every 3 weeks)+ carboplatin + carboplatin

Efficacy Parameter (N=521) (N=531)

Overall Response Rate (independent review)

Confirmed complete or partial overall response, n (%) 170 (33%) 132 (25%)95% CI (%) 28.6, 36.7 21.2, 28.5pA/pT (95.1% CI) 1.313 (1.082, 1.593)

P-valuea 0.005

CI = confidence interval; HRA/T = hazard ratio of Abraxane/carboplatin to solvent-based paclitaxel/carboplatin; pA/pT = response rate ratio of

Abraxane/carboplatin to solvent-based paclitaxel/carboplatin.a P-value is based on a chi-square test.

There was no statistically significant difference in progression-free survival (by blinded radiologistassessment) and overall survival between the two treatment arms. A non-inferiority analysis wasconducted for PFS and OS, with a pre-specified non-inferiority margin of 15%. The non-inferioritycriterion was met for both PFS and OS with the upper bound of the 95% confidence interval for theassociated hazard ratios being less than 1.176 (Table 11).

Table 11: Non-inferiority analyses on progression-free survival and overall survival in randomizednon-small cell lung cancer trial (intent-to-treat population)

Abraxane Solvent-based paclitaxel(100 mg/m2/week) (200 mg/m2 every 3 weeks)+ carboplatin + carboplatin

Efficacy Parameter (N=521) (N=531)

Progression-free Survivala (independent review)

Death or progression, n (%) 429 (82%) 442 (83%)

Median PFS (95% CI) (months) 6.8 (5.7, 7.7) 6.5 (5.7, 6.9)

HRA/T (95% CI) 0.949 (0.830, 1.086)

Overall Survival

Number of deaths, n (%) 360 (69%) 384 (72%)

Median OS (95% CI) (months) 12.1 (10.8, 12.9) 11.2 (10.3, 12.6)

HRA/T (95.1% CI) 0.922 (0.797, 1.066)

CI = confidence interval; HRA/T = hazard ratio of Abraxane/carboplatin to solvent-based paclitaxel/carboplatin; pA/pT = response rate ratio of

Abraxane/carboplatin to solvent-based paclitaxel/carboplatin.a Per EMA methodological considerations for PFS endpoint, missing observations or initiation of subsequent new therapy were not used forcensoring.

Safety and effectiveness in paediatric patients have not been established (see section 4.2).

Study ABI-007-PST-001, a Phase 1/2, multicenter, open-label, dose-finding study to assess the safety,tolerability and preliminary efficacy of weekly Abraxane in paediatric patients with recurrent or refractorysolid tumours included a total of 106 patients aged ≥ 6 months to ≤ 24 years.

The Phase 1 portion of the study included a total of 64 patients aged from 6 months to less than 18 yearsold and determined the maximum tolerated dose (MTD) to be 240 mg/m2, administered as an intravenousinfusion over 30 minutes, on Days 1, 8, and 15 of each 28-day cycle.

The Phase 2 portion enrolled a total of 42 patients using a Simon two-stage minimax design, aged from 6months to 24 years with recurrent or refractory Ewing’s sarcoma, neuroblastoma or rhabdomyosarcomafor the evaluation of antitumour activity assessed by the overall response rate (ORR). Of the 42 patients, 1patient was < 2, 27 were aged ≥ 2 to < 12, 12 were aged ≥12 to < 18 and 2 adult patients were aged ≥ 18 to24 years old.

Patients were treated for a median of 2 cycles at the MTD. From the 41 patients eligible for efficacyevaluation in stage 1, 1 patient in the rhabdomyosarcoma group (N=14) had a confirmed partial response(PR) resulting in an ORR of 7.1% (95% CI: 0.2, 33.9). No confirmed complete response (CR) or PR wasobserved in either the Ewing’s sarcoma group (N=13) or the neuroblastoma group (N=14). None of thestudy arms continued into stage 2 because the protocol-defined requirement of ≥ 2 patients to have aconfirmed response was not met.

The median overall survival results, including the 1-year follow-up period were 32.1 weeks (95% CI:21.4, 72.9), 32.0 weeks (95% CI: 12, not established) and 19.6 weeks (95% CI: 4, 25.7) for the Ewing’ssarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively.

