ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Abraxane
5 mg/ml powder for suspension for infusion.
2.
Each vial contains 100 mg of paclitaxel (as paclitaxel albumin).
After reconstitution, each ml of suspension contains 5 mg of paclitaxel (as paclitaxel albumin).
Excipients
The reconstituted medicinal product contains approximately 425 mg sodium per dose.
For a full list of excipients, see section 6.1.
3.
Powder for suspension for infusion.
The reconstituted suspension has a pH of 6-7.5 and an osmolality of 300-360 mOsm/kg.
The powder is white to yellow.
4.
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).
Posology
The recommended dose of Abraxane is 260 mg/m
2
administered intravenously over 30 minutes every
3 weeks.
Dose adjustments during treatment:
Patients who experience severe neutropenia (neutrophil count < 0.50 x 10
9
/l for a week or longer) or
severe sensory neuropathy during Abraxane therapy should have the dose reduced to 220 mg/m
2
for
subsequent courses. Following recurrence of severe neutropenia or severe sensory neuropathy,
additional dose reduction should be made to 180 mg/m
2
. Abraxane should not be administered until
neutrophil counts recover to >1.5 x 10
9
/l. For grade 3 sensory neuropathy withhold treatment until
resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses.
Patients with hepatic impairment
:
Insufficient data are currently available to recommend dose modifications in patients with mild to
moderate hepatic impairment that ensure acceptable toxicity while maintaining efficacy. Patients with
severe hepatic impairment should not be treated with paclitaxel (see sections 4.4.and 5.2).
2
Patients with impaired renal function:
Studies in patients with impaired renal function have not been performed and insufficient data are
currently available to recommend dose modifications in patients with renal impairment (see section
5.2).
Paediatric population:
The safety and efficacy of Abraxane in children has not been established. There is no relevant use of
Abraxane in the paediatric population in the indication of metastatic breast cancer.
Elderly patients:
In the clinical studies, no toxicities occurred notably more frequently among elderly patients who
received Abraxane.
Method of administration
Abraxane should only be administered under the supervision of a qualified oncologist in units
specialised in the administration of cytotoxic agents.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
Hypersensitivity to the active substance or to any of the excipients.
Lactation.
Patients who have baseline neutrophil counts < 1.5 x 10
9
/l.
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:
If hypersensitivity occurs, the medicinal product should be discontinued immediately, symptomatic
treatment should be initiated, and that patient should not be rechallenged with paclitaxel.
Haematology:
Bone marrow suppression (primarily neutropenia) occurs frequently with Abraxane. Neutropenia is
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 >1.5 x 10
9
/l and platelets recover to >100 x 10
9
/l.
Neuropathy:
Sensory neuropathy occurs frequently with Abraxane, although development of severe symptoms is
less common. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose
reduction. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to
grade 1 or 2 followed by a dose reduction for all subsequent courses of Abraxane is recommended (see
section 4.2).
3
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, and such patients
should be closely monitored for development of profound myelosuppression.
Patients with severe hepatic impairment (bilirubin > 5 x ULN or AST/ALT > 10 x ULN) have not
been studied and should not be treated with Abraxane. The appropriate dose regimen in patients with
less severe hepatic impairment is unknown. A dose reduction in patients with bilirubin >2 ULN must
be considered since paclitaxel clearance is decreased in patients with high bilirubin levels (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 drugs,
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.
Excipients:
When reconstituted, Abraxane contains approximately 425 mg sodium per dose. To be taken into
consideration by patients on a controlled sodium diet.
No interaction studies have been performed.
The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and
CYP3A4 (see section 5.2). Therefore, caution should be exercised when administering paclitaxel
concomitantly with medicines known to inhibit (e.g. ketoconazole and other imidazole
antifungals,erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir,
and
nelfinavir)) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) either
CYP2C8 or CYP3A4.
Abraxane is indicated for mono-therapy. Abraxane should not be used in combination with other
anticancer agents.
