ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1
1.
NAME OF THE MEDICINAL PRODUCT
Apealea 60 mg powder for solution for infusion.
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial of powder contains 60 mg of paclitaxel.
After reconstitution, each mL of solution contains 1 mg of paclitaxel (micellar).
Excipients with known effect
Each vial contains 3.77 mg (0.164 mmol) sodium. After reconstitution, each mL of solution contains
approximately 3.06 mg (0.133 mmol) sodium.
For the full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Powder for solution for infusion.
Greenish-yellow to yellow powder.
4.
CLINICAL PARTICULARS
Therapeutic indications
4.1
Apealea in combination with carboplatin is indicated for the treatment of adult patients with first
relapse of platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer and fallopian tube
cancer (see section 5.1).
4.2
Posology and method of administration
Apealea should only be administered under the supervision of a qualified oncologist in units
specialised in the administration of cytotoxic agents. It should not be interchanged with other
paclitaxel formulations.
Posology
The recommended dose of Apealea is 250 mg/m body surface area (BSA) given as an intravenous
2
infusion over 1 hour followed by carboplatin every three weeks for six cycles. The recommended dose
of carboplatin is AUC = 5–6 mg/mL×min.
Dose adjustments and delays during treatment
Patients who experience neutropenia (neutrophil count < 1.5 × 10
thrombocytopenia (platelet count < 100 × 10 /L) during treatment should have the next treatment cycle
delayed until neutrophil counts recover to ≥ 1.5 × 10 /L and platelets recover to ≥ 100 × 10 /L. For
Apealea, dose reductions of initially 50 mg/m and additionally 25 mg/m should be considered for
9
/L), febrile neutropenia or
9
9
9
2
2
subsequent courses (see Table 1).
In the case of febrile neutropenia or low platelet count (< 75 × 10 /L), the dose of carboplatin should
9
be reduced by 1 AUC unit in the treatment cycles following recovery. For appropriate use of
carboplatin, the prescriber is advised to consult the prescribing information for carboplatin as well.
2
Dose reductions or/and delays should be considered as a result of any clinically significant adverse
reaction as presented in Table 1.
Table 1. Treatment delay and dose level reductions for adverse drug reactions
Observation
a
Delay of next cycle
Apealea/carboplatin
Apealea dose for subsequent courses
2 b
(mg/m )
Haematological toxicity
b
neutrophil count < 1.5 × 10
9
/L
Withhold treatment until Standard dose:
recovery
250
or
Possible dose reductions:
platelet count < 100 × 10 /L
9
or
First dose level reduction:
200
175
Second dose level reduction:
febrile neutropenia
Nervous system disorders
grade ≥ 2 peripheral sensory
Withhold treatment until Dose reduction:
neuropathy
recovery to < grade 2
First dose level reduction:
Possible dose reduction:
Second dose level reduction:
200
175
or
grade ≥ 2 motor neuropathy
All other adverse reactions
Any grade 4 toxicity
Discontinue treatment
Any grade 3 toxicity except
nausea, vomiting and
diarrhoea
Withhold treatment until Possible dose reductions:
symptoms resolve to
First dose level reduction:
grade ≤ 1
200
175
Second dose level reduction:
a
Grade of the adverse reaction is defined according to Common Terminology Criteria for Adverse
Events (CTCAE).
The dose of carboplatin should be reduced by 1 AUC unit for treatment cycles following the
b
9
occurrence of febrile neutropenia or low platelet count (< 75 × 10 /L).
Special populations
Hepatic impairment
Patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 × upper limit of normal (ULN) and
aspartate aminotransferase (AST) ≤ 10 × ULN) may be treated with the same doses as patients with
normal hepatic function.
For patients with moderate to severe impairment (total bilirubin > 1.5 to ≤ 5 × ULN and
AST ≤ 10 × 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 total bilirubin > 5 × ULN or AST > 10 × ULN, there are insufficient data to permit
dosage recommendations (see sections 4.4 and 5.2).
Renal impairment
Patients with mildly or moderately impaired renal function (glomerular filtration rate (GFR)
89−60 mL/min or GFR 59−30 mL/min, respectively) may be treated with Apealea without a dose
modification. Patients with severe renal impairment (GFR < 30 mL/min) should not be treated with
paclitaxel (see section 5.2).
3
Elderly
No additional dosage reductions, other than those for all patients, are recommended for patients
65 years and older.
Of the 391 patients with ovarian cancer in the randomised study who received Apealea in combination
with carboplatin, 13% were between 65 and 74 years old. In this limited number of patients, anorexia,
fatigue, myalgia, arthralgia, peripheral sensory neuropathy, and diarrhoea were observed more
frequently compared to patients younger than 65 years. Limited data are available on use in patients
≥ 75 years (2% of the patients in the study).
Non-Caucasian patients
There are limited data of Apealea in non-Caucasian patients and current data is insufficient to
recommend additional dose adjustments (see section 4.4). If neuropathy is observed, follow dose
reduction recommendations in Table 1.
Paediatric population
There is no relevant use of paclitaxel in the paediatric population for the indications of epithelial
ovarian cancer, primary peritoneal cancer and fallopian tube cancer. The safety and efficacy of
Apealea in children and adolescents aged 0−17 years has not been established.
Method of administration
Apealea is for intravenous use.
After reconstitution of the powder, the solution for infusion is a clear, greenish-yellow solution. The
solution should be administered by an intravenous infusion over approximately one hour
(120−140 drops/min). Administration sets containing a 15 µm polyamide fluid filter should be used. It
is important to flush the infusion set and catheter/cannula before and after the administration using the
solution for reconstitution in order to avoid accidental administration into the surrounding tissue and to
ensure administration of the complete dose.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
4.3
Contraindications
Severe hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see
section 4.4).
Breast-feeding (see section 4.6).
Baseline neutrophil count < 1.5 × 10
9
/L.
4.4
Special warnings and precautions for use
Haematology
Paclitaxel causes myelosuppression (primarily neutropenia). Neutropenia is dose-dependent and a
dose-limiting toxicity. Therefore, frequent complete blood cell counts should be performed during
treatment with Apealea. In the pivotal study, about a third of the patients received granulocyte colony
stimulating factor (GCSF) to treat neutropenia and clinicians should consider whether individual cases
could benefit from GCSF. Patients should not be treated with subsequent cycles until neutrophils
recover to ≥ 1.5 × 10 /L and platelets recover to ≥ 100 × 10 /L. Patients with low neutrophil count
9 9
should be made aware of the increased risk of infections. The risk of myelosuppression is increased
due to the combination use with carboplatin. Dose recommendations for Apealea as well as for
carboplatin in the case of myelosuppression should be followed (see section 4.2).