The overall safety profile of Abraxane in paediatric patients was consistent with the known safety profileof Abraxane in adults (see section 4.8). Based on these results, it was concluded that Abraxane asmonotherapy does not have meaningful clinical activity or survival benefit that warrants furtherdevelopment in the paediatric population.

The pharmacokinetics of total paclitaxel following 30- and 180-minute infusions of Abraxane at doselevels of 80 to 375 mg/m2 were determined in clinical studies. The paclitaxel exposure (AUC) increasedlinearly from 2653 to 16736 ng.hr/ml following dosing from 80 to 300 mg/m2.

In a study in patients with advanced solid tumours, the pharmacokinetic characteristics of paclitaxelfollowing Abraxane administered intravenously at 260 mg/m2 over 30 minutes were compared with thosefollowing 175 mg/m2 of the solvent-based paclitaxel injection administered over 3 hours. Based onnon-compartmental PK analysis, the plasma clearance of paclitaxel with Abraxane was larger (43%) thanthat following a solvent-based paclitaxel injection and its volume of distribution was also higher (53%).

There were no differences in terminal half-lives.

In a repeat dose study with 12 patients receiving Abraxane administered intravenously at 260 mg/m2,intra-patient variability in AUC was 19% (range = 3.21%-37.70%). There was no evidence foraccumulation of paclitaxel with multiple treatment courses.

Following Abraxane administration to patients with solid tumours, paclitaxel is evenly distributed intoblood cells and plasma and is highly bound to plasma proteins (94%).

The protein binding of paclitaxel following Abraxane was evaluated by ultrafiltration in a within-patientcomparison study. The fraction of free paclitaxel was significantly higher with Abraxane (6.2%) than withsolvent-based paclitaxel (2.3%). This resulted in significantly higher exposure to unbound paclitaxel with

Abraxane compared with solvent-based paclitaxel, even though the total exposure is comparable. This ispossibly due to paclitaxel not being trapped in Cremophor EL micelles as with solvent-based paclitaxel.

Based on the published literature, in vitro studies of binding to human serum proteins, (using paclitaxel atconcentrations ranging from 0.1 to 50 µg/ml), indicate that the presence of cimetidine, ranitidine,dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

Based on population pharmacokinetic analysis, the total volume of distribution is approximately 1741 L;the large volume of distribution indicates extensive extravascular distribution and/or tissue binding ofpaclitaxel.

Based on the published literature, in vitro studies with human liver microsomes and tissue slices show thatpaclitaxel is metabolised primarily to 6α-hydroxypaclitaxel; and to two minor metabolites,3’-p-hydroxypaclitaxel and 6α-3’-p-dihydroxypaclitaxel. The formation of these hydroxylated metabolitesis catalysed by CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4 isoenzymes, respectively.

In patients with metastatic breast cancer, after a 30-minute infusion of Abraxane at 260 mg/m2, the meanvalue for cumulative urinary excretion of unchanged active substance accounted for 4% of the totaladministered dose with less than 1% as the metabolites 6α-hydroxypaclitaxel and 3’-p-hydroxypaclitaxel,indicating extensive non-renal clearance. Paclitaxel is principally eliminated by hepatic metabolism andbiliary excretion.

At the clinical dose range of 80 to 300 mg/m2, the mean plasma clearance of paclitaxel ranges from 13 to30 L/h/m2, and the mean terminal half-life ranges from 13 to 27 hours.

The effect of hepatic impairment on population pharmacokinetics of Abraxane was studied in patientswith advanced solid tumours. This analysis included patients with normal hepatic function (n=130), andpre-existing mild (n=8), moderate (n=7), or severe (n=5) hepatic impairment (according to NCI Organ

Dysfunction Working Group criteria). The results show that mild hepatic impairment (total bilirubin >1 to≤1.5 x ULN) has no clinically important effect on pharmacokinetics of paclitaxel. Patients with moderate(total bilirubin >1.5 to ≤3 x ULN) or severe (total bilirubin >3 to ≤5 x ULN) hepatic impairment have a22% to 26% decrease in the maximum elimination rate of paclitaxel and approximately 20% increase inmean paclitaxel AUC compared with patients with normal hepatic function. Hepatic impairment has noeffect on mean paclitaxel Cmax. In addition, elimination of paclitaxel shows an inverse correlation withtotal bilirubin and a positive correlation with serum albumin.