Contraception in males and females
Women of childbearing potential should use effective contraception during and up to 1 month after
receiving treatment with Abraxane. Male patients treated with Abraxane are advised not to father a
child during and up to six months after treatment.
4
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). 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.
Breastfeeding:
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. Breastfeeding must be
discontinued for the duration of therapy.
Fertility:
Abraxane induced infertility in male rats (see section 5.3). Male patients should seek advice on
conservation of sperm prior to treatment because of the possibility of irreversible infertility due to
therapy with Abraxane.
Sexually active men and women should use effective methods of contraception during treatment and
up to six months after treatment for men, and one month after treatment for women.
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.
The following are the most common and important incidences of adverse reactions related to 229
patients with metastatic breast cancer who were treated with 260 mg/m
2
Abraxane once every three
weeks in the pivotal phase III clinical study.
Blood and lymphatic system disorders:
Neutropenia was the most notable important haematological
toxicity (reported in 79% of patients), and was rapidly reversible and dose dependent; leukopenia was
reported in 71% of patients. Grade 4 neutropenia (< 0.5 x 10
9
/l) occurred in 9% of patients treated with
Abraxane. Febrile neutropenia occurred in four patients on Abraxane. Anaemia
(Hb < 10 g/dl) was
observed in 46% of patients on Abraxane, and was severe (Hb < 8 g/dl) in three cases. Lymphopenia
was observed in 45% of the patients.
Nervous system disorders
: In general, the frequency and severity of neurotoxicity was 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.
Gastrointestinal disorders
: Nausea occurred in 29% of the patients and diarrhoea in 25% of the
patients.
Skin and subcutaneous tissue disorders
: Alopecia was observed in 90% of the patients treated with
Abraxane.
Musculoskeletal and connective tissue disorders
: Arthralgia occurred in 32% of patients on Abraxane
and was severe in 6% of cases. Myalgia occurred in 24% of patients on Abraxane and was severe in
5
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
: Asthenia/Fatigue was reported in 40% of the
patients.
Table 1 lists adverse reactions associated with the administration of Abraxane to patients from studies
in which Abraxane has been administered as a single agent at any dose in any indication (N = 789).
The frequency of undesirable effects listed in table 1 is defined using the following convention:
Very common (≥1/10); common (≥ 1/100 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, undesirable effects are presented in order of decreasing seriousness.
Table 1: Adverse reactions reported with Abraxane at any dose in clinical studies
.
Common
: Infection, urinary tract infection, folliculitis, upper respiratory
tract infection, candidiasis, sinusitis
Infections and
infestations
Uncommon
: Oral candidiasis, nasopharyngitis, cellulitis, herpes simplex,
viral infection, pneumonia, catheter-related infection, fungal infection,
herpes zoster, injection site infection
Neoplasms benign,
malignant and
unspecified (including
cysts and polyps)
Uncommon:
Metastatic pain, tumour necrosis
Very Common
: Neutropenia, anaemia, leukopenia, thrombocytopenia,
lymphopenia, bone marrow suppression
Blood and lymphatic
system disorders
Common
: Febrile neutropenia
Rare
: Pancytopenia
Uncommon
1
:
Hypersensitivity
Immune system
disorders
Rare:
Severe
hypersensitivity
Very common:
Anorexia
Metabolism and
nutrition disorders
Common:
Dehydration, decreased appetite, hypokalaemia
Uncommon:
Hypophosphataemia, fluid retention, hypoalbuminaemia,
polydipsia, hyperglycaemia, hypocalcaemia, hypoglycaemia,
hyponatraemia
Common
: Insomnia, depression, anxiety
Psychiatric disorders
Uncommon
: Restlessness
Very Common
: Peripheral neuropathy, neuropathy, hypoaesthesia,
paraesthesia.
Nervous system
disorders
Common
: Peripheral sensory neuropathy, headache, dysgeusia, dizziness,
peripheral motor neuropathy, ataxia, sensory disturbance, somnolence.