4
Neuropathy
Peripheral sensory neuropathy and peripheral neuropathy are very common adverse reactions. For
CTCAE grade ≥ 2 sensory or motor neuropathy withhold treatment until resolution to < grade 2,
followed by a dose reduction for all subsequent courses (see section 4.2).
Hepatic impairment
Patients with hepatic impairment have not been studied with Apealea but may be at increased risk of
toxicity, particularly from myelosuppression. Administration in patients with hepatic impairment
defined as total bilirubin > 1 to ≤ 5 × ULN and AST ≤ 10 × ULN (see section 4.2) should therefore be
performed with caution and they should be closely monitored with regard to increased liver
impairment and myelosuppression. Patients that have total bilirubin > 5 × ULN or AST > 10 × ULN
should not be treated with paclitaxel.
Gastrointestinal symptoms
Gastrointestinal adverse reactions are very common. If patients experience nausea, vomiting and
diarrhoea following the administration of Apealea, they may be treated with antiemetics and/or
antidiarrhoeal agents. Premedication may be considered in patients who have previously experienced
gastrointestinal symptoms when being treated with cytotoxic medicinal products.
Infusion-associated reactions
Local reactions at the infusion site are very common during Apealea infusions. The infusion site
reactions observed include pain, phlebitis, discolouration, redness, oedema and rash. These reactions
are more common on the first infusion and may be improved by slowing the rate of infusion. Patients
who experience severe pain or other reactions to the infusion of Apealea are recommended to be
considered for a central venous catheter. Care should be taken to avoid accidental administration into
the surrounding tissue during intravenous administration. If any sign of extravasal injection occurs,
take immediate action; terminate the infusion, aspirate fluid from the catheter/cannula before the
needle is withdrawn, infuse the affected area with sterile saline or lactated or acetated Ringer’s
solution and closely monitor the area. To avoid accidental administration into the surrounding tissue
and to ensure intravenous delivery of the complete dose, flush the infusion set and catheter/cannula
before as well as after the administration.
Hypersensitivity
Most hypersensitivity reactions related to Apealea are mild to moderate and mainly occur as skin and
subcutaneous tissue disorders, general disorders and administration site conditions, but serious
hypersensitivity reactions including anaphylactic shock have been reported. Minor symptoms such as
flushing or skin reactions do not require interruption of therapy. Moderate cases may require
premedication with corticosteroids, antihistamines and/or H2 antagonists for the following treatment
cycles. Severe reactions, such as hypotension requiring treatment, dyspnoea requiring bronchodilators,
angioedema or generalised urticaria require immediate discontinuation of paclitaxel and initiation of
symptomatic treatment. Patients experiencing severe reactions should not be re-challenged with
paclitaxel. Patients should be observed closely during treatment, particularly those patients who
previously suffered hypersensitivity reactions with any taxane formulation.
The true incidence, severity and time to onset of hypersensitivity reactions due to Apealea could not
be established during clinical development due to the combination treatment with carboplatin. Delayed
reactions related to paclitaxel occurring during or after infusion of carboplatin cannot be excluded.
Alopecia
Alopecia is a very common adverse reaction and occurs early in treatment. It can have a marked
impact on the patients’ self-image and quality of life and patients should be counselled about the
5
likelihood of this adverse effect and on what measures might be available to mitigate it, for example
the use of cold caps. In studies with Apealea, 45% of patients reported alopecia during therapy.
Cardiotoxicity
Heart failure has been observed in some patients receiving Apealea. In some of the cases, the patients
had previously been exposed to cardiotoxic medicinal products such as doxorubicin or had underlying
cardiac history. These patients should be vigilantly monitored by physicians for the occurrence of
cardiac events.
Patients 65 years and older
There was no marked difference in overall tolerability between the 65–74 age group and younger
patients. Limited data are available on use in patients ≥ 75 years. In view of this, and of the potential
for frailty and co-morbidities, elderly patients should be carefully monitored.
Race
There are limited data on the use of Apealea in non-Caucasian patients. However, studies in breast
cancer patients treated with paclitaxel-containing regimens indicate a possible increased risk of
neuropathy in non-Caucasian patients (see section 4.2).
Excipients
When reconstituted, this medicinal product contains approximately 1.4 g sodium per dose (0.77 g/m
2
BSA; 3.06 mg per mL), equivalent to 70% of the WHO recommended maximum daily intake of 2 g
sodium for an adult.
4.5
Interaction with other medicinal products and other forms of interaction
No studies have been performed to evaluate drug-drug interactions between Apealea and other
medicinal products.
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 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.
Apealea contains a mixture of two retinoic acid derivatives as excipients. In vitro studies using human
microsomes have shown these derivatives to have inhibitory activity on CYP2B6, CYP2C8, CYP2C9,
and to a lesser extent on CYP2D6. In the absence of in vivo studies addressing inhibition of CYP2B6
and CYP2C9, the concomitant use of Apealea and substances metabolised primarily by these CYP
enzymes should be exercised with caution.
Apealea is indicated to be used in combination with carboplatin (see section 4.1). Apealea should be
administered first, then carboplatin. Based on literature data, no clinically relevant pharmacokinetic
interaction between paclitaxel and carboplatin is expected.
Clinically relevant pharmacokinetic interaction has been observed between paclitaxel and cisplatin.
When paclitaxel is given before cisplatin, the safety profile of solvent-based paclitaxel is consistent
with that reported for single-agent use. When solvent-based paclitaxel was given after cisplatin,
patients showed a more profound myelosuppression and an approximately 20% decrease in paclitaxel
clearance. A similar effect can be anticipated for Apealea (paclitaxel micellar). Patients treated with
6
paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in
gynaecological cancers.
4.6
Fertility, pregnancy and lactation
Women of childbearing potential/Contraception
Women of childbearing potential must use effective contraception during treatment and for six months
afterwards.
Pregnancy
There are very limited data on the use of paclitaxel in pregnant women. Paclitaxel is suspected to
cause serious birth defects when administered during pregnancy. Studies in animals have shown
reproductive toxicity (see section 5.3). Paclitaxel should not be used during pregnancy unless the
clinical condition requires this treatment.
Breast-feeding
Paclitaxel is excreted in human milk. Because of potential serious adverse reactions in children being
breastfed, Apealea is contraindicated during lactation. Breast-feeding must be discontinued for the
duration of therapy.
Fertility
Studies in animals being treated with paclitaxel have shown decreased fertility (see section 5.3).
4.7
Effects on ability to drive and use machines
Apealea has moderate influence on the ability to drive or use machines. Apealea may cause adverse
reactions such as fatigue (very common) and dizziness (common) that may affect the ability to drive or
use machinery. Patients should be advised not to drive or 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 Apealea are
neutropenia, gastrointestinal disorders, peripheral neuropathy, arthralgia/myalgia, and infusion site
reactions. Approximately 86% of patients experienced adverse reactions.
Tabulated list of adverse reactions
The frequency of undesirable effects listed in Table 2 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), and not known (cannot be estimated from the
available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 2 lists adverse reactions associated with the administration of Apealea in combination with
carboplatin observed in a clinical study (N = 391).
7
Table 2. Listing of adverse reactions
System Organ Class
Frequency
Preferred term
Infections and infestations
Uncommon:
Sepsis, abscess, pneumonia, influenza,
respiratory tract infection viral, herpes simplex,
infusion site cellulitis, tonsillitis,
urinary tract infection, skin infection, cystitis
Neoplasms benign,
Uncommon:
Metastatic pain
malignant and unspecified
(incl. cysts and polyps)
Blood and lymphatic
system disorders
Very common:
Common:
Neutropenia
a
Febrile neutropenia
thrombocytopenia , granulocytopenia, anaemia
a
, leukopenia ,
a a
a
Uncommon:
Disseminated intravascular coagulation ,
a
pancytopenia, haematotoxicity, coagulopathy
Immune system disorders
Common:
Hypersensitivity
Uncommon:
Very common:
Uncommon:
Anaphylactic shock, drug hypersensitivity
Anorexia
Metabolism and nutrition
disorders
Hyponatraemia, hypokalaemia, hypomagnesaemia,
dehydration, decreased appetite
Psychiatric disorders
Uncommon:
Depression, insomnia, anxiety
Nervous system disorders
Very common: Peripheral sensory neuropathy ,
a
neuropathy peripheral
a
Common:
Hypoaesthesia, dizziness, paraesthesia,
peripheral motor neuropathy, dysgeusia, headache
Uncommon:
Status epilepticus, coma, cerebrovascular accident,
peripheral sensorimotor neuropathy, lethargy,
hypotonia, neurotoxicity, polyneuropathy,
polyneuropathy in malignant disease,
burning sensation, somnolence, cognitive disorder,
facial palsy, encephalopathy, hydrocephalus
Eye disorders
Uncommon:
Uncommon:
Vision blurred, eye irritation, ocular discomfort,
lacrimation increased
Ear and labyrinth
disorders
Vertigo, deafness, inner ear disorder, tinnitus
Cardiac disorders
Vascular disorders
Common:
Angina pectoris, tachycardia
Uncommon:
Cardiac arrest, cardiac failure chronic, cyanosis,
atrial fibrillation, sinus tachycardia, palpitations,
sinus bradycardia
Common:
Hypotension, flushing, phlebitis, vein pain,
hyperaemia
Uncommon:
Circulatory collapse, venous thrombosis, vasculitis,
thrombosis, hypertension, deep vein thrombosis,
lymphoedema, phlebitis superficial,
thrombophlebitis, blood pressure fluctuation,
haemorrhage, angiopathy, hot flush, pallor
8
System Organ Class
Frequency
Common:
Preferred term
Respiratory, thoracic and
mediastinal disorders
Dyspnoea, nasal congestion
Uncommon:
Respiratory failure, epistaxis, cough, rhinorrhoea,
oropharyngeal pain, pharyngeal disorder, asphyxia,
bronchospasm, dysphonia, rhinitis allergic,
allergic cough, oropharyngeal discomfort
Gastrointestinal disorders
Very common:
Common:
Diarrhoea , nausea , vomiting
a a a
Abdominal pain, constipation, abdominal pain upper,
flatulence, dry mouth, stomatitis
Uncommon:
Abdominal distension, gastritis,
abdominal discomfort, abdominal pain lower,
dyspepsia, faecaloma, intestinal functional disorder,
gingival bleeding, haematochezia, paraesthesia oral
Hepatobiliary disorders
Uncommon:
Very common:
Common:
Hepatitis, liver disorder
Skin and subcutaneous
tissue disorders
Alopecia
a
Erythema, rash, pruritus, urticaria
Uncommon:
Angioedema, rash generalised, skin discolouration,
hyperhidrosis, rash papular, dermatitis bullous,
swelling face, pigmentation disorder, dry skin, cold
sweat, livedo reticularis, nail disorder, pruritus
allergic, skin disorder
Musculoskeletal and
connective tissue disorders
Very common:
Common:
Arthralgia , myalgia
a a
Back pain, bone pain, musculoskeletal pain,
muscular weakness, pain in extremity
Uncommon:
Uncommon:
Uncommon:
Haemarthrosis, musculoskeletal discomfort,
sensation of heaviness
Renal and urinary
disorders
Azotaemia
Reproductive system and
breast disorders
Vaginal haemorrhage, pelvic pain, breast pain
General disorders and
administration site
conditions
Very common:
Common:
Asthenia , fatigue , infusion site reaction
a a a,b
Oedema peripheral, pain, pyrexia, chest discomfort,
hyperthermia, face oedema
Uncommon:
Death, multi-organ failure, oedema, administration
site pain, catheter site haemorrhage, catheter site
oedema, local swelling, generalised oedema, hernia,
chest pain, influenza like illness, localised oedema,
hypothermia, chills, feeling hot
Investigations
Uncommon:
Alanine aminotransferase increased
a
See Description of selected adverse reactions.
Includes the following preferred terms: infusion site pain, infusion site phlebitis,
b
infusion site reaction, infusion site discolouration, infusion site erythema, infusion site extravasation,
infusion site inflammation, infusion site oedema, infusion site paraesthesia, infusion site irritation, and
infusion site rash.
9
Description of selected adverse reactions
In the pivotal clinical study, patients were either treated with Apealea (paclitaxel micellar) at a dose of
2 2
250 mg/m in combination with carboplatin or with solvent-based paclitaxel at a dose of 175 mg/m in
combination with carboplatin (N = 391 in each arm). Overall, there were higher rates of serious
adverse events with paclitaxel micellar (41%) than with solvent-based paclitaxel (27%). In both
groups, the majority of the serious adverse events were haematological toxicities. There were no
differences in Eastern Cooperative Oncology Group (ECOG) performance score between the two
study groups at any time during or after treatment (mainly score 0 or 1).
Blood and lymphatic system disorders
Almost all patients treated with Apealea had neutropenia of some grade, 79% of the patients had grade
3 or 4. Neutropenia as a serious adverse reaction occurred in 29% of the patients and febrile
neutropenia occurred in 3% of the patients. Neutropenia resolved to ≥ 1.5 × 10 /L before the next
9
course of treatment. Almost all patients experienced anaemia, decreased platelet count and decreased
white blood cell count of any grade during the treatment period (98%, 93% and 98%, respectively).
Anaemia as serious adverse event occurred in 5% of the patients, thrombocytopenia and leukopenia in
3% and 6% of the patients, respectively.
In comparison to the patients receiving solvent-based paclitaxel, there were more patients in the group
receiving paclitaxel micellar who experienced haematological toxicities with grade 3 and 4.
Neutropenia occurred in 79% and 66%, leukopenia in 53% and 34%, thrombocytopenia in 18% and
10%, and anaemia in 24% and 14% of the patients in the treatment arms receiving either paclitaxel
micellar or solvent-based paclitaxel, respectively.
Disseminated intravascular coagulation (DIC), often in association with sepsis or multi-organ failure,
has been reported.
Gastrointestinal disorders
Nausea (38%), vomiting (22%) and diarrhoea (15%) were among the most commonly reported
adverse reactions in the study.
Nervous system disorders
Peripheral neuropathies (including the preferred terms neuropathy peripheral, peripheral motor
neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy, and
polyneuropathy in malignant disease) were reported in 29% of the patients and were mostly (98%)
mild to moderate (CTCAE grade ≤ 2). The average time to onset was 53 days from the first dose.
Peripheral sensory neuropathy represented the most common reaction and was reported in 16% of
patients. Other associated reactions were reported in 10% of the patients and were mostly (98%) mild
to moderate (CTCAE grade ≤ 2). Paraesthesia and hypoaesthesia were the most common ones. During
the course of the pivotal study, 46% of the peripheral neuropathies as well as the majority (78%) of the
associated reactions resolved. The dose-dependency of frequency and severity of neurotoxicity was
not studied for Apealea, but has been observed for other paclitaxel formulations in other indications.
Hypersensitivity reactions
Most hypersensitivity reactions related to Apealea were mild to moderate (see section 4.4). The
frequency of paclitaxel-related hypersensitivity reactions was similar in both groups (5% of the
patients receiving paclitaxel micellar and 7% of the patients receiving solvent-based paclitaxel),
whereas a higher frequency of carboplatin-related hypersensitivity reactions was observed in the group
receiving paclitaxel micellar (12% vs 7%). As a result of the combined treatment, it is not possible to
determine whether this observation is due to Apealea or to other factors, and delayed reactions related
to paclitaxel cannot be excluded.
Skin and subcutaneous tissue disorders
Alopecia was observed in 45% of patients and was abrupt in onset. Pronounced hair loss of ≥ 50% is
expected for the majority of patients who experience alopecia.
10
Musculoskeletal and connective tissue disorders
Arthralgia occurred in 19% of patients and myalgia in 10%.
General disorders and administration site conditions
Asthenia and fatigue were very common and occurred in 23% and 11% of patients, respectively.
Infusion site reactions seen in 12% of patients, such as pain, phlebitis, and erythema, were very
common (see section 4.4).
There were more reports of infusion site pain in the group receiving paclitaxel micellar as compared to
the group treated with solvent-based paclitaxel (8% and 1%, respectively).
Additional experience from clinical studies
Apealea has been given as monotherapy in a total of 132 patients at doses ranging between 90 mg/m
in a 3-week regimen to weekly doses of 250 mg/m for various indications. Based on the combined
2
2
data from monotherapy studies, very common adverse reactions and those of special interest were the
following: neutropenia (45%), fatigue (37%), leukopenia (33%), alopecia (30%), nausea (27%),
a
infusion site reaction (23%), peripheral sensory neuropathy (20%), diarrhoea (17%), asthenia (15%),
pyrexia (12%), constipation (12%), arthralgia (12%), paraesthesia (11%), pain (11%), vomiting (9%),
myalgia (9%), peripheral motor neuropathy (5%), neuropathy (5%), neuropathy peripheral (5%),
thrombocytopenia (4%), febrile neutropenia (2%), sepsis (2%), tachycardia (2%), phlebitis (2%),
thrombosis (2%).
a
Includes the following preferred terms: infusion site phlebitis, infusion site pain, injection site
reaction, injection site inflammation, infusion site erythema, injection site extravasation, infusion site
reaction, injection site oedema.
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 nausea,
vomiting, diarrhoea, myelosuppression, peripheral sensory neuropathy and peripheral neuropathy.
5.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
5.1
Pharmacotherapeutic group: Antineoplastic agents, 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. Stabilisation 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 microtubule bundle formation throughout the
cell cycle and induces microtubule aster formation during mitosis.
11
Clinical efficacy and safety
The safety and efficacy of Apealea were evaluated in an open, randomised, multicentre study in
782 women with recurrent epithelial ovarian cancer, primary peritoneal cancer and fallopian tube
cancer in combination with carboplatin. Patients were treated every three weeks for six cycles, either
2
with Apealea (paclitaxel micellar) 250 mg/m given as a 1-hour intravenous infusion (N = 391) or with
solvent-based paclitaxel 175 mg/m given as a 3-hour infusion (N = 391). The paclitaxel infusion was
2
followed by carboplatin after an interval of 30 minutes in both treatment arms.
The proportions of patients treated at first or second relapse were equal in both treatment groups (76%
were treated at first relapse and 24% at second relapse). Patients who had pre-existing neuropathy of
grade ≥ 2 or serious medical risk factors involving any of the major organ systems were not allowed to
enter the study. The mean age was 56 years of age in both treatment groups (range 26–81). Most of the
patients enrolled in the study had ECOG performance status of 0 or 1 (≥ 96%), in similar proportions
between the treatment arms. Only a few patients had ECOG performance status of 2.
In the clinical study, the proportion of patients receiving six treatment cycles was 81% in the group
treated with paclitaxel micellar and 87% in the group receiving solvent-based paclitaxel. The
corresponding median number of cycles (min;max) for the two groups were 6 (1;12) and 6 (1;9),
respectively.
Patients received premedication prior to infusion of solvent-based paclitaxel, paclitaxel micellar and
carboplatin as summarised in Table 3 below. Premedication was not mandated prior to infusion of
paclitaxel micellar.
Table 3. Proportions of patients who received premedication prior to infusion of paclitaxel or
carboplatin or overall (safety population)
Apealea
Paclitaxel (solvent-based)
(N = 391)
(N = 391)
Type of
premedication
Overall
Paclitaxel
Carboplatin
Overall
Paclitaxel
Carboplatin
Corticosteroids
Antihistamines
H2 antagonists
43%
19%
5%
6%
4%
2%
39%
16%
2%
99%
85%
90%
97%
85%
90%
15%
9%
1%
Antiemetics and
antinauseants
87%
8%
81%
92%
38%
63%
In the study, 35% of the patients receiving paclitaxel micellar and 30% of the patients treated with
solvent-based paclitaxel, respectively, received GCSF to treat neutropenia. The median number of
cycles with paclitaxel/carboplatin treatment for patients receiving GCSF was 6 in both groups. The
median number of cycles with administration of GCSF was 3 (1;6) and the mean value 3.1, each in
both groups.
The principle measures of efficacy were progression-free survival (PFS) and overall survival (OS).
PFS was evaluated by blinded assessment of computerised tomography images using Response
Evaluation Criteria in Solid Tumours (RECIST) 1.0. There was no statistically significant difference
in PFS or OS between the two treatment arms. A non-inferiority analysis in the per-protocol (PP)
population was conducted for PFS with pre-specified non-inferiority margin. The non-inferiority
criterion was met for PFS with the upper bound limit of the one-sided 97.5% confidence interval (CI)
for the associated hazard ratios being less than 1.2. The non-inferiority criterion was met for OS with
the upper bound limit of the one-sided 97.5% CI for the associated hazard ratios being less than 1.185
in the PP population (Table 4; Figures 1 and 2). In the intention-to-treat (ITT) population the hazard
ratios for PFS and OS were 0.85 (95% CI: 0.72;1.00) and 1.02 (95% CI: 0.85;1.22), respectively.
12
Thereby, non-inferiority for PFS was also established in the ITT population, but not for OS. At the
time of analysis of the OS data, death had occurred in 56% of the patients in the group treated with
paclitaxel micellar compared to 60% in the group treated with solvent-based paclitaxel (ITT
population).
Table 4. Efficacy in recurrent epithelial ovarian cancer, primary peritoneal cancer and fallopian
tube cancer in combination with carboplatin (per-protocol population)
Apealea
Paclitaxel (solvent-based)
(N = 311)
(N = 333)
Progression free survival
Median time to death or disease
progression [months] (95% CI)
10.3 (10.1;10.7)
10.1 (9.9;10.2)
Log rank p-value
Hazard ratio (95% CI)
p-value
0.0919
0.86 (0.72;1.03)
0.0938
Overall survival
Median time to death [months]
(95% CI)
25.7 (22.9;28.1)
24.8 (21.7;27.1)
Log rank p-value
Hazard ratio (95% CI)
p-value
0.6196
0.95 (0.78; 1.16)
0.6202
Figure 1. Kaplan-Meier curve of progression free survival (per-protocol population)
Patients
311
Events
239
Apealea:
solvent-based paclitaxel:
333
270
Months
Apealea:
solvent-based paclitaxel:
Number at risk
13
Figure 2. Kaplan-Meier curve of overall survival (per-protocol population)
Patients
311
333
Events
179
206
Apealea:
solvent-based paclitaxel:
Months
Apealea:
solvent-based paclitaxel:
Number at risk
For safety data comparing the results of combination treatment with Apealea (paclitaxel
micellar)/carboplatin and solvent-based paclitaxel/carboplatin, see section 4.8.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
Apealea in all subsets of the paediatric population in the treatment of ovarian carcinoma (excluding
rhabdomyosarcoma and germ cell tumours), peritoneal carcinoma (excluding blastomas and sarcomas)
and fallopian tube carcinoma (excluding rhabdomyosarcoma and germ cell tumours) (see section 4.2
for information on paediatric use).
5.2
Pharmacokinetic properties
When Apealea (paclitaxel micellar) is administered intravenously, its pharmacokinetic profile suggests
that the formulation immediately releases paclitaxel into the blood. The pharmacokinetics of paclitaxel
were studied in 22 patients with solid tumours after 1-hour infusions of Apealea (dose levels of 90 to
275 mg/m
2
). In addition, a study with a crossover design compared total and unbound paclitaxel
with those after a 1-hour
concentrations in plasma after a 1-hour infusion of Apealea 260 mg/m
2
infusion of albumin-bound paclitaxel at the same dose. Total plasma levels of paclitaxel were similar
after infusion of the two formulations. The plasma levels of unbound paclitaxel, i.e. the concentration
that represents pharmacologically active paclitaxel in the body, were demonstrated to be bioequivalent
(Cmax and AUC) after administration of albumin-bound paclitaxel and Apealea. Based on limited data,
Cmax and AUC increased with dose after 1-hour infusions of Apealea in doses ranging from 150 to
275 mg/m . Dose-linearity could not be ascertained since a large inter-individual variability was
2
observed.
Distribution
Paclitaxel is distributed equally between plasma and blood as described in published in vitro data. The
mean unbound fraction of paclitaxel (fu) varied between 5.2% and 4.3% over time after Apealea
infusion. This was in agreement with the mean fu after albumin-bound paclitaxel infusion which
varied between 5.5% and 4.5% over time.
Binding of paclitaxel to both albumin and α1-acid glycoprotein has been reported, but other binding
proteins such as lipoproteins might be important. There are no reports of active substances able to
displace protein-bound paclitaxel, nor is paclitaxel a likely candidate as a displacer of other active
substances given its low molar concentrations in plasma. Based on the published literature, in vitro
14
studies indicate that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine does
not affect protein binding of paclitaxel. Paclitaxel has been shown in vitro to be a substrate for the
influx transporter proteins OATP1B3 and OATP1A2.
During and after infusion of Apealea, paclitaxel rapidly leaves the plasma compartment with a
distribution half-life of about 0.6 hours. Thus, the distribution phase is essentially complete at 2 hours
after the end of infusion. The tissue distribution is extensive, with a volume of distribution on the
2
terminal elimination phase of about 155 L/m corresponding to about 280 L for an average patient
with a body surface area of 1.8 m . Thus, only about 1% of the paclitaxel in the body is located in
2
plasma during the elimination phase.
Biotransformation and elimination
The terminal half-life of paclitaxel after Apealea infusion varied about 5-fold between the subjects,
5–23 hours. Likewise, total plasma clearance varied about 5-fold from 8 to 41 L/hour. The high
interindividual variability in clearance is believed to be a consequence of variability in hepatic enzyme
activity.
The biotransformation and elimination of paclitaxel have been reported in published studies; paclitaxel
is mainly eliminated by hepatic metabolism and biliary excretion. The main metabolite of paclitaxel is
6α-hydroxypaclitaxel. Other metabolites are 3’-p-hydroxypaclitaxel and 6α,3’-p-dihydroxypaclitaxel.
The formation of these metabolites is catalysed by CYP2C8 and CYP3A4. No pharmacologically
active metabolite has been found. In vitro and in vivo studies have demonstrated that paclitaxel is a
substrate for the efflux protein P-glycoprotein. The major route of excretion of paclitaxel-derived
material in humans is the faeces, where 6α-hydroxypaclitaxel constitutes the main material. Renal
excretion accounts for a minor part, less than 15% of the dose.
Special populations
Hepatic impairment
No clinical studies in patients with hepatic impairment have been undertaken with Apealea (see
sections 4.2 and 4.4). A population pharmacokinetics study with albumin-bound paclitaxel
demonstrated that patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 × ULN) have an
elimination rate in the normal range. In contrast, patients with moderate hepatic impairment (total
bilirubin > 1.5 to ≤ 3 × ULN) and severe hepatic impairment (total bilirubin > 3 to ≤ 5 × ULN) had a
22% or a 26% reduction in paclitaxel elimination rate, respectively. Compared to patients with normal
hepatic function, hepatically impaired patients with total bilirubin > 1.5 × ULN have an increase in
mean paclitaxel AUC of approximately 20%. Hepatic impairment has no effect on mean paclitaxel
Cmax. Pharmacokinetic data for patients with total bilirubin > 5 × ULN are not available.
Renal impairment
No clinical studies in patients with renal impairment have been undertaken with Apealea (see
section 4.2 for dose recommendations). Since renal elimination is a minor pathway for paclitaxel,
increased plasma levels are not expected in this patient group. A population pharmacokinetics study
with albumin-bound paclitaxel demonstrated that patients with mild and moderate renal impairment
(creatinine clearance ≥ 30 to < 90 mL/min) have an elimination rate similar to that of patients with
normal renal function. Information is lacking for patients with severe renal impairment
(GFR < 30 mL/min).
Effects of age, gender, race and body size
No analysis of the effect of age, gender or body size on the elimination of Apealea has been
undertaken. However, a population pharmacokinetics study of 168 patients (86 males and 82 females)
treated with solvent-based paclitaxel has been reported. On average, the paclitaxel elimination rate
was 20% higher in males compared to in females. With regard to age, the population model indicated
an approximate 5% decline in paclitaxel elimination rate for each 10-year increase in age compared to
the median age of 56 years of the study. This amounted to a 14% decline in an 86-year-old patient
compared to one aged 56. Further it has been shown that the rate of paclitaxel elimination increased
15
with increasing body size. The model indicated that a 0.2 m increase in BSA would lead to a 9%
2
increase in the elimination rate. There is very little information available on whether the elimination of
paclitaxel differs between races.
5.3
Preclinical safety data
Mutagenesis, carcinogenesis, impairment of fertility
In vitro studies using different cell systems have shown paclitaxel to be clastogenic inducing
chromosomal aberrations, micronuclei and DNA damage. Chromosomal aberrations have also been
detected in in vivo studies in mice and monkeys. Paclitaxel was devoid of mutagenic activity in the
Ames test or the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl transferase
(CHO/HGPRT) gene mutation assay. The carcinogenic activity of paclitaxel has not been studied.
However, paclitaxel is potentially carcinogenic based on its mechanism of action and demonstrated
genotoxic activity. Paclitaxel at doses below the human therapeutic dose was associated with low
fertility and foetal toxicity in rats. Repeat dose toxicity studies have shown non-reversible, toxic
effects on male reproductive organs.
6.
PHARMACEUTICAL PARTICULARS
List of excipients
6.1
N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt
N-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt
Sodium hydroxide (for pH adjustment)
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 vial
2 years.
After reconstitution
Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C when
protected from light. From a microbiological point of view, unless the method of opening and
reconstituting precludes the risks of microbial contamination, the product should be used immediately.
If not used immediately, in-use storage times and conditions are the responsibility of the user.
6.4
Special precautions for storage
Store in a refrigerator (2 °C – 8 °C).
Keep the vial in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5
Nature and contents of container
Clear type I glass vial with a silicon coated butyl rubber stopper, an aluminium overseal and a plastic
flip-off cap containing powder equivalent to 60 mg of paclitaxel.
16
Pack size: 1 vial.
6.6
Special precautions for disposal and other handling
Administration precautions
Paclitaxel is an antineoplastic medicinal product and as with other potentially toxic compounds,
caution should be exercised in handling Apealea. The use of gloves, goggles and protective clothing is
recommended. If the solution 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. Apealea should only be prepared and administered by personnel appropriately
trained in the handling of cytotoxic agents. Pregnant and breast-feeding staff should not handle
Apealea. The reconstituted product should not be diluted.
Reconstitution of the medicinal product
Apealea is supplied as a sterile powder for reconstitution before use. After reconstitution, the solution
contains 1 mg/mL of paclitaxel formulated as micellar nanoparticles. The reconstituted solution for
infusion is a clear, greenish-yellow solution.
Protect from direct and/or bright light throughout the preparation process. The (reconstituted) product
can only withstand short-term handling in absence of light protection.
Only reconstitute using commercially available lactated or acetated Ringer’s solutions suitable for
infusion. The pH of the solution of reconstitution must be in the range of 5.0 to 7.5, and acceptable ion
concentrations of calcium and magnesium are listed below (Table 5).
Table 5. Acceptable ion concentrations for calcium and magnesium in lactated and acetated
Ringer’s solutions suitable for reconstitution
Ion
Range (mmol/L)
1.0–3.5*
Ca
2+
Mg
2+
0.0–2.5*
* Solutions containing both Mg
2+
and Ca
2+
should have a total (combined) concentration of Mg and
2+
Ca
2+
within the range of 1.0 to 3.5 mmol/L.
a.
Take the desired number of vials from the refrigerator. The powder should be greenish-yellow
to yellow. In case of discolouration (orange-reddish), discard the vial. To reach room
temperature, let the vials stand protected from light for approximately 20 to 30 minutes not
above 25 °C.
b.
Due to negative pressure in the vial, pressure must be equilibrated by a needle or a spike before
injection of the solution for reconstitution. Using a sterile syringe, inject 60 mL of solution for
reconstitution per vial. The solution should be injected slowly, directed onto the inside wall of
the vial and not directly onto the powder as this will result in foaming.
Gently swirl the solution manually for 20 to 30 seconds, protect from light and allow the vial to
stand for three to five minutes.
Then the vial should gently and slowly be swirled and/or inverted until the powder is
completely dissolved. To avoid generation of foam, do not shake. In case of particulate matter,
the vial should be placed on a shaker and rotated for up to 15 minutes, while being protected
from light (orbital shake pattern; 200–250 rpm). Steps c and d should not be more than
30 minutes.
c.
d.
e.
f.
The solution should be clear and greenish-yellow without visible particles or precipitates. If
particles, precipitates or discolouration (orange-reddish) are observed, the solution should be
discarded.
Inject the appropriate amount of reconstituted Apealea into an empty, sterile ethylene-vinyl
acetate (EVA) bag. Place a light protective bag over the EVA infusion bag.
17
Compatibility with administration sets made of DEHP-free PVC (i.e. polyvinyl chloride without the
plasticizer di-(2-ethylhexyl) phthalate) has been demonstrated. However, compatibility with
DEHP-containing administration sets has not been demonstrated. Administration sets containing a
15 µm polyamide fluid filter should be used.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
7.
MARKETING AUTHORISATION HOLDER
Oasmia Pharmaceutical AB
Vallongatan 1
SE-752 28 Uppsala
Sweden
Tel +46 18 50 54 40
8.
MARKETING AUTHORISATION NUMBER(S)
EU/1/18/1292/001
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
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.
18
ANNEX II
A.
B.
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY
AND USE
C.
D.
OTHER CONDITIONS AND REQUIREMENTS OF THE
MARKETING AUTHORISATION
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE
SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
19
A.
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer(s) responsible for batch release
Oasmia Pharmaceutical AB
Vallongatan 1
SE-752 28 Uppsala
Sweden
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
The requirements for submission of periodic safety update reports 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 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.
20
ANNEX III
LABELLING AND PACKAGE LEAFLET
21
A. LABELLING
22
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
NAME OF THE MEDICINAL PRODUCT
Apealea 60 mg powder for solution for infusion
paclitaxel
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial of powder contains 60 mg paclitaxel.
After reconstitution, each mL of solution contains 1 mg of paclitaxel (micellar).
3.
LIST OF EXCIPIENTS
Excipients: N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt,
N-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt, sodium hydroxide. See leaflet for further
information.
4.
PHARMACEUTICAL FORM AND CONTENTS
Powder for solution for infusion
1 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 SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Cytotoxic: Handle with caution.
Apealea should not be interchanged with other paclitaxel formulations.
23
8.
EXPIRY DATE
EXP:
After reconstitution: Use immediately.
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
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
Single-use vial
11.
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Oasmia Pharmaceutical AB
Vallongatan 1
752 28 Uppsala
Sweden
12.
MARKETING AUTHORISATION NUMBER(S)
EU/1/18/1292/001
13.
BATCH NUMBER
Lot:
14.
15.
16.
GENERAL CLASSIFICATION FOR SUPPLY
INSTRUCTIONS ON USE
INFORMATION IN BRAILLE
Justification for not including Braille accepted
17.
UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
24
18.
UNIQUE IDENTIFIER - HUMAN READABLE DATA
PC:
SN:
NN:
25
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
VIAL LABEL
1.
NAME OF THE MEDICINAL PRODUCT
Apealea 60 mg powder for solution for infusion
paclitaxel
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial of powder contains 60 mg paclitaxel.
After reconstitution, each mL of solution contains 1 mg of paclitaxel (micellar).
3.
LIST OF EXCIPIENTS
Excipients: N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt,
N-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt, sodium hydroxide. See leaflet for further
information.
4.
PHARMACEUTICAL FORM AND CONTENTS
Powder for solution for infusion
1 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 SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Cytotoxic
Apealea should not be interchanged with other paclitaxel formulations.
8.
EXPIRY DATE
EXP:
26
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
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
11.
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Oasmia Pharmaceutical AB
Uppsala, Sweden
12.
MARKETING AUTHORISATION NUMBER(S)
EU/1/18/1292/001
13.
BATCH NUMBER
Lot:
14.
15.
16.
GENERAL CLASSIFICATION FOR SUPPLY
INSTRUCTIONS ON USE
INFORMATION IN BRAILLE
Justification for not including Braille accepted
17.
18.
UNIQUE IDENTIFIER – 2D BARCODE
UNIQUE IDENTIFIER - HUMAN READABLE DATA
27
B. PACKAGE LEAFLET
28
Package leaflet: Information for the user
Apealea 60 mg powder for solution 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.
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.
2.
3.
4.
5.
6.
What Apealea is and what it is used for
What you need to know before you are given Apealea
How Apealea is given
Possible side effects
How to store Apealea
Contents of the pack and other information
1.
What Apealea is and what it is used for
Apealea is a cancer medicine containing the active substance paclitaxel, which belongs to a group of
medicines called taxanes. Paclitaxel affects or stops growth of rapidly dividing cells, such as tumour
cells.
Apealea is used to treat the following cancers in adults, in combination with another medicine called
carboplatin:
•
•
epithelial ovarian cancer – a cancer of the ovary, the organ that produces a woman’s egg cells
primary peritoneal cancer – a cancer of the cells lining the space between the wall of the belly
and the internal organs
•
cancer of the fallopian tubes (the connection between the ovaries and the womb)
It is used when other therapies have not worked.
2.
What you need to know before you are given Apealea
Do not use Apealea if you:
•
•
•
are allergic to paclitaxel or any of the other ingredients of this medicine (listed in section 6)
are breast-feeding
have a count of white blood cells called neutrophils below 1.5 × 10
9
/L before start of the therapy
Talk to your doctor or nurse, if you are not sure if any of the above applies to you.
Warnings and precautions
Talk to your doctor or nurse before you are given Apealea if you have:
•
reduced liver, kidney or heart function
Apealea is not recommended for patients with severely reduced liver or kidney function.
previously had nausea, vomiting and diarrhoea during cancer treatment
•
29
Contact your doctor immediately, if during treatment you develop:
•
•
•
•
•
fever, pain, chills, weakness or other signs of infection
severe nausea, vomiting or diarrhoea
severe reactions at the site of infusion
an allergic reaction
numbness, tingling, pricking sensation, sensitivity to touch or muscle weakness
You may need additional medicines if you develop any of these symptoms. Your doctor may wish to
delay further treatment with Apealea or reduce the dose.
Ask your doctor or nurse about hair loss and what can be done to avoid it.
You will be observed closely during treatment:
•
•
regular blood tests to ensure it is safe for you to continue treatment
symptoms of allergic reaction during the infusion, such as:
−
−
−
−
reddening and swelling at the site of infusion
low blood pressure
breathing difficulties
puffing of the face
Children and adolescents
Apealea is not recommended for children and adolescents under 18 years, because it has not been
studied in this age group.
Other medicines and Apealea
Tell your doctor if you are using, have recently used or might use any other medicines.
In particular, tell your doctor or nurse before you are given Apealea if you are using:
•
•
•
•
•
•
•
ketoconazole, or other medicines to treat fungal infections
erythromycin, rifampicin: medicines to treat bacterial infections
fluoxetine: a medicine to treat depression
gemfibrozil: a medicine to lower blood fats
clopidogrel: a medicine that reduces the chances of getting blood clots
cimetidine: a medicine to reduce stomach acid
efavirenz, nevirapine, ritonavir, saquinavir, indinavir, nelfinavir: medicines to treat HIV
infection
•
•
carbamazepine, phenytoin: medicines to treat epilepsy and certain pain conditions
cisplatin: a medicine to treat cancer
Pregnancy and breast-feeding
Tell your doctor before treatment if you are pregnant, think you may be pregnant or are breast-feeding.
Apealea is not recommended during pregnancy, as paclitaxel may cause serious birth defects.
Patients who can become pregnant should use effective contraception during treatment with Apealea
and for six months afterwards.
Stop breast-feeding while being treated, as paclitaxel passes into breast milk and may harm the child.
Driving and using machines
Apealea may cause side effects such as tiredness or dizziness that may reduce your ability to drive or
use machines. Do not drive or use machines if you have these symptoms.
30
Apealea contains sodium
After reconstitution, this medicine contains approximately 1.4 g sodium (component of cooking salt)
per dose. This is equivalent to 70% of the recommended maximum daily dietary intake of sodium for
an adult.
3.
How Apealea is given
Apealea is given to you by a doctor or nurse by a slow drip (infusion) into a vein. This will take about
one hour. The dose is based on your body surface area (worked out from your height and weight) and
blood test results. The usual dose is 250 mg/m
2
body surface area given every three weeks for up to six
treatments.
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 everybody gets them.
Tell your doctor or nurse immediately if you have any of the following:
•
Very common (may affect more than 1 in 10 people):
nerve disorder in arms and legs, which causes tingling, numbness or burning pain
Common (may affect up to 1 in 10 people):
−
•
−
−
−
fever
muscle weakness, cramps or spasms
allergic reactions, such as breathing difficulties, fainting, swelling of the face, itching,
feeling hot, chills, particularly during your infusion. Uncommonly these can lead to
severe allergic shock.
Other side effects and their frequencies include:
Very common (may affect more than 1 in 10 people):
•
•
•
•
•
•
•
low level of white blood cells called neutrophils
lack of appetite
diarrhoea, nausea, vomiting
hair loss
joint or muscle pain or discomfort
weakness, tiredness
reactions at the infusion site such as pain, inflammation, discolouration, redness, swelling,
tingling, rash, bleeding
Common (may affect up to 1 in 10 people):
•
•
•
•
•
•
•
•
•
•
low level of white blood cells called leukocytes and granulocytes
low level of blood platelets or red blood cells
reduced sense of touch or sensation
abnormal sensation such as tingling, burning, pricking or numbness of the skin or in the mouth
dizziness or feeling of spinning
taste disturbance
headache
rapid heartbeat
chest pain or discomfort
low blood pressure, flushing, vein inflammation, vein pain, increased blood flow to some parts
of the body
•
•
breathing difficulties, nasal congestion
abdominal pain, constipation, wind
31
•
•
•
•
•
dry mouth, inflammation of the inner lining of the mouth
skin reddening, rash, itching, nettle-rash
pain for instance in arms, legs, breast or at site of tumour
back pain, bone pain
swelling of ankles, feet, face or fingers
Uncommon (may affect up to 1 in 100 people):
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
blood poisoning
pus in body tissue
lung inflammation, influenza, tonsil inflammation
herpes simplex (a viral infection), viral airways infections
urinary tract infection, inflammation of the bladder
skin infections, including infections at the infusion site
disturbed blood clotting mechanisms in the body
lack of white and red blood cells, and blood platelets
low blood levels of potassium, magnesium or sodium
excessive water loss (dehydration)
allergic reactions to other medicines, such as penicillin
depression, sleeplessness, anxiety
epileptic fit lasting longer than five minutes or more than one fit within five minutes
coma, feeling very sleepy, drowsy and/or being deeply unresponsive
low muscle tone, facial palsy
toxicity to the nervous system
cognitive disorder (difficulty thinking or processing thoughts, difficulty remembering)
brain damage, abnormal fluid accumulation within the brain
stroke
blurred vision, eye discomfort or irritation, watery eyes
deafness, inner ear disorder, ringing in the ears
blood vessel disorders, such as:
−
−
−
−
−
formation of blood clots
blood vessel inflammation
build-up of water in tissue because of blocked lymph vessel
hot flushes
bleeding
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
cardiac arrest, heart failure
blue tinged lips or skin
a heart rhythm disorder causing irregular rapid activity in the upper heart chambers
feeling your heartbeat (palpitations), slow heartbeat
blood circulation failure
high blood pressure, blood pressure changes, paleness
lung failure, narrowing of airways
severe lack of oxygen, arising from abnormal breathing
difficulty producing voice sounds
nosebleed, allergic inflammation inside the nose, runny nose
cough
mouth and throat pain or discomfort, throat disorder, bleeding gums
inflammation of the stomach lining, abdominal discomfort or bloating, lower abdominal pain
indigestion, disorder of bowel function, very hard stools, bloody stool
liver inflammation or disorder, raised liver enzyme