Pharmacokinetic/pharmacodynamic modeling indicates that there is no correlation between hepaticfunction (as indicated by the baseline albumin or total bilirubin level) and neutropenia after adjusting for

Abraxane exposure.

Pharmacokinetic data are not available for patients with total bilirubin >5 x ULN or for patients withmetastatic adenocarcinoma of the pancreas (see section 4.2).

Population pharmacokinetic analysis included patients with normal renal function (n=65), and pre-existingmild (n=61), moderate (n=23), or severe (n=l) renal impairment (according to draft FDA guidance criteria2010). Mild to moderate renal impairment (creatinine clearance ≥30 to <90 ml/min) has no clinicallyimportant effect on the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel.

Pharmacokinetic data are insufficient for patients with severe renal impairment and not available forpatients with end stage kidney disease.

Population pharmacokinetic analysis for Abraxane included patients with ages ranging from 24 to 85years old and shows that age does not significantly influence the maximum elimination rate and systemicexposure (AUC and Cmax) of paclitaxel.

Pharmacokinetic/pharmacodynamic modelling using data from 125 patients with advanced solid tumoursindicates that patients ≥ 65 years of age may be more susceptible to development of neutropenia within thefirst treatment cycle, although the plasma paclitaxel exposure is not affected by age.

The pharmacokinetics of paclitaxel following 30 minutes of intravenous administration at dose levels of120 mg/m2 to 270 mg/m2 were determined in 64 patients (2 to ≤ 18 years) in Phase 1 of a Phase 1/2 studyin recurrent or refractory paediatric solid tumours. Following dosing increase from 120 to 270 mg/m2, thepaclitaxel mean AUC(0-inf) and Cmax ranged from 8867 to 14361 ng*hr/ml and from 3488 to 8078 ng/ml,respectively.

Dose normalized peak drug exposure values were comparable across the dose range studied; however,dose-normalized total drug exposure values were only comparable across 120 mg/m2 to 240 mg/m2; withlower dose-normalized AUC∞ at the 270 mg/m2 dose level. At the MTD of 240 mg/m2, the mean CL was19.1 L/h and the mean terminal half-life was 13.5 hours.

In children and adolescent patients, exposure to paclitaxel increased with higher dosing and weekly drugexposures were higher than in adult patients.

Other intrinsic factors

Population pharmacokinetic analyses for Abraxane indicate that gender, race (Asian vs. White), and typeof solid tumours do not have a clinically important effect on systemic exposure (AUC and Cmax) ofpaclitaxel. Patients weighing 50 kg had paclitaxel AUC approximately 25% lower than those weighing 75kg. The clinical relevance of this finding is uncertain.

The carcinogenic potential of paclitaxel has not been studied. However, based on the published literature,paclitaxel is a potentially carcinogenic and genotoxic agent at clinical doses, based upon itspharmacodynamic mechanism of action. Paclitaxel has been shown to be clastogenic in vitro(chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel hasbeen shown to be genotoxic in vivo (micronucleus test in mice), but it did not induce mutagenicity in the

Ames test or the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl transferase (CHO/HGPRT)gene mutation assay.

Paclitaxel at doses below the human therapeutic dose was associated with low fertility when administeredprior and during mating in male and female rats and foetal toxicity in rats. Animal studies with Abraxaneshowed non-reversible, toxic effects on the male reproductive organs at clinically relevant exposure levels.

Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Following intravenousadministration of radiolabelled paclitaxel to rats on days 9 to 10 postpartum, concentrations ofradioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations.

Human albumin solution (containing sodium caprylate and N-acetyl-L-tryptophan).

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vials3 years

Stability of reconstituted dispersion in the vial

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C-8°C in the originalcarton, protected from light.

Stability of the reconstituted dispersion in the infusion bag

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C-8°C followed by 4 hoursat 25°C, protected from light.

However, from a microbiological point of view, unless the method of reconstituting and filling of theinfusion bags precludes the risks of microbial contamination, the product should be used immediately afterreconstitution and filling of the infusion bags.

