Abraxane, INN-paclitaxel

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Abraxane

5 mg/ml powder for dispersion for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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 bound

nanoparticles.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

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.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Abraxane monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who

have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing

therapy is not indicated (see section 4.4).

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

metastatic adenocarcinoma of the pancreas.

Abraxane in combination with carboplatin is indicated for the first-line treatment of non-small cell lung

cancer in adult patients who are not candidates for potentially curative surgery and/or radiation therapy.

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/m

administered intravenously over 30 minutes every 3

weeks.

Dose adjustments during treatment of breast cancer

Patients who experience severe neutropenia (neutrophil count < 500 cells/mm

for a week or longer) or

severe sensory neuropathy during Abraxane therapy should have the dose reduced to 220 mg/m

for

subsequent courses. Following recurrence of severe neutropenia or severe sensory neuropathy, additional

dose reduction should be made to 180 mg/m

. Abraxane should not be administered until neutrophil

counts recover to >1500 cells/mm

. 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/m

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/m

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/m

) Gemcitabine Dose (mg/m

)

Full dose 125 1000

dose level reduction 100 800

dose level reduction 75 600

If additional dose reduction

required

Discontinue treatment Discontinue treatment

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

Day

ANC count

(cells/mm

)

Platelet count

(cells/mm

)

Abraxane

Dose

Gemcitabine

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:

Day 15 ≥ 500 but < 1000 OR ≥ 50,000 but < 75,000

Treat with Day 8 dose level and

follow with WBC Growth Factors

Reduce doses 1 dose level from

Day 8 doses

< 500 OR < 50,000 Withhold doses

Day 15: If Day 8 doses were reduced:

Day 15 ≥ 1000 AND ≥ 75,000

Return to the Day 1 dose levels and

follow with WBC Growth Factors

Treat with same doses as Day 8

≥ 500 but < 1000 OR ≥ 50,000 but < 75,000

Treat with Day 8 dose levels and

follow with WBC Growth Factors

Reduce doses 1 dose level from

Day 8 doses

< 500 OR < 50,000 Withhold doses

Day 15: IF Day 8 doses were withheld:

Day 15 ≥ 1000 AND ≥ 75,000

Return to Day 1 dose levels and

follow with WBC Growth Factors

Reduce doses 1 dose level from

Day 1 doses

≥ 500 but < 1000 OR ≥ 50,000 but < 75,000

Reduce 1 dose level and follow

with WBC Growth Factors

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

(ADR)

Abraxane Dose Gemcitabine Dose

Febrile Neutropenia:

Grade 3 or 4

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

lower dose level

Peripheral Neuropathy:

Grade 3 or 4

Withhold dose until improves to

≤ Grade 1;

resume at next lower dose level

Treat with same dose

Cutaneous Toxicity:

Grade 2 or 3

Reduce to next lower dose level

;

discontinue treatment if ADR persists

Gastrointestinal

Toxicity:

Grade 3 mucositis or

diarrhoea

Withhold doses until improves to ≤ Grade 1;

resume at next lower dose level

a. See Table 1 for dose level reductions

Non-small cell lung cancer:

The recommended dose of Abraxane is 100 mg/m

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/mm

and platelet count is ≥100,000 cells/mm

. For each subsequent weekly dose of Abraxane,

patients must have an ANC ≥500 cells/mm

and platelets >50,000 cells/mm

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

(mg/m

)

Dose of carboplatin

(AUC mg•min/mL)

Nadir ANC <500/mm

with neutropenic

fever > 38°C

Delay of next cycle due to persistent

neutropenia

(Nadir ANC <1500/mm

)

Nadir ANC <500/mm

for > 1 week

First

4.5

Second

3.0

Third

Discontinue Treatment

Nadir platelets <50,000/mm

First

4.5

Second

Discontinue Treatment

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.

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

(mg/m

)

Dose of carboplatin

(AUC mg•min/mL)

Grade 2 or 3 cutaneous toxicity

Grade 3 diarrhoea

Grade 3 mucositis

≥ Grade 3 peripheral neuropathy

Any other Grade 3 or 4 non-

haematologic toxicity

First

4.5

Second

3.0

Third

Discontinue Treatment

Grade 4 cutaneous toxicity, diarrhoea, or

mucositis

First

Discontinue Treatment

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

The safety and efficacy of Abraxane in children and adolescents aged 0 to less than 18 years has not been

established. Currently available data are described in section s 4.8, 5.1 and 5.2 but no recommendation on

a posology can be made. 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.

4.3 Contraindications

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/mm

4.4 Special warnings and precautions for use

Abraxane is an albumin-bound nanoparticle formulation of paclitaxel, which may have substantially

different pharmacological properties compared to other formulations of paclitaxel (see sections 5.1 and

5.2). It should not be substituted for or with other paclitaxel formulations.

Hypersensitivity

Rare occurrences of severe hypersensitivity reactions, including very rare events of anaphylactic reactions

with fatal outcome, have been reported. If a hypersensitivity reaction occurs, the medicinal product should

be discontinued immediately, symptomatic treatment should be initiated, and the patient should not be

rechallenged with paclitaxel.

Haematology

Bone marrow suppression (primarily neutropenia) occurs frequently with Abraxane. Neutropenia is

dose-dependent and a dose-limiting 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 >1500 cells/mm

and platelets recover to >100,000 cells/mm

(see section

4.2).

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.

When Abraxane is used as monotherapy, 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 (see section 4.2). For combination use of Abraxane and gemcitabine, if Grade

3 or higher peripheral neuropathy develops, withhold Abraxane; continue treatment with gemcitabine at

the 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 peripheral

neuropathy develops, treatment should be withheld until improvement to Grade 0 or 1 followed by a dose

reduction for all subsequent courses of Abraxane and carboplatin (see section 4.2).

Sepsis

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane in

combination with gemcitabine. Complications due to the underlying pancreatic cancer, especially biliary

obstruction or presence of biliary stent, were identified as significant contributing factors. If a patient

becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For

febrile neutropenia, withhold Abraxane and gemcitabine until fever resolves and ANC ≥ 1500 cells/mm

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 patients

when Abraxane was used in combination with gemcitabine. Closely monitor all patients for signs and

symptoms of pneumonitis. After ruling out infectious etiology and upon making a diagnosis of

pneumonitis, permanently discontinue treatment with Abraxane and gemcitabine and promptly initiate

appropriate treatment and supportive measures (see section 4.2).

Hepatic impairment

Because the toxicity of paclitaxel can be increased with hepatic impairment, administration of Abraxane in

patients with hepatic impairment should be performed with caution. Patients with hepatic impairment may

be at increased risk of toxicity, particularly from myelosuppression; such patients should be closely

monitored for development of profound myelosuppression.

Abraxane is not recommended in patients that have total bilirubin > 5 x ULN or AST > 10 x ULN. In

addition, Abraxane is not recommended in patients with metastatic adenocarcinoma of the pancreas that

have moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and AST ≤ 10 x ULN) (see

section 5.2).

Cardiotoxicity

Rare reports of congestive heart failure and left ventricular dysfunction have been observed among

individuals receiving Abraxane. Most of the individuals were previously exposed to cardiotoxic medicinal

products such as anthracyclines or had underlying cardiac history. Thus, patients receiving Abraxane

should 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 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 anti-emetics and constipating agents.

Eye disorders

Cystoid macular oedema (CMO) has been reported in patients treated with Abraxane. Patients with

impaired vision should undergo a prompt and complete ophthalmologic examination. In case CMO is

diagnosed, Abraxane treatment should be discontinued and appropriate treatment initiated (see

section 4.8).

Patients 75 years and older

For patients of 75 years and older, no benefit for the combination treatment of Abraxane and gemcitabine

in comparison to gemcitabine monotherapy has been demonstrated. In the very elderly (≥ 75 years) who

received Abraxane and gemcitabine, there was a higher incidence of serious adverse reactions and adverse

reactions that led to treatment discontinuation including haematologic toxicities, peripheral neuropathy,

decreased appetite and dehydration. Patients with pancreatic adenocarcinoma aged 75 years and older

should be carefully assessed for their ability to tolerate Abraxane in combination with gemcitabine with

special consideration to performance status, co-morbidities and increased risk of infections (see section

4.2 and 4.8).

Other

Although limited data is available, no clear benefit in terms of prolonged overall survival has been

demonstrated in pancreatic adenocarcinoma patients with normal CA 19-9 levels prior to start of treatment

with Abraxane and gemcitabine (see section 5.1).

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

Excipients

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

free’.

4.5 Interactions with other medicinal products and other forms of interaction

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 should

be 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 of

paclitaxel may be increased due to higher paclitaxel exposure. Administering paclitaxel concomitantly

with 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 lower

paclitaxel exposures.

Paclitaxel and gemcitabine do not share a common metabolic pathway. Paclitaxel clearance is primarily

determined by CYP2C8 and CYP3A4 mediated metabolism followed by biliary excretion, while

gemcitabine is inactivated by cytidine deaminase followed by urinary excretion. Pharmacokinetic

interactions between Abraxane and gemcitabine have not been evaluated in humans.

A pharmacokinetic study was conducted with Abraxane and carboplatin in non-small cell lung cancer

patients. There were no clinically relevant pharmacokinetic interactions between Abraxane and

carboplatin.

Abraxane is indicated as monotherapy for breast cancer, in combination with gemcitabine for pancreatic

adenocarcinoma, 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.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Contraception in males and females

Women of childbearing potential should use effective contraception during treatment and up to 1 month

after receiving treatment with Abraxane. Male patients treated with Abraxane are advised to use effective

contraception and to avoid fathering a child during and up to six months after treatment.

Pregnancy

There are very limited data on the use of paclitaxel in human pregnancy. Paclitaxel is suspected to cause

serious birth defects when administered during pregnancy. Studies in animals have shown reproductive

toxicity (see section 5.3). Women of childbearing potential should have a pregnancy test prior to starting

treatment with Abraxane. Abraxane should not be used in pregnancy, and in women of childbearing

potential not using effective contraception, unless the clinical condition of the mother requires treatment

with paclitaxel.

Breast-feeding

Paclitaxel and/or its metabolites were excreted into the milk of lactating rats (see section 5.3). It is not

known if paclitaxel is excreted in human milk. Because of potential serious adverse reactions in

breast-feeding infants, Abraxane is contraindicated during lactation. Breast-feeding must be discontinued

for the duration of therapy.

Fertility

Abraxane induced infertility in male rats (see section 5.3). Based on findings in animals, male and female

fertility may be compromised. Male patients should seek advice on conservation of sperm prior to

treatment because of the possibility of irreversible infertility due to therapy with Abraxane.

4.7 Effects on ability to drive and use machines

Abraxane has minor or moderate influence on the ability to drive and use machines. Abraxane may cause

adverse reactions such as tiredness (very common) and dizziness (common) that may affect the ability to

drive and use machinery. Patients should be advised not to drive and use machines if they feel tired or

dizzy.

4.8 Undesirable effects

Summary of the safety profile

The most common clinically significant adverse reactions associated with the use of Abraxane have been

neutropenia, peripheral neuropathy, arthralgia/myalgia and gastrointestinal disorders.

Tabulated list of adverse reactions

Table 6 lists adverse reactions associated with Abraxane monotherapy at any dose in any indication during

clinical trials (N = 789), Abraxane in combination with gemcitabine for pancreatic adenocarcinoma from

the phase III clinical trial (N = 421), Abraxane in combination with carboplatin for non-small cell lung

cancer 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 (≥1/1,000

to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the

available data). Within each frequency grouping, adverse reactions are presented in order of decreasing

seriousness.

Table 6: Adverse reactions reported with Abraxane

Monotherapy (N=789)

Combination therapy

with gemcitabine

(N =421)

Combination therapy

with carboplatin

(N = 514)

Infections and infestations

Common:

Infection, urinary tract infection,

folliculitis, upper respiratory tract

infection, candidiasis, sinusitis

Sepsis, pneumonia, oral

candidiasis

Pneumonia, bronchitis,

upper respiratory tract

infection, urinary tract

infection

Uncommon:

Sepsis

, neutropenic sepsis

pneumonia, oral candidiasis,

nasopharyngitis, cellulitis, herpes

simplex, viral infection, herpes

zoster, fungal infection,

catheter-related infection, injection

site infection

Sepsis, oral candidiasis

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

Uncommon:

Tumour necrosis, metastatic pain

Blood and lymphatic system disorders

Very

common:

Bone marrow suppression,

neutropenia, thrombocytopenia,

anaemia, leukopenia, lymphopenia

Neutropenia,

thrombocytopenia,

anaemia

Neutropenia

thrombocytopenia

anaemia

, leukopenia

Common:

Febrile neutropenia

Pancytopenia

Febrile neutropenia,

lymphopenia

Uncommon:

Thrombotic

thrombocytopenic

purpura

Pancytopenia

Rare:

Pancytopenia

Immune system disorders

Monotherapy (N=789)

Combination therapy

with gemcitabine

(N =421)

Combination therapy

with carboplatin

(N = 514)

Uncommon:

Hypersensitivity

Drug hypersensitivity,

hypersensitivity

Rare:

Severe hypersensitivity

Metabolism and nutrition disorders

Very

common:

Anorexia

Dehydration, decreased

appetite, hypokalaemia

Decreased appetite

Common:

Dehydration, decreased appetite,

hypokalaemia

Dehydration

Uncommon:

Hypophosphataemia, fluid retention,

hypoalbuminaemia, polydipsia,

hyperglycaemia, hypocalcaemia,

hypoglycaemia, hyponatraemia

Not known:

Tumour lysis syndrome

Psychiatric disorders

Very

common:

Depression, insomnia

Common:

Depression, insomnia, anxiety

Anxiety

Insomnia

Uncommon:

Restlessness

Nervous system disorders

Very

common:

Peripheral neuropathy, neuropathy,

hypoaesthesia, paraesthesia

Peripheral neuropathy,

dizziness, headache,

dysgeusia

Peripheral neuropathy

Common:

Peripheral sensory neuropathy,

dizziness, peripheral motor

neuropathy, ataxia, headache,

sensory disturbance, somnolence,

dysgeusia

Dizziness, headache,

dysgeusia

Uncommon:

Polyneuropathy, areflexia, syncope,

postural dizziness, dyskinesia,

hyporeflexia, neuralgia, neuropathic

pain, tremor, sensory loss

VII

nerve paralysis

Not known:

Cranial nerve palsies multiple

Eye disorders

Common:

Vision blurred, lacrimation

increased, dry eye,

keratoconjunctivitis sicca, madarosis

Lacrimation increased

Vision blurred

Uncommon:

Reduced visual acuity, abnormal

vision, eye irritation, eye pain,

conjunctivitis, visual disturbance,

eye pruritus, keratitis

Cystoid macular

oedema

Rare:

Cystoid macular oedema

Ear and labyrinth disorders

Common:

Vertigo

Uncommon:

Tinnitus, ear pain

Cardiac disorders

Common:

Arrhythmia, tachycardia,

supraventricular tachycardia

Cardiac failure

congestive, tachycardia

Monotherapy (N=789)

Combination therapy

with gemcitabine

(N =421)

Combination therapy

with carboplatin

(N = 514)

Rare:

Cardiac arrest, cardiac failure

congestive, left ventricular

dysfunction, atrioventricular block

bradycardia

Vascular disorders

Common:

Hypertension, lymphoedema,

flushing, hot flushes

Hypotension,

hypertension

Hypotension,

hypertension

Uncommon:

Hypotension, orthostatic

hypotension, peripheral coldness

Flushing

Rare:

Thrombosis

Respiratory, thoracic and mediastinal disorders

Very

common:

Dyspnoea, epistaxis,

cough

Dyspnoea

Common:

Interstitial pneumonitis

, dyspnoea,

epistaxis, pharyngolaryngeal pain,

cough, rhinitis, rhinorrhoea

Pneumonitis, nasal

congestion

Haemoptysis, epistaxis,

cough

Uncommon:

Pulmonary emboli, pulmonary

thromboembolism, pleural effusion,

exertional dyspnoea, sinus

congestion, decreased breath sounds,

productive cough, allergic rhinitis,

hoarseness, nasal congestion, nasal

dryness, wheezing

Dry throat, nasal

dryness

Pneumonitis

Not known:

Vocal cord paresis

Gastrointestinal disorders

Very

common:

Diarrhoea, vomiting, nausea,

constipation, stomatitis

Diarrhoea, vomiting,

nausea, constipation,

abdominal pain,

abdominal pain upper

Diarrhoea, vomiting,

nausea, constipation

Common:

Gastrooesophageal reflux disease,

dyspepsia, abdominal pain,

abdominal distension, abdominal

pain upper, oral hypoaesthesia

Intestinal obstruction,

colitis, stomatitis, dry

mouth

Stomatitis, dyspepsia,

dysphagia, abdominal

pain

Uncommon:

Rectal haemorrhage, dysphagia,

flatulence, glossodynia, dry mouth,

gingival pain, loose stools,

oesophagitis, abdominal pain lower,

mouth ulceration, oral pain

Hepatobiliary disorders

Common:

Cholangitis

Hyperbilirubinaemia

Uncommon:

Hepatomegaly

Skin and subcutaneous tissue disorders

Very

common:

Alopecia, rash

Common:

Pruritus, dry skin, nail disorder,

erythema, nail

pigmentation/discolouration, skin

hyperpigmentation, onycholysis, nail

changes

Pruritus, dry skin, nail

disorder

Pruritus, nail disorder

Monotherapy (N=789)

Combination therapy

with gemcitabine

(N =421)

Combination therapy

with carboplatin

(N = 514)

Uncommon:

Photosensitivity reaction, urticaria,

skin pain, generalised pruritus,

pruritic rash, skin disorder,

pigmentation disorder,

hyperhidrosis, onychomadesis,

erythematous rash, generalised rash,

dermatitis, night sweats,

maculo-papular rash, vitiligo,

hypotrichosis, nail bed tenderness,

nail discomfort, macular rash,

papular rash, skin lesion, swollen

face

Skin exfoliation,

dermatitis allergic,

urticaria

Very rare:

Stevens-Johnson syndrome

, toxic

epidermal necrolysis

Not known:

Palmar-plantar erythrodysaesthesiae

syndrome

1, 4

, scleroderma

Musculoskeletal and connective tissue disorders

Very

common:

Arthralgia, myalgia

Arthralgia, myalgia,

pain in extremity

Arthralgia, myalgia

Common:

Back pain, pain in extremity, bone

pain, muscle cramps, limb pain

Muscular weakness,

bone pain

Back pain, pain in

extremity,

musculoskeletal pain

Uncommon:

Chest wall pain, muscular weakness,

neck pain, groin pain, muscle

spasms, musculoskeletal pain, flank

pain, limb discomfort, muscle

weakness

Renal and urinary disorders

Common:

Acute renal failure

Uncommon:

Haematuria, dysuria, pollakiuria,

nocturia, polyuria, urinary

incontinence

Haemolytic uraemic

syndrome

Reproductive system and breast disorders

Uncommon:

Breast pain

General disorders and administration site conditions

Very

common:

Fatigue, asthenia, pyrexia

Fatigue, asthenia,

pyrexia, oedema

peripheral, chills

Fatigue, asthenia,

oedema peripheral

Common:

Malaise, lethargy, weakness,

peripheral oedema, mucosal

inflammation, pain, rigors, oedema,

decreased performance status, chest

pain, influenza-like illness,

hyperpyrexia

Infusion site reaction

Pyrexia, chest pain

Uncommon:

Chest discomfort, abnormal gait,

swelling, injection site reaction

Mucosal inflammation,

infusion site

extravasation, infusion

site inflammation,

infusion site rash

Monotherapy (N=789)

Combination therapy

with gemcitabine

(N =421)

Combination therapy

with carboplatin

(N = 514)

Rare:

Extravasation

Investigations

Very

common:

Weight decreased,

alanine

aminotransferase

increased

Common:

Decreased weight, increased alanine

aminotransferase, increased aspartate

aminotransferase, decreased

haematocrit, decreased red blood cell

count, increased body temperature,

increased

gamma-glutamyltransferase,

increased blood alkaline phosphatase

Aspartate

aminotransferase

increased, blood

bilirubin increased,

blood creatinine

increased

Weight decreased,

alanine

aminotransferase

increased, aspartate

aminotransferase

increased, blood

alkaline phosphatase

increased

Uncommon:

Increased blood pressure, increased

weight, increased blood lactate

dehydrogenase, increased blood

creatinine, increased blood glucose,

increased blood phosphorus,

decreased blood potassium,

increased bilirubin

Injury, poisoning and procedural complications

Uncommon:

Contusion

Rare:

Radiation recall phenomenon,

radiation pneumonitis

As reported in the post-marketing surveillance of Abraxane.

The frequency of pneumonitis is calculated based on pooled data in 1310 patients in clinical trials receiving Abraxane monotherapy for breast

cancer and for other indications.

Based on laboratory assessments: maximal degree of myelosuppression (treated population).

In some patients previously exposed to capecitabine.

Description of selected adverse reactions

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 with

260 mg/m

Abraxane once every three weeks in the pivotal phase III clinical study (Abraxane

monotherapy).

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

Abraxane in combination with gemcitabine (125 mg/m

Abraxane in combination with gemcitabine at a

dose of 1000 mg/m

given on Days 1, 8 and 15 of each 28-day cycle) and 402 gemcitabine

monotherapy-treated patients receiving first-line systemic treatment for metastatic adenocarcinoma of the

pancreas (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/m

Abraxane given on Days 1, 8 and 15 of each 21-day

cycle 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 4

subscales of the Functional Assessment of Cancer Therapy (FACT)-Taxane questionnaire. Using repeated

measure 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 the

treatment arms.

Infections and infestations

Abraxane/gemcitabine

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane in

combination with gemcitabine during the conduct of a trial in pancreatic adenocarcinoma. Of the 22 cases

of sepsis reported in patients treated with Abraxane in combination with gemcitabine, 5 had a fatal

outcome. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence

of biliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardless

of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold

Abraxane and gemcitabine until fever resolves and ANC ≥ 1500 cells/mm

, then resume treatment at

reduced dose levels (see section 4.2).

Blood and lymphatic system disorders

Abraxane monotherapy-metastatic breast cancer

In patients with metastatic breast cancer, 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 (< 500 cells/mm

) 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.

Abraxane/gemcitabine

Table 7 provides the frequency and severity of haematologic laboratory-detected abnormalities for

patients treated with Abraxane in combination with gemcitabine or with gemcitabine.

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

Abraxane (125 mg/m

Gemcitabine

Grades 1-4

(%)

Grade 3-4

(%)

Grades 1-4

(%)

Grade 3-4

(%)

Anaemia

a,b

97 13 96 12

Neutropenia

a,b

73 38 58 27

Thrombocytopenia

b,c

74 13 70 9

405 patients assessed in Abraxane/gemcitabine-treated group

388 patients assessed in gemcitabine-treated group

404 patients assessed in Abraxane/gemcitabine-treated group

Abraxane/carboplatin

Anaemia and thrombocytopenia were more commonly reported in the Abraxane and carboplatin arm than

in the Taxol and carboplatin arm (54% versus 28% and 45% versus 27% respectively).

Nervous system disorders

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% of

patients 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 occurrence

of Grade 3 peripheral neuropathy was 140 days. The median time to improvement by at least 1 grade was

21 days, and the median time to improvement from Grade 3 peripheral neuropathy to Grade 0 or 1 was 29

days. Of the patients with treatment interrupted due to peripheral neuropathy, 44% (31/70 patients) were

able to resume Abraxane at a reduced dose. No patients treated with Abraxane in combination with

gemcitabine had Grade 4 peripheral neuropathy.

Abraxane/carboplatin

For non-small cell lung cancer patients treated with Abraxane and carboplatin, the median time to first

occurrence of Grade 3 treatment-related peripheral neuropathy was 121 days, and the median time to

improvement from Grade 3 treatment related peripheral neuropathy to Grade 1 was 38 days. No patients

treated with Abraxane and carboplatin experienced Grade 4 peripheral neuropathy.

Eye disorders

There have been rare reports during post-marketing surveillance of reduced visual acuity due to cystoid

macular oedema during treatment with Abraxane (see section 4.4).

Respiratory, thoracic and mediastinal disorders

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 with

gemcitabine, 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 discontinue

treatment with Abraxane and gemcitabine and promptly initiate appropriate treatment and supportive

measures (see section 4.2).

Gastrointestinal disorders

Abraxane monotherapy-metastatic breast cancer

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

Skin and subcutaneous tissue disorders

Abraxane monotherapy-metastatic breast cancer

Alopecia was observed in >80% of the patients treated with Abraxane. The majority of alopecia events

occurred less than one month after initiation of Abraxane. Pronounced hair loss ≥ 50% is expected for the

majority of patients who experience alopecia.

Musculoskeletal and connective tissue disorders

Abraxane monotherapy-metastatic breast cancer

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 conditions

Abraxane monotherapy-metastatic breast cancer

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

Paediatric population

The study consisted of 106 patients, 104 of whom were paediatric patients aged from 6 months to less than

18 years (see section 5.1). Every patient experienced at least 1 adverse reaction. The most frequently

reported adverse reactions were neutropenia, anaemia, leukopenia and pyrexia. Serious adverse reactions

reported in more than 2 patients were pyrexia, back pain, peripheral oedema and vomiting. No new safety

signals were identified in the limited number of paediatric patients treated with Abraxane and the safety

profile was similar to that of the adult population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are

asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

There is no known antidote for paclitaxel overdose. In the event of an overdose, the patient should be

closely monitored. Treatment should be directed at the major anticipated toxicities, which are bone

marrow suppression, mucositis and peripheral neuropathy.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

ATC Code: L01CD01

Mechanism of action

Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and

stabilises microtubules by preventing depolymerisation. This stability results in the inhibition of the

normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic

cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules

throughout the cell cycle and multiple asters of microtubules during mitosis.

Abraxane contains human serum albumin-paclitaxel nanoparticles of approximately 130 nm in size, where

the paclitaxel is present in a non-crystalline, amorphous state. Upon intravenous administration, the

nanoparticles dissociate rapidly into soluble, albumin bound paclitaxel complexes of approximately 10 nm

in size. Albumin is known to mediate endothelial caveolar transcytosis of plasma constituents, and in vitro

studies demonstrated that the presence of albumin in Abraxane enhances transport of paclitaxel across

endothelial cells. It is hypothesised that this enhanced transendothelial caveolar transport is mediated by

the gp-60 albumin receptor, and that there is enhanced accumulation of paclitaxel in the area of tumour

due to the albumin-binding protein Secreted Protein Acidic Rich in Cysteine (SPARC).

Clinical efficacy and safety

Breast cancer

Data from 106 patients accrued in two single-arm open-label studies and from 454 patients treated in a

randomised Phase III comparative study are available to support the use of Abraxane in metastatic breast

cancer. 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/m

to 43 patients

with metastatic breast cancer. The second trial utilised a dose of 300 mg/m

as a 30-minute infusion in 63

patients 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 were

39.5% (95% CI: 24.9%-54.2%) and 47.6% (95% CI: 35.3%-60.0%), respectively. The median time to

disease progression was 5.3 months (175 mg/m

; 95% CI: 4.6-6.2 months) and 6.1 months (300 mg/m

;

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 3

weeks with single-agent paclitaxel, either as solvent-based paclitaxel 175 mg/m

given as a 3-hour

infusion with premedication to prevent hypersensitivity (N = 225), or as Abraxane 260 mg/m

given as a

30 minute infusion without premedication (N = 229).

Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had

visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received

prior chemotherapy; 27% had received chemotherapy in the adjuvant setting only, 40% in the metastatic

setting only, and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study medicinal

product as second or greater than second-line therapy. Seventy-seven percent of the patients had been

previously exposed to anthracyclines.

Results for overall response rate and time to disease progression, and progression-free survival and

survival for patients receiving > 1

-line therapy, are shown below.

Table 8: Results for overall response rate, median time to disease progression, and

progression-free survival as assessed by the investigator

Efficacy variable

Abraxane

(260 mg/m

)

Solvent-based paclitaxel

(175 mg/m

)

p-value

Response rate [95% CI] (%)

> 1

-line therapy

26.5 [18.98, 34.05] (n = 132)

13.2 [7.54, 18.93] (n = 136)

0.006

*Median time to disease progression [95% CI] (weeks)

> 1

-line therapy

20.9 [15.7, 25.9] (n = 131)

16.1 [15.0, 19.3] (n = 135)

0.011

*Median progression free survival [95% CI] (weeks)

> 1

-line therapy

20.6 [15.6, 25.9] (n = 131)

16.1 [15.0, 18.3] (n = 135)

0.010

*Survival [95% CI] (weeks)

> 1

-line therapy

56.4 [45.1, 76.9] (n = 131)

46.7 [39.0, 55.3] (n = 136)

0.020

This data is based on Clinical Study Report: CA012-0 Addendum dated Final (23 March-2005)

Chi-squared test

Log-rank test

Two hundred and twenty nine patients treated with Abraxane in the randomized, controlled clinical trial

were evaluated for safety. Neurotoxicity to paclitaxel was evaluated through improvement by one grade

for patients experiencing Grade 3 peripheral neuropathy at any time during therapy. The natural course of

peripheral neuropathy to resolution to baseline due to cumulative toxicity of Abraxane after > 6 courses of

treatment 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 metastatic

adenocarcinoma of the pancreas. Abraxane was administered to patients (N = 431) as an intravenous

infusion over 30-40 minutes at a dose of 125 mg/m

followed by gemcitabine as an intravenous infusion

over 30-40 minutes at a dose of 1000 mg/m

given on Days 1, 8 and 15 of each 28-day cycle. In the

comparator treatment arm, gemcitabine monotherapy was administered to patients (N = 430) in

accordance with the recommended dose and regimen. Treatment was administered until disease

progression or development of an unacceptable toxicity. Of the 431 patients with pancreatic

adenocarcinoma who were randomized to receive Abraxane in combination with gemcitabine, the

majority (93%) were white, 4% were black and 2% were Asian. 16% had a Karnofsky Performance Status

of 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 KPS

of below 70. Patients with high cardiovascular risk, history of peripheral artery disease and/or of

connective 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 2.8

months in the gemcitabine arm. 32% of patients in the Abraxane/gemcitabine arm compared with 15% of

patients in the gemcitabine arm received 6 or more months of treatment. For the treated population, the

median relative dose intensity for gemcitabine was 75% in the Abraxane/gemcitabine arm and 85% in the

gemcitabine arm. The median relative dose intensity of Abraxane was 81%. A higher median cumulative

dose of gemcitabine was delivered in the Abraxane/gemcitabine arm (11400 mg/m

) when compared with

the gemcitabine arm (9000 mg/m

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, blinded

radiological 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/m

)/gemcitabine

(N=431)

Gemcitabine

(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)

+G/G

(95% CI)

0.72 (0.617, 0.835)

P-value

<0.0001

Survival Rate % (95% CI) at

1 Year

35% (29.7, 39.5)

22% (18.1, 26.7)

2 Year

9% (6.2, 13.1)

4% (2.3, 7.2)

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)

+G/G

(95% CI)

0.69 (0.581, 0.821)

P-value

<0.0001

Abraxane(125 mg/m

)/gemcitabine

(N=431)

Gemcitabine

(N=430)

Overall Response Rate

Confirmed complete or partial

overall response, n (%)

99 (23) 31 (7)

95% CI

19.1, 27.2

5.0, 10.1

(95% CI)

3.19 (2.178, 4.662)

P-value

(chi-square test)

<0.0001

CI = confidence interval, HR

A+G/G

= hazard ratio of Abraxane+gemcitabine/gemcitabine, p

A+G

=response rate

ratio of

Abraxane+gemcitabine/gemcitabine

stratified Cox proportional hazard model

stratified log-rank test, stratified by geographic region (North America versus others), KPS (70 to 80 versus 90 to 100), and presence of liver

metastasis (yes versus no).

There was a statistically significant improvement in OS for patients treated with Abraxane/gemcitabine

versus 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)

Treatment effects on OS favoured the Abraxane/gemcitabine arm across the majority of pre-specified

subgroups (including gender, KPS, geographic region, primary location of pancreatic cancer, stage at

diagnosis, 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 the

survival HR was 1.07 (95% CI 0.692, 1.661).

(PT at Risk)

ABX/GEM

GEM

Time (months)

ABRAXANE+Gemcitabine

Gemcitabine

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Proportion

Survival

Proportion of Survival

There was a statistically significant improvement in PFS for patients treated with Abraxane/gemcitabine

versus gemcitabine alone, with 1.8 months increase in median PFS.

Non-small cell lung cancer

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 carboplatin

versus solvent-based paclitaxel in combination with carboplatin as first-line treatment in patients with

advanced 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 serious

medical risk factors involving any of the major organ systems were excluded. Abraxane was administered

to patients (N=521) as an intravenous infusion over 30 minutes at a dose of 100 mg/m

on Days 1, 8 and

15 of each 21-day cycle without any steroid premedication and without granulocyte colony stimulating

factor prophylaxis. Beginning immediately after the end of Abraxane administration, carboplatin at a dose

of 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/m

as an intravenous infusion

over 3 hours with standard premedication, immediately followed by carboplatin administered

intravenously at AUC = 6 mg•min/mL. Each drug was administered on Day 1 of each 21-day cycle. In

both study arms treatment was administered until disease progression or development of an unacceptable

toxicity. 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 who

achieved 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 a

significantly 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 of

squamous histology (N=450, 41% vs. 24%, p<0.001), however this difference did not translate into a

difference in PFS or OS. There was no difference in ORR between the treatment arms in patients with

non-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-treat

population)

Efficacy Parameter

Abraxane

(100 mg/m

/week)

+ carboplatin

(N=521)

Solvent-based paclitaxel

(200 mg/m

every 3 weeks)

+ carboplatin

(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, 28.5

(95.1% CI)

1.313 (1.082, 1.593)

P-value

0.005

CI = confidence interval; HR

A/T

= hazard ratio of Abraxane/carboplatin to solvent-based paclitaxel/carboplatin; p

= response rate ratio of

Abraxane/carboplatin to solvent-based paclitaxel/carboplatin.

P-value is based on a chi-square test.

There was no statistically significant difference in progression-free survival (by blinded radiologist

assessment) and overall survival between the two treatment arms. A non-inferiority analysis was

conducted for PFS and OS, with a pre-specified non-inferiority margin of 15%. The non-inferiority

criterion was met for both PFS and OS with the upper bound of the 95% confidence interval for the

associated hazard ratios being less than 1.176 (Table 11).

Table 11: Non-inferiority analyses on progression-free survival and overall survival in randomized

non-small cell lung cancer trial (intent-to-treat population)

Efficacy Parameter

Abraxane

(100 mg/m

/week)

+ carboplatin

(N=521)

Solvent-based paclitaxel

(200 mg/m

every 3 weeks)

+ carboplatin

(N=531)

Progression-free Survival

(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)

A/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)

A/T

(95.1% CI)

0.922 (0.797, 1.066)

CI = confidence interval; HR

A/T

= hazard ratio of Abraxane/carboplatin to solvent-based paclitaxel/carboplatin; p

= response rate ratio of

Abraxane/carboplatin to solvent-based paclitaxel/carboplatin.

Per EMA methodological considerations for PFS endpoint, missing observations or initiation of subsequent new therapy were not used for

censoring.

Paediatric population

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 refractory

solid 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 years

old and determined the maximum tolerated dose (MTD) to be 240 mg/m

, administered as an intravenous

infusion 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 6

months to 24 years with recurrent or refractory Ewing’s sarcoma, neuroblastoma or rhabdomyosarcoma

for the evaluation of antitumour activity assessed by the overall response rate (ORR). Of the 42 patients, 1

patient was < 2, 27 were aged ≥ 2 to < 12, 12 were aged ≥12 to < 18 and 2 adult patients were aged ≥ 18 to

24 years old.

Patients were treated for a median of 2 cycles at the MTD. From the 41 patients eligible for efficacy

evaluation 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 was

observed in either the Ewing’s sarcoma group (N=13) or the neuroblastoma group (N=14). None of the

study arms continued into stage 2 because the protocol-defined requirement of ≥ 2 patients to have a

confirmed 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’s

sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively.

The overall safety profile of Abraxane in paediatric patients was consistent with the known safety profile

of Abraxane in adults (see section 4.8). Based on these results, it was concluded that Abraxane as

monotherapy does not have meaningful clinical activity or survival benefit that warrants further

development in the paediatric population.

5.2 Pharmacokinetic properties

The pharmacokinetics of total paclitaxel following 30- and 180-minute infusions of Abraxane at dose

levels of 80 to 375 mg/m

were determined in clinical studies. The paclitaxel exposure (AUC) increased

linearly from 2653 to 16736 ng.hr/ml following dosing from 80 to 300 mg/m

In a study in patients with advanced solid tumours, the pharmacokinetic characteristics of paclitaxel

following Abraxane administered intravenously at 260 mg/m

over 30 minutes were compared with those

following 175 mg/m

of the solvent-based paclitaxel injection administered over 3 hours. Based on

non-compartmental PK analysis, the plasma clearance of paclitaxel with Abraxane was larger (43%) than

that 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/m

intra-patient variability in AUC was 19% (range = 3.21%-37.70%). There was no evidence for

accumulation of paclitaxel with multiple treatment courses.

Distribution

Following Abraxane administration to patients with solid tumours, paclitaxel is evenly distributed into

blood 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-patient

comparison study. The fraction of free paclitaxel was significantly higher with Abraxane (6.2%) than with

solvent-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 is

possibly 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 at

concentrations 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 of

paclitaxel.

Biotransformation and elimination

Based on the published literature, in vitro studies with human liver microsomes and tissue slices show that

paclitaxel is metabolised primarily to 6α-hydroxypaclitaxel; and to two minor metabolites,

3’-p-hydroxypaclitaxel and 6α-3’-p-dihydroxypaclitaxel. The formation of these hydroxylated metabolites

is 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/m

, the mean

value for cumulative urinary excretion of unchanged active substance accounted for 4% of the total

administered 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 and

biliary excretion.

At the clinical dose range of 80 to 300 mg/m

, the mean plasma clearance of paclitaxel ranges from 13 to

30 L/h/m

, and the mean terminal half-life ranges from 13 to 27 hours.

Hepatic impairment

The effect of hepatic impairment on population pharmacokinetics of Abraxane was studied in patients

with advanced solid tumours. This analysis included patients with normal hepatic function (n=130), and

pre-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 a

22% to 26% decrease in the maximum elimination rate of paclitaxel and approximately 20% increase in

mean paclitaxel AUC compared with patients with normal hepatic function. Hepatic impairment has no

effect on mean paclitaxel C

max

. In addition, elimination of paclitaxel shows an inverse correlation with

total bilirubin and a positive correlation with serum albumin.

Pharmacokinetic/pharmacodynamic modeling indicates that there is no correlation between hepatic

function (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 with

metastatic adenocarcinoma of the pancreas (see section 4.2).

Renal impairment

Population pharmacokinetic analysis included patients with normal renal function (n=65), and pre-existing

mild (n=61), moderate (n=23), or severe (n=l) renal impairment (according to draft FDA guidance criteria

2010). Mild to moderate renal impairment (creatinine clearance ≥30 to <90 ml/min) has no clinically

important effect on the maximum elimination rate and systemic exposure (AUC and C

max

) of paclitaxel.

Pharmacokinetic data are insufficient for patients with severe renal impairment and not available for

patients with end stage kidney disease.

Elderly

Population pharmacokinetic analysis for Abraxane included patients with ages ranging from 24 to 85

years old and shows that age does not significantly influence the maximum elimination rate and systemic

exposure (AUC and C

max

) of paclitaxel.

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, although the plasma paclitaxel exposure is not affected by age.

Paediatric population

The pharmacokinetics of paclitaxel following 30 minutes of intravenous administration at dose levels of

120 mg/m

to 270 mg/m

were determined in 64 patients (2 to ≤ 18 years) in Phase 1 of a Phase 1/2 study

in recurrent or refractory paediatric solid tumours. Following dosing increase from 120 to 270 mg/m

, the

paclitaxel mean AUC

(0-inf)

and C

max

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/m

to 240 mg/m

; with

lower dose-normalized AUC

∞

at the 270 mg/m

dose level. At the MTD of 240 mg/m

, the mean CL was

19.1 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 drug

exposures were higher than in adult patients.

Other intrinsic factors

Population pharmacokinetic analyses for Abraxane indicate that gender, race (Asian vs. White), and type

of solid tumours do not have a clinically important effect on systemic exposure (AUC and C

max

) of

paclitaxel. Patients weighing 50 kg had paclitaxel AUC approximately 25% lower than those weighing 75

kg. The clinical relevance of this finding is uncertain.

5.3 Preclinical safety data

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 its

pharmacodynamic 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 has

been 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 administered

prior and during mating in male and female rats and foetal toxicity in rats. Animal studies with Abraxane

showed 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 intravenous

administration of radiolabelled paclitaxel to rats on days 9 to 10 postpartum, concentrations of

radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

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

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in

section 6.6.

6.3 Shelf life

Unopened vials

3 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 original

carton, 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 hours

at 25°C, protected from light.

However, from a microbiological point of view, unless the method of reconstituting and filling of the

infusion bags precludes the risks of microbial contamination, the product should be used immediately after

reconstitution 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 bag

when refrigerated and protected from light is 24 hours. This may be followed by storage in the infusion

bag for 4 hours below 25°C.

6.4 Special precautions for storage

Unopened vials

Keep the vial in the outer carton in order to protect from light. Neither freezing nor refrigeration adversely

affects the stability of the product. This medicinal product does not require any special temperature

storage conditions.

Reconstituted dispersion

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

6.5 Nature and contents of container

50 ml vial (type 1 glass) with a stopper (butyl rubber), with an overseal (aluminium), containing 100 mg

of paclitaxel formulated as albumin bound nanoparticles.

100 ml vial (type 1 glass) with a stopper (butyl rubber), with an overseal (aluminium), containing 250 mg

of paclitaxel formulated as albumin bound nanoparticles.

Pack size of one vial.

6.6 Special precautions for disposal and other handling

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 is

recommended. If the dispersion contacts the skin, the skin should be washed immediately and thoroughly

with soap and water. If it contacts mucous membranes, the membranes should be flushed thoroughly with

water. Abraxane should only be prepared and administered by personnel appropriately trained in the

handling of cytotoxic agents. Pregnant staff should not handle Abraxane.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible

infiltration during administration of the medicinal product. Limiting the infusion of Abraxane to 30

minutes, 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 infusion

should 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 infusion

should 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 injected

directly 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 ensure

proper wetting of the solid. Then, the vial should gently and slowly be swirled and/or inverted for at least

2 minutes until complete redispersion of any powder occurs. The generation of foam must be avoided. If

foaming 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 settling

of the reconstituted dispersion may occur. If precipitates or settling are visible, the vial should be gently

inverted again to ensure complete redispersion prior to use.

Inspect the dispersion in the vial for particulate matter. Do not administer the reconstituted dispersion if

particulate matter is observed in the vial.

The exact total dosing volume of 5 mg/ml dispersion required for the patient should be calculated and the

appropriate amount of reconstituted Abraxane should be injected into an empty, sterile, PVC or non-PVC

type intravenous bag.

The use of medical devices containing silicone oil as a lubricant (i.e. syringes and IV bags) to reconstitute

and administer Abraxane may result in the formation of proteinaceous strands. Administer Abraxane using

an infusion set incorporating a 15 µm filter to avoid administration of these strands. Use of a 15 µm filter

removes 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 is

not necessary to prepare or administer Abraxane infusions.

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.

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

7. MARKETING AUTHORISATION HOLDER

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/428/001

EU/1/07/428/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11 January 2008

Date of latest renewal: 14 January 2013

10. DATE OF REVISION OF THE TEXT

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

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

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Celgene Distribution B.V.

Orteliuslaan 1000

3528 BD Utrecht

Netherlands

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product

Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION

• Periodic safety update reports (PSUR)

The requirements for submission of PSURs for this medicinal product are set out in the list of Union

reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any

subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT

• Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and

interventions detailed in the agreed RMP presented in Module 1.8.2. of the marketing authorisation and

any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• At the request of the European Medicines Agency;

• Whenever the risk management system is modified, especially as the result of new information

being received that may lead to a significant change to the benefit/risk profile or as the result of an

important (pharmacovigilance or risk minimisation) milestone being reached.

ANNEX III

LABELLING AND PACKAGE LEAFLET

A. LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Carton

1. NAME OF THE MEDICINAL PRODUCT

Abraxane 5 mg/ml powder for dispersion for infusion

paclitaxel

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

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

nanoparticles.

3. LIST OF EXCIPIENTS

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

4. PHARMACEUTICAL FORM AND CONTENTS

Powder for dispersion for infusion.

1 vial

100 mg/20 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Intravenous use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Abraxane should not be substituted for or with other paclitaxel formulations.

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Unopened vials: Keep the vial in the outer carton in order to protect from light.

Reconstituted dispersion: It can be stored refrigerated at 2°C to 8°C for up to 24 hours in either the vial

or an infusion bag, protected from light. The total combined storage time of reconstituted medicinal

product in the vial and in the infusion bag when refrigerated and protected from light is 24 hours. This

may be followed by storage in the infusion bag for 4 hours below 25°C.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/428/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2 D bar code carrying the unique identifier

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

Vial

1. NAME OF THE MEDICINAL PRODUCT

Abraxane 5 mg/ml powder for dispersion for infusion

paclitaxel

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

After reconstitution, each ml of dispersion contains 5 mg of paclitaxel.

3. LIST OF EXCIPIENTS

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

4. PHARMACEUTICAL FORM AND CONTENTS

Powder for dispersion for infusion.

1 vial

100 mg/20 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Intravenous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Unopened vials: Keep the vial in the outer carton in order to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/428/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2 D bar code carrying the unique identifier

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Carton

1. NAME OF THE MEDICINAL PRODUCT

Abraxane 5 mg/ml powder for dispersion for infusion

paclitaxel

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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 bound

nanoparticles.

3. LIST OF EXCIPIENTS

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

4. PHARMACEUTICAL FORM AND CONTENTS

Powder for dispersion for infusion.

1 vial

250 mg/50 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Intravenous use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Abraxane should not be substituted for or with other paclitaxel formulations.

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Unopened vials: Keep the vial in the outer carton in order to protect from light.

Reconstituted dispersion: It can be stored refrigerated at 2°C to 8°C for up to 24 hours in either the vial

or an infusion bag, protected from light. The total combined storage time of reconstituted medicinal

product in the vial and in the infusion bag when refrigerated and protected from light is 24 hours. This

may be followed by storage in the infusion bag for 4 hours below 25°C.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/428/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2 D bar code carrying the unique identifier

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

Vial

1. NAME OF THE MEDICINAL PRODUCT

Abraxane 5 mg/ml powder for dispersion for infusion

paclitaxel

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

After reconstitution, each ml of dispersion contains 5 mg of paclitaxel.

3. LIST OF EXCIPIENTS

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

4. PHARMACEUTICAL FORM AND CONTENTS

Powder for dispersion for infusion.

1 vial

250 mg/50 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Intravenous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Unopened vials: Keep the vial in the outer carton in order to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/07/428/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2 D bar code carrying the unique identifier

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

B. PACKAGE LEAFLET

Package leaflet: Information for the user

Abraxane 5 mg/ml powder for dispersion for infusion

paclitaxel

Read all of this leaflet carefully before you start using this medicine because it contains important

information for you.

- Keep this leaflet. You may need to read it again.

- If you have any further questions, ask your doctor or nurse.

- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even

if their signs of illness are the same as yours.

- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not

listed in this leaflet. See section 4.

What is in this leaflet:

1. What Abraxane is and what it is used for

2. What you need to know before you are given Abraxane

3. How to use Abraxane

4. Possible side effects

5. How to store Abraxane

6. Contents of the pack and other information

1. What Abraxane is and what it is used for

What Abraxane is

Abraxane contains, as its active substance, paclitaxel attached to the human protein albumin, in the form

of tiny particles known as nanoparticles. Paclitaxel belongs to a group of medicines called “taxanes” used

in cancer.

• Paclitaxel is the part of the medicine that affects the cancer, it works by stopping cancer cells from

dividing – this means that they die.

• Albumin is the part of the medicine that helps paclitaxel dissolve in the blood and get across the

walls of the blood vessels into the tumour. This means that other chemicals that can cause side

effects that can be life threatening are not needed. Such side effects occur far less with Abraxane.

What Abraxane is used for

Abraxane is used to treat the following types of cancer:

Breast Cancer

• Breast cancer which has spread to other parts of the body (this is called “metastatic” breast cancer).

• Abraxane is used in metastatic breast cancer when at least one other therapy has been tried but has

not worked and you are unsuitable for treatments containing a group of medicines called

“anthracyclines”.

• People with metastatic breast cancer who received Abraxane where another therapy had failed, were

more likely to experience a reduction in tumour size, and lived longer than people who took an

alternative therapy.

Pancreatic cancer

• Abraxane is used together with a medicine called gemcitabine if you have metastatic cancer of the

pancreas. People with metastatic pancreatic cancer (pancreatic cancer that has spread to other parts

of the body) who received Abraxane with gemcitabine in a clinical trial lived longer than people

who had only received gemcitabine.

Lung Cancer

• Abraxane is also used together with a medicine called carboplatin if you have the most common

type of lung cancer, called “non-small cell lung cancer”.

• Abraxane is used in non-small cell lung cancer where surgery or radiotherapy would not be suitable

to treat the disease.

2. What you need to know before you are given Abraxane

Do not use Abraxane

• if you are allergic (hypersensitive) to paclitaxel or any of the other ingredients of Abraxane (listed in

section 6);

• if you are breast-feeding;

• if you have a low white blood cell count (baseline neutrophil counts <1500 cells/mm

- your doctor

will advise you on this).

Warnings and precautions

Talk to your doctor or nurse before using Abraxane

• if you have poor kidney function;

• if you have severe liver problems;

• if you have heart problems.

Talk to your doctor or nurse if you experience any of these conditions whilst being treated with Abraxane,

your doctor may wish to stop treatment or reduce the dose:

• if you experience any abnormal bruising, bleeding, or signs of infections such as a sore throat or a

fever;

• if you experience numbness, tingling, pricking sensations, sensitivity to touch, or muscle weakness;

• if you experience breathing problems, like shortness of breath or dry cough.

Children and adolescents

Abraxane is only for adults and should not be taken by children and adolescents aged below 18 years.

Other medicines and Abraxane

Tell your doctor if you are taking or have recently taken any other medicines. This includes medicines

obtained without a prescription, including herbal medicines. This is because Abraxane can affect the way

some other medicines work. Also, some other medicines can affect the way Abraxane works.

Take care and speak to your doctor when taking Abraxane at the same time as any of the following:

• medicines for treating infections (i.e. antibiotics such erythromycin, rifampicin, etc.; ask your

doctor, nurse or pharmacist if you are unsure whether the medicine you are taking is an antibiotic),

and including medicines for treating fungal infections (e.g. ketoconazole)

• medicines used to help you stabilize your mood also sometimes referred to as anti-depressants (e.g.

fluoxetine)

• medicines used to treat seizures (epilepsy) (e.g. carbamazepine, phenytoin)

• medicines used to help you lower blood lipid levels (e.g. gemfibrozil)

• medicine used for heartburn or stomach ulcers (e.g. cimetidine)

• medicines used to treat HIV and AIDS (e.g. ritonavir, saquinavir, indinavir, nelfinavir, efavirenz,

nevirapine)

• a medicine called clopidogrel used to prevent blood clots.

Pregnancy breast-feeding and fertility

Paclitaxel may cause serious birth defects and should therefore not be used if you are pregnant. Your

doctor will arrange a pregnancy test before starting treatment with Abraxane.

Women of childbearing age should use effective contraception during and up to 1 month after receiving

treatment with Abraxane.

Do not breast feed when taking Abraxane as it is not known if the active ingredient paclitaxel passes into

the mother’s milk.

Male patients are advised to use effective contraception and to avoid fathering a child during and up to six

months after treatment and should seek advice on conservation of sperm prior to treatment because of the

possibility of irreversible infertility due to therapy with Abraxane.

Ask your doctor for advice before taking this medicine.

Driving and using machines

Some people may feel tired or dizzy after being given Abraxane. If this happens to you, do not drive or use

any tools or machines.

If you are given other medicines as part of your treatment, you should ask your doctor for advice on

driving and using machines.

Abraxane contains sodium

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

free’.

3. How to use Abraxane

Abraxane will be given to you by a doctor or nurse into a vein from an intravenous drip. The dose you

receive is based on your body surface area and blood test results. The usual dose is for breast cancer is

260 mg/m

of body surface area given over a 30 minute period. The usual dose for advanced pancreatic

cancer is 125 mg/m

of body surface area given over a 30 minute period. The usual dose for non-small cell

lung cancer is 100 mg/m

of body surface area given over a 30 minute period.

How often will you receive Abraxane?

For treatment of metastatic breast cancer, Abraxane is usually given once every three weeks (on day 1 of a

21-day cycle).

For treatment of advanced pancreatic cancer, Abraxane is given on days 1, 8 and 15 of each 28-day

treatment cycle with gemcitabine being given immediately after the Abraxane.

For treatment of non-small cell lung cancer Abraxane is given once every week (i.e. on days 1, 8 and 15 of

a 21-day cycle), with carboplatin being given once every three weeks (i.e. only on day 1 of each 21-day

cycle), immediately after the Abraxane dose has been given.

If you have any further questions on the use of this medicine, ask your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.

The very common side effects may affect more than 1 in 10 people:

• Loss of hair (the majority of cases of hair loss happened less than one month after starting

Abraxane. When it happens, hair loss is pronounced (over 50%) in the majority of patients)

• Rash

• Abnormal decrease in the number of types of white blood cells (neutrophils, lymphocytes or

leukocytes) in the blood

• Deficiency of red blood cells

• Reduction in the number of platelets in the blood

• Effect on peripheral nerves (pain, numbness, tingling or loss of feeling)

• Pain in a joint or joints

• Pain in the muscles

• Nausea, diarrhoea, constipation, sore mouth, loss of appetite

• Vomiting

• Weakness and tiredness, fever

• Dehydration, taste disturbance, weight loss

• Low levels of potassium in the blood

• Depression, sleep problems

• Headache

• Chills

• Difficulty in breathing

• Dizziness

• Swelling of mucosal and soft tissues

• Increased liver function tests

• Pain in extremities

• Cough

• Abdominal pain

• Nose bleeds

The common side effects may affect up to 1 in 10 people:

• Itching, dry skin, nail disorder

• Infection, fever with decrease in the number of a type of white blood cell (neutrophils) in the blood,

flushing, thrush, severe infection in your blood which may be caused by reduced white blood cells

• Reduction in all blood cell counts

• Chest or throat pain

• Indigestion, abdominal discomfort

• Stuffy nose

• Pain in back, bone pain

• Diminished muscular coordination or difficulty in reading, increased or decreased tears, loss of

eyelashes

• Changes in heart rate or rhythm, heart failure

• Decreased or increased blood pressure

• Redness or swelling at the site where the needle entered the body

• Anxiety

• Infection in the lungs

• Infection in the urinary tract

• Obstruction in the gut, inflammation of the large bowel, inflammation of the bile duct

• Acute kidney failure

• Increased bilirubin in the blood

• Coughing up blood

• Dry mouth, difficulty in swallowing

• Muscle weakness

• Blurred vision

The uncommon side effects may affect up to 1 in 100 people:

• Increased weight, increased lactate dehydrogenase in the blood, decreased kidney function,

increased blood sugar, increased phosphorus in the blood

• Decreased or lack of reflexes, involuntary movements, pain along a nerve, fainting, dizziness when

standing up, shaking, facial nerve paralysis

• Irritated eyes, painful eyes, red eyes, itchy eyes, double vision, reduced vision, or seeing flashing

lights, blurred vision due to swelling of the retina (cystoid macular oedema)

• Ear pain, ringing in your ears

• Coughing with phlegm, shortness of breath when walking or climbing stairs, runny nose, or dry

nose, decreased breath sounds, water on the lung, loss of voice, blood clot in the lung, dry throat

• Gas, stomach cramps, painful or sore gums, rectal bleeding

• Painful urination, frequent urination, blood in the urine, inability to hold your urine

• Fingernail pain, fingernail discomfort, loss of fingernails, hives, skin pain, red skin from sunlight,

skin discolouration, increased sweating, night sweats, white areas on the skin, sores, swollen face

• Decreased phosphorus in the blood, fluid retention, low albumin in the blood, increased thirst,

decreased calcium in the blood, decreased sugar in the blood, decreased sodium in the blood

• Pain and swelling in the nose, skin infections, infection due to catheter line

• Bruising

• Pain at site of tumour, death of the tumour

• Decreased blood pressure when standing up, coldness in your hands and feet

• Difficulty walking, swelling

• Allergic reaction

• Decreased liver function, increased size of liver

• Pain in the breast

• Restlessness

• Small bleedings in your skin due to blood clots

• A condition involving destruction of red blood cells and acute kidney failure

The rare side effects may affect up to 1 in 1,000 people:

• Skin reaction to another agent or lung inflammation following radiation

• Blood clot

• Very slow pulse, heart attack

• Leaking of drug outside the vein

• A disorder of the electrical conduction system of the heart (atrioventricular block)

The very rare side effects may affect up to 1 in 10,000 people:

• Severe inflammation/eruption of the skin and mucous membranes (Stevens-Johnson syndrome,

toxic epidermal necrolysis)

Not known side effects (frequency cannot be estimated from the available data):

• Hardening/thickening of the skin (scleroderma).

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in

this leaflet. You can also report side effects directly via the national reporting system listed in Appendix

V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Abraxane

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and the vial after EXP. The

expiry date refers to the last day of that month.

Unopened vials: Keep the vial in the outer carton in order to protect from light.

After first reconstitution the dispersion should be used immediately. If not used immediately, the

dispersion may be stored in a refrigerator (2°C-8°C) for up to 24 hours in the vial when kept in the outer

carton in order to protect it from light.

The reconstituted dispersion in the intravenous drip may be stored in a refrigerator (2°C-8°C) for up to 24

hours protected from light.

The total combined storage time of reconstituted medicinal product in the vial and in the infusion bag

when refrigerated and protected from light is 24 hours. This may be followed by storage in the infusion

bag for 4 hours below 25°C.

Your doctor or pharmacist is responsible for disposing of any unused Abraxane correctly.

6. Contents of the pack and further information

What Abraxane contains

The active substance is paclitaxel.

Each vial contains 100 mg or 250 mg of paclitaxel formulated as albumin bound nanoparticles.

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

nanoparticles.

The other ingredient is human albumin solution (containing sodium caprylate and N-acetyl-L-tryptophan),

see section 2 “Abraxane contains sodium”.

What Abraxane looks like and contents of the pack

Abraxane is a white to yellow powder for dispersion for infusion. Abraxane is available in glass vials

containing 100 mg or 250 mg of paclitaxel formulated as albumin bound nanoparticles.

Each pack contains 1 vial.

Marketing Authorisation Holder

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

Manufacturer

Celgene Distribution B.V.

Orteliuslaan 1000

3528 BD Utrecht

Netherlands

For any information about this medicine, please contact the Marketing Authorisation Holder.

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu

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Medical or healthcare professionals

The following information is intended for medical or healthcare professionals only:

Instructions for use, handling and disposal

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. Gloves, goggles and protective clothing should be

used. If Abraxane dispersion contacts the skin, the skin should be washed immediately and thoroughly

with soap and water. If Abraxane contacts mucous membranes, the membranes should be flushed

thoroughly with water. Abraxane should only be prepared and administered by personnel appropriately

trained in the handling of cytotoxic agents. Pregnant staff should not handle Abraxane.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible

infiltration during administration of the medicinal product. Limiting the infusion of Abraxane to 30

minutes, as directed, reduces the likelihood of infusion-related reactions.

Reconstitution of the product and administration

Abraxane should be administered under the supervision of a qualified oncologist in units specialised in the

administration of cytotoxic agents.

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.

Reconstituted Abraxane dispersion is administered intravenously using an infusion set incorporating a

15 µm filter.

Reconstitution of 100 mg:

Using a sterile syringe, 20 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion should slowly be

injected into the 100 mg vial of Abraxane over a minimum of 1 minute.

Reconstitution of 250 mg:

Using a sterile syringe, 50 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion should slowly be

injected into the 250 mg 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 injected

directly 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 ensure

proper wetting of the solid. Then, the vial should gently and slowly be swirled and/or inverted for at least

2 minutes until complete redispersion of any powder occurs. The generation of foam should be avoided. If

foaming or clumping occurs, the dispersion should stand for at least 15 minutes until foam subsides.

The reconstituted dispersion should be milky and homogenous without visible precipitates. Some settling

of the reconstituted dispersion may occur. If precipitates or settling are visible, the vial should be gently

inverted again to ensure complete redispersion prior to use.

Inspect the dispersion in the vial for particulate matter. Do not administer the reconstituted dispersion if

particulate matter is observed in the vial.

The exact total dosing volume of 5 mg/ml dispersion required for the patient should be calculated and the

appropriate amount of reconstituted Abraxane should be injected into an empty, sterile, PVC or non-PVC

type intravenous bag

The use of medical devices containing silicone oil as a lubricant (i.e. syringes and IV bags) to reconstitute

and administer Abraxane may result in the formation of proteinaceous strands. Administer Abraxane using

an infusion set incorporating a 15 µm filter to avoid administration of these strands. Use of a 15 µm filter

removes 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 DEHP-free solution containers or administration sets is not necessary to prepare or

administer Abraxane infusions.

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.

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

Stability

Unopened vials of Abraxane are stable until the date indicated on the package when the vial is kept in the

outer carton in order to protect from light. Neither freezing nor refrigeration adversely affects the stability

of the product. This medicinal product does not require any special temperature storage conditions.

Stability of the reconstituted dispersion in the vial

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C-8°C in the original

carton, 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 hours

at 25°C, protected from light.

However, from a microbiological point of view, unless the method of reconstituting and filling of the

infusion bags precludes the risks of microbial contamination, the product should be used immediately

after reconstitution 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 bag

when refrigerated and protected from light is 24 hours. This may be followed by storage in the infusion

bag for 4 hours below 25°C.