Uncommon
: Polyneuropathy, areflexia, dyskinesia, hyporeflexia,
neuralgia, sensory loss, syncope, postural dizziness, neuropathic pain,
tremor
6
Table 1: Adverse reactions reported with Abraxane at any dose in clinical studies
.
Common:
Increased lacrimation, blurred vision, dry eye,
keratoconjunctivitis sicca, madarosis
Eye disorders
Uncommon
: Eye irritation, eye pain, abnormal vision, reduced visual
acuity, conjunctivitis, visual disturbance, eye pruritus, keratitis
Ear and labyrinth
disorders
Common
: Vertigo
Uncommon
: Ear pain, tinnitus
Common
: Tachycardia, arrhythmia, supraventricular tachycardia
Cardiac disorders
Rare:
bradycardia, cardiac arrest, left ventricular dysfunction, congestive
heart failure
Common
: Flushing, hot flushes, hypertension, lymphoedema
Vascular disorders
Uncommon
: Hypotension, peripheral coldness, orthostatic hypotension
Rare:
Thrombosis
Common
: Dyspnoea, epistaxis, pharyngolaryngeal pain, cough, rhinitis,
rhinorrhoea
Respiratory, thoracic and
mediastinal disorders
Uncommon
: Productive cough, exertional dyspnoea, sinus congestion,
decreased breath sounds, pleural effusion, allergic rhinitis, hoarseness,
nasal congestion, nasal dryness, wheezing, pulmonary emboli, pulmonary
thromboembolism
Rare:
Interstitial pneumonitis
Very Common
: Nausea, diarrhoea, vomiting, constipation, stomatitis
Gastrointestinal
disorders
Common
: Abdominal pain, abdominal distension, upper abdominal pain,
dyspepsia, gastrooesophageal reflux disease, oral hypoaesthesia
Uncommon
: Dysphagia, flatulence, glossodynia, dry mouth, gingival pain,
loose stools, oesophagitis, lower abdominal pain, mouth ulceration, oral
pain, rectal haemorrhage
Hepatobiliary disorders
Uncommon
: Hepatomegaly
Very Common
: Alopecia, rash
Skin and subcutaneous
tissue disorders
Common
: Nail disorder, pruritus, dry skin, erythema, nail
pigmentation/discolouration, skin hyperpigmentation, onycholysis, nail
changes
Uncommon
: Nail bed tenderness, urticaria, skin pain, photosensitivity
reaction, pigmentation disorder, pruritic rash, skin disorder, hyperhidrosis,
onychomadesis, erythematous rash, generalised rash, dermatitis, night
sweats, maculo-papular rash, vitiligo, hypotrichosis, nail discomfort,
generalized pruritus, macular rash, papular rash, skin lesion, swollen face
Very Common
: Arthralgia, myalgia.
Musculoskeletal and
connective tissue
disorders
Common
: Pain in extremity, bone pain, back pain, muscle cramps, limb
pain
Uncommon
: Chest wall pain, muscular weakness, neck pain, groin pain,
muscle spasms, musculoskeletal pain, flank pain, limb discomfort, muscle
weakness
7
Table 1: Adverse reactions reported with Abraxane at any dose in clinical studies
.
Renal and urinary
disorders
Uncommon
: Dysuria, pollakiuria, haematuria, nocturia, polyuria, urinary
incontinence
Reproductive system and
breast disorders
Uncommon
: Breast pain
Very Common
: Fatigue, asthenia, pyrexia.
General disorders and
administration site
conditions
Common
: Peripheral oedema, mucosal inflammation, pain, rigors, oedema,
weakness, decreased performance status, chest pain, influenza-like illness,
malaise, lethargy, hyperpyrexia
Uncommon
: Chest discomfort, abnormal gait, swelling, injection site
reaction
Investigations
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
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
1
The frequency of hypersensitivity reactions is calculated based on one definitely related case in a
population of 789 patients
Post-marketing experience:
Cranial nerve palsies, vocal cord paresis, and rare reports of severe hypersensitivity reactions have
been reported during post-marketing surveillance of Abraxane.
In some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae
have been reported as part of the continuing surveillance of Abraxane. Because these events have been
reported voluntarily during clinical practice, true estimates of frequency cannot be made and a causal
relationship to the events has not been established.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Taxanes, ATC Code: L01CD01
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.
8
Abraxane contains human serum albumin-paclitaxel nanoparticles, where the paclitaxel is present in a
non-crystalline, amorphous state. Albumin is known to mediate endothelial transcytosis of plasma
constituents and
in vitro
studies demonstrated that the presence of albumin enhances transport of
paclitaxel across endothelial cells. It is hypothesised that this enhanced transendothelial transport is
mediated by the gp-60 albumin receptor, and that there is accumulation of paclitaxel in the area of
tumour due to the albumin-binding protein SPARC (secreted protein acidic rich in cysteine).
Breast carcinoma:
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
2
to
43 patients with metastatic breast cancer. The second trial utilised a dose of 300 mg/m
2
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
2
; 95% CI: 4.6-6.2 months) and 6.1
months (300 mg/m
2
; 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
2
given as a 3-hour
infusion with premedication to prevent hypersensitivity (N = 225), or as Abraxane 260 mg/m
2
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
st
-line therapy, are shown below.
Table 2: 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
2
)
Solvent-based paclitaxel
(175 mg/m
2
)
p-value
Response rate [95% CI] (%)
> 1
st
-line therapy
26.5 [18.98, 34.05] (n = 132) 13.2 [7.54, 18.93] (n = 136)
0.006
a
9
Table 2: 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
2
)
Solvent-based paclitaxel
(175 mg/m
2
)
p-value
*Median time to disease progression [95% CI] (weeks)
> 1
st
-line therapy
20.9 [15.7, 25.9] (n = 131)
16.1 [15.0, 19.3] (n = 135)
0.011
b
*Median Progression Free Survival [95% CI] (weeks)
> 1
st
-line therapy
20.6 [15.6, 25.9] (n = 131)
16.1 [15.0, 18.3] (n = 135)
0.010
b
*Survival [95% CI] (weeks)
> 1
st
-line therapy
56.4 [45.1, 76.9] (n = 131)
46.7 [39.0, 55.3] (n = 136)
0.020
b
*
This data is based on Clinical Study Report: CA012-0 Addendum dated Final (23 March-2005)
a
Chi-squared test
b
Log-rank test
229 patients treated with Abraxane in the randomized, controlled clinical trial were evaluated for
safety. Neurotoxictiy 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.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
Abraxane in all subsets of the paediatric population in the treatment of metastatic breast cancer (see
section 4.2 for information on paediatric use).
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
2
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
2
.
Following intravenous administration of Abraxane to patients with metastatic breast cancer at the
recommended clinical dose of 260 mg/m
2
, paclitaxel plasma concentrations declined in a multiphasic
manner. The mean C
max
of paclitaxel, which occurred at the end of the infusion, was 18.7 µg/ml. The
mean total clearance was 15 l/hr/m
2
. The terminal half-life was about 27 hours. The mean volume of
distribution was 632 l/m
2
; the large volume of distribution indicates extensive extravascular
distribution and/or tissue binding of paclitaxel.
In a study in patients with advanced solid tumours, the pharmacokinetic characteristics of paclitaxel
following Abraxane administered intravenously at 260 mg/m
2
over 30 minutes were compared with
those following 175 mg/m
2
of the solvent-based paclitaxel injection administered over 3 hours. The
clearance of paclitaxel with Abraxane was larger (43%) than that following a solvent-based paclitaxel
10
injection and its volume of distribution was also higher (53%). Differences in C
max
and C
max
corrected
for dose reflected differences in total dose and rate of infusion. There were no differences in terminal
half-lives.
In a repeat dose study with 12 patients receiving Abraxane administered intravenously at the approved
dose, intrapatient variability in systemic paclitaxel exposure (AUC
inf
) was 19% (range = 3.21%-
27.70%). There was no evidence for accumulation of paclitaxel with multiple treatment courses.
An analysis of patient exposure (AUC
inf
) against bodyweight indicated a trend toward reduced AUC at
260 mg/m
2
Abraxane, with decreased body weight. Patients weighing 50 kg had paclitaxel AUC
approximately 25% lower than those weighing 75 kg. The clinical relevance of this finding is
uncertain.
The protein binding of paclitaxel following Abraxane was evaluated by ultrafiltration. 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 6µM) the
presence of ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of
paclitaxel.
Based on the published literature,
in vitro
studies with human liver microsomes and tissue slices show
that paclitaxel is metabolised primarily to 6-hydroxypaclitaxel; and to two minor metabolites,
3’-
p
-hydroxypaclitaxel and 6-3’-
p
-dihydroxypaclitaxel. The formation of these hydroxylated
metabolites is catalysed by CYP2C8, -3A4, and both -2C8 and -3A4 respectively.
The pharmacokinetic profile of Abraxane administered as a 30 minute infusion was evaluated in 15
out of 30 patients with three levels of hepatic impairment based on serum bilirubin and liver enzyme
levels. Figure 1 shows the correlation between paclitaxel clearance and total blood bilirubin as
measured just prior to dosing.
Figure 1 Correlation between paclitaxel clearance and total blood bilirubin
35000
Paclitaxel
clearance
(ml/h/m
2
)
30000
25000
20000
15000
10 20 30 40 50 60 70 80 90
Total bilirubin (µmol/l)
The effect of renal dysfunction on the disposition of paclitaxel has not been formally investigated.
11
In patients with metastatic breast cancer, after a 30 minute infusion of Abraxane at 260 mg/m
2
, 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 6-hydroxypaclitaxel and
3’-
p
-hydroxypaclitaxel, indicating extensive non-renal clearance. Paclitaxel is principally eliminated
by hepatic metabolism and biliary excretion.
Pharmacokinetics of paclitaxel in patients aged over 65 years seems comparable to that in patients less
than 65 years. However, little information in patients over 75 years is available as only 3 patients over
75 years of age where included in the pharmacokinetic analysis.
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 and foetal
toxicity in rats. Animal studies with Abraxane showed non-reversible, toxic effects on the male
reproductive organs at clinically relevant exposure levels.
6.
6.1
List of excipients
Human albumin solution (containing sodium, sodium caprylate and N-acetyl DL tryptophanate).
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 suspension in the vial:
After first reconstitution, the suspension should be filled into an infusion bag immediately. However,
chemical and physical in use stability has been demonstrated for 8 hours at 2°C-8°C in the original
carton, and protected from bright light. Alternative light-protection may be used in the clean room.
Stability of the reconstituted suspension in the infusion bag:
After reconstitution, the reconstituted suspension in the infusion bag should be used immediately.
However chemical and physical in use stability has been demonstrated for 8 hours not above 25°C.
6.4
Special precautions for storage
Unopened vials
:
This medicinal product does not require any special temperature storage conditions.
Keep the vial in the outer carton in order to protect from light.
12
Reconstituted suspension:
For storage conditions of the reconstituted 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 paclitaxel.
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 suspension 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.
Reconstitution and administration of the product:
Abraxane is supplied as a sterile lyophilised powder for reconstitution before use. After reconstitution,
each ml of suspension contains 5 mg of paclitaxel.
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. 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 resuspension of any powder occurs. The generation of foam must
be avoided. If foaming or clumping occurs, the solution must stand for at least 15 minutes until foam
subsides.
The reconstituted suspension should be milky and homogenous without visible precipitates. If
precipitates or settling are visible, the vial should be gently inverted again to ensure complete
resuspension prior to use. Some settling of the reconstituted suspension may occur. Complete
resuspension should be ensured by mild agitation before use.
Discard the reconstituted suspension if precipitates are observed.
Calculate the exact total dosing volume of 5 mg/ml suspension required for the patient and inject the
appropriate amount of reconstituted Abraxane into an empty, sterile, PVC or non-PVC type
intravenous bag. The use of specialized DEHP-free solution containers or administration sets is not
necessary to prepare or administer Abraxane infusions. In-line filters should not be used.
Any unused product or waste material should be disposed of in accordance with local requirements.
13
7.
Celgene Europe Limited
Riverside House
Riverside Walk
Windsor
SL4 1NA
United Kingdom
8.
EU/1/07/428/001
9.
11 January 2008
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
14
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
15
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Catalent UK Packaging Ltd.
Lancaster Way
Wingates Industrial Park
Westhoughton BL5 3XX
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 4.0 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 5 of the Risk Management Plan (RMP) and
presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of
the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities.
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached.
At the request of the European Medicines Agency.
16
ANNEX III
LABELLING AND PACKAGE LEAFLET
17
A.
LABELLING
18
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
Abraxane 5 mg/ml powder for suspension for infusion
paclitaxel
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 100 mg paclitaxel (as paclitaxel albumin).
After reconstitution, each ml of suspension contains 5 mg of paclitaxel.
3.
LIST OF EXCIPIENTS
Excipients: Human albumin solution (containing sodium, sodium caprylate and N-acetyl DL
tryptophanate).
Contains sodium, see package leaflet for further information.
4.
Powder for suspension for infusion.
One vial
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Abraxane should not be substituted for or with other paclitaxel formulations.
8.
EXPIRY DATE
EXP.:
19
9.
SPECIAL STORAGE CONDITIONS
Unopened Vials: Keep the vial in the outer carton in order to protect from light.
After first reconstitution: 8 hours in a refrigerator in the vial when kept in the outer carton in order to
protect from light.
In an infusion bag: up to 8 hours not above 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.
Celgene Europe Limited
Riverside House
Riverside Walk
Windsor
SL4 1NA
United Kingdom
12. MARKETINGAUTHORISATIONNUMBER(S)
EU/1/07/428/001
13. BATCHNUMBER
Batch:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATIONINBRAILLE
Justification for not including Braille accepted.
20
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
Vial
1.
Abraxane 5 mg/ml powder for suspension for infusion
paclitaxel
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 100 mg paclitaxel (as paclitaxel albumin).
After reconstitution, each ml of suspension contains 5 mg of paclitaxel.
3.
LIST OF EXCIPIENTS
Excipients: Human albumin solution (containing sodium, sodium caprylate and N-acetyl DL
tryptophanate).
Contains sodium, see package leaflet for further information.
4.
Powder for suspension for infusion
1 vial of 100mg
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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.
21
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.
Celgene Europe Limited
Riverside House
Riverside Walk
Windsor
SL4 1NA
United Kingdom
EU/1/07/428/001
13. BATCH NUMBER
Batch:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
22
B.
PACKAGE LEAFLET
23
PACKAGE LEAFLET: INFORMATION FOR THE USER
Abraxane 5 mg/ml powder for suspension for infusion
paclitaxel
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1.
What Abraxane is and what it is used for
2.
Before you use Abraxane
3.
How to use Abraxane
4.
Possible side effects
5.
How to store Abraxane
6.
Further information
1.
WHAT ABRAXANE IS AND WHAT IT IS USED FOR
Abraxane is a medicine containing paclitaxel albumin. Albumin is a part of human blood. Paclitaxel
belongs to a group of medicines called taxanes used to treat cancers.
Abraxane is used for the treatment of breast cancer when other therapies have been tried but have not
worked and if you are unsuitable for anthracycline containing treatments.
2.
BEFORE YOU USE ABRAXANE
Do not use Abraxane
if you are allergic (hypersensitive) to paclitaxel or any of the other ingredients of Abraxane;
if you are breast feeding;
if you have a low white blood cell count (baseline neutrophil counts <1.5 x 10
9
/l - your doctor
will advise you on this).
Take special care with Abraxane
if you have poor kidney function;
if you experience numbness, tingling, pricking sensations, sensitivity to touch, or muscle
weakness;
if you have severe liver problems;
if you have heart problems.
If you experience any of these conditions your doctor may wish to stop treatment or reduce the dose.
Taking other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription, because they could interact with Abraxane.
24
-
If you have any further questions, ask your doctor.
Using Abraxane with food and drink
Abraxane is unaffected by food and drink.
Pregnancy and breast-feeding
Paclitaxel may cause serious birth defects and should therefore not be used if you are pregnant.
Women of childbearing age should use effective contraception during and up to 1 month after
receiving treatment with Abraxane. Male patients are advised to not father 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.
It is not known if paclitaxel passes into breast milk. Because of the possibility of harm to the infant,
breast-feeding must be discontinued for the duration of treatment.
Ask your doctor for advice before taking this medicine.
Driving and using machines
Abraxane may cause side effects such as tiredness (very common) and dizziness (common) that may
affect your ability to drive and use machinery. If you experience these symptoms, do not drive or
operate machinery until they have fully resolved.
If you are given other medicines as part of your treatment, you should ask your doctor for advice on
driving and using machines.
Important information about some of the ingredients of Abraxane
This medicine contains approximately 425 mg sodium per dose. This should be taken into
consideration by patients on a controlled sodium diet.
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 260 mg/m
2
of body
surface area.
How often will you receive Abraxane?
Abraxane is usually given every three weeks.
How long will it take to give you your intravenous drip?
Abraxane is given over a 30 minute period.
If you have any further questions on the use of this medicine, ask your doctor.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Abraxane can cause side effects, although not everyone gets them.
The frequency of possible side effects listed below is defined using the following convention:
very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
25
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
not known (frequency cannot be estimated from the available data).
The very common side effects are:
Loss of hair, rash
Abnormal decrease in the number of neutrophils in the blood
Decrease in the number of white blood cells in the blood
Deficiency of red blood cells
Reduction in the number of lymphocytes in the blood
Reduction in the number of platelets in the blood
Effect of peripheral nerves (pain, and numbness)
Pain in a joint or joints
Pain in the muscles
Nausea, diarrhoea, constipation, sore mouth, loss of appetite
Vomiting
Weakness and tiredness, fever
The common side effects are:
Itching, dry skin, nail disorder
Infection, fever with decrease in the number of neutrophils in the blood, flushing
Chest, throat or abdominal pain, headache
Indigestion, abdominal discomfort
Difficulty in breathing
Dehydration, taste disturbance, weight loss, hypokalaemia
Pain in extremities, back or limbs, bone pain, muscle cramps
Dizziness, diminished muscular coordination or difficulty in reading, increased or decreased
tears, loss of eyelashes
Changes in heart rate or rhythm
Swelling of mucosal and soft tissues
Sleep problems, depression, anxiety
Increased liver function tests
The uncommon side effects are:
Increased blood pressure, increased weight, increased lactate dehydrogenase in the blood,
decreased kidney function, increased blood sugar, increased phosphorus in the blood,
decreased potassium in the blood
Nerve disorder, decreased or lack of reflexes, involuntary movements, pain along a nerve, loss
of feeling, fainting, dizziness when standing up, painful numbness or tingling, shaking
Irritated eyes, painful eyes, red eyes, itchy eyes, blurred or double vision, reduced vision, or
seeing flashing lights
Ear pain, ringing in your ears
Coughing with phlegm, shortness of breath when walking or climbing stairs, stuffy nose,
runny nose, or dry nose, decreased breath sounds, water on the lung, loss of voice, difficulty
breathing, blood clot in the lung
Difficulty swallowing, gas, dry mouth, loose stools, heartburn, stomach cramps, painful or
sore mouth and 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, red rash, itchy rash, increased sweating, night sweats, white
areas on the skin, less hair, overall itching, 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
26
Thrush, pain and swelling in the nose and throat, skin infections, infection in the lungs,
infection due to catheter line, infection, redness or swelling at the site where the needle
entered the body
Bruising
Pain at site of tumour, death of the tumour
Decreased blood pressure, decreased blood pressure when standing up, coldness in your hands
and feet
Chest pain or heaviness, difficulty walking, swelling
Allergic reaction
Decreased liver function, increased size of liver
Pain in the breast
Restlessness
The rare side effects are:
Reduced blood cells
Lung infection
Skin reaction to another agent or lung inflammation following radiation
Blood clot
Very slow pulse, heart attack, heart failure.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5.
HOW TO STORE ABRAXANE
Keep out of the reach and sight of children.
Do not use Abraxane 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: This medicine does not require any special temperature storage conditions. Keep the
vial in the outer carton in order to protect from light.
After first reconstitution the suspension should be used immediately. If not used immediately, the
suspension may be stored in a refrigerator (2°C-8°C) for up to 8 hours in the vial when kept in the
outer carton in order to protect it from light.
The reconstituted suspension in the intravenous drip may be stored for up to 8 hours at a temperature
not above 25ºC.
6.
FURTHER INFORMATION
What Abraxane contains
The active substance is paclitaxel. Each vial contains 100 mg of paclitaxel (as paclitaxel
albumin).
After reconstitution, each ml of suspension contains 5 mg of paclitaxel.
The other ingredient is human albumin (containing sodium, sodium caprylate and N-acetyl DL
tryptophanate).
What Abraxane looks like and contents of the pack
27
Abraxane is a white to yellow powder for suspension for infusion available in glass vials containing
100 mg paclitaxel. Each pack contains 1 vial.
Marketing Authorisation Holder
Celgene Europe Limited
Riverside House
Riverside Walk
Windsor
SL4 1NA
United Kingdom
+44 (0)207 081 0850
Manufacturer
Catalent UK Packaging Ltd
Lancaster Way
Wingates Industrial Park
Westhoughton
BL5 3XX
United Kingdom
For any information about this medicine, please contact the Marketing Authorisation Holder
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
-------------------------------------------------------------------------------------------------------------------------
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 suspension 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.
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 suspension contains 5 mg of paclitaxel.
Using a sterile syringe, 20 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion should be
injected into a vial of Abraxane over a minimum of 1 minute. The solution should be directed onto the
28
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 resuspension of any powder occurs. The generation of foam
should be avoided. If foaming or clumping occurs, the suspension should stand for at least 15 minutes
until foam subsides.
The reconstituted suspension should be milky and homogenous without visible precipitates. If
precipitates or settling are visible, the vial should be gently inverted again to ensure complete
resuspension prior to use. Some settling of the reconstituted suspension may occur. Complete
resuspension should be ensured by mild agitation of the vial before use.
If precipitates are observed, the reconstituted suspension should be discarded.
The exact total dosing volume of 5 mg/ml suspension required for the patient should be calculated and
the appropriate amount of reconstituted Abraxane should be injected into an empty, sterile, polyvinyl
chloride (PVC) type IV bag. The use of specialized DEHP-free solution containers or administration
sets is not necessary to prepare or administer Abraxane infusions. In-line filters should not be used.
Parenteral medicinal products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
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 suspension in the vial
After first reconstitution, the suspension should be filled into an infusion bag immediately. However,
chemical and physical in use stability has been demonstrated for 8 hours at 2°C-8°C in the original
carton, and protected from bright light.
Stability of the reconstituted suspension in the infusion bag
After reconstitution, the reconstituted suspension in the infusion bag should be used immediately.
However chemical and physical in use stability has been demonstrated for 8 hours not above 25°C.
29
Source: European Medicines Agency
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