If not used immediately, in-use storage times and conditions are the responsibility of the user.

The total combined storage time of reconstituted medicinal product in the vial and in the infusion bagwhen refrigerated and protected from light is 24 hours. This may be followed by storage in the infusionbag for 4 hours below 25°C.

Keep the vial in the outer carton in order to protect from light. Neither freezing nor refrigeration adverselyaffects the stability of the product. This medicinal product does not require any special temperaturestorage conditions.

Reconstituted dispersion

For storage conditions after reconstitution of the medicinal product, see section 6.3.

50 ml vial (type 1 glass) with a stopper (butyl rubber), with an overseal (aluminium), containing 100 mgof paclitaxel formulated as albumin bound nanoparticles.

100 ml vial (type 1 glass) with a stopper (butyl rubber), with an overseal (aluminium), containing 250 mgof paclitaxel formulated as albumin bound nanoparticles.

Pack size of one vial.

Preparation and administration precautions

Paclitaxel is a cytotoxic anticancer medicinal product and, as with other potentially toxic compounds,caution should be exercised in handling Abraxane. The use of gloves, goggles and protective clothing isrecommended. If the dispersion contacts the skin, the skin should be washed immediately and thoroughlywith soap and water. If it contacts mucous membranes, the membranes should be flushed thoroughly withwater. Abraxane should only be prepared and administered by personnel appropriately trained in thehandling of cytotoxic agents. Pregnant staff should not handle Abraxane.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possibleinfiltration during administration of the medicinal product. Limiting the infusion of Abraxane to 30minutes, as directed, reduces the likelihood of infusion-related reactions.

Reconstitution and administration of the product

Abraxane is supplied as a sterile lyophilised powder for reconstitution before use. After reconstitution,each ml of dispersion contains 5 mg of paclitaxel formulated as albumin bound nanoparticles.

100 mg vial: Using a sterile syringe, 20 ml of sodium chloride 9 mg/ml (0.9%) solution for infusionshould slowly be injected into a vial of Abraxane over a minimum of 1 minute.

250 mg vial: Using a sterile syringe, 50 ml of sodium chloride 9 mg/ml (0.9%) solution for infusionshould slowly be injected into a vial of Abraxane over a minimum of 1 minute.

The solution should be directed onto the inside wall of the vial. The solution should not be injecteddirectly onto the powder as this will result in foaming.

Once the addition is complete, the vial should be allowed to stand for a minimum of 5 minutes to ensureproper wetting of the solid. Then, the vial should gently and slowly be swirled and/or inverted for at least2 minutes until complete redispersion of any powder occurs. The generation of foam must be avoided. Iffoaming or clumping occurs, the dispersion must stand for at least 15 minutes until foam subsides.

The reconstituted dispersion should be milky and homogenous without visible precipitates. Some settlingof the reconstituted dispersion may occur. If precipitates or settling are visible, the vial should be gentlyinverted again to ensure complete redispersion prior to use.

Inspect the dispersion in the vial for particulate matter. Do not administer the reconstituted dispersion ifparticulate matter is observed in the vial.

The exact total dosing volume of 5 mg/ml dispersion required for the patient should be calculated and theappropriate amount of reconstituted Abraxane should be injected into an empty, sterile, PVC or non-PVCtype intravenous bag.

The use of medical devices containing silicone oil as a lubricant (i.e. syringes and IV bags) to reconstituteand administer Abraxane may result in the formation of proteinaceous strands. Administer Abraxane usingan infusion set incorporating a 15 µm filter to avoid administration of these strands. Use of a 15 µm filterremoves strands and does not change the physical or chemical properties of the reconstituted product.

Use of filters with a pore size less than 15 µm may result in blockage of the filter.

The use of specialized di(2-ethylhexyl)phthalate (DEHP)-free solution containers or administration sets isnot necessary to prepare or administer Abraxane infusions.

Following administration, it is recommended that the intravenous line be flushed with sodium chloride 9mg/ml (0.9%) solution for injection to ensure administration of the complete dose.

Any unused product or waste material should be disposed of in accordance with local requirements.

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

EU/1/07/428/001

EU/1/07/428/002

Date of first authorisation: 11 January 2008

Date of latest renewal: 14 January 2013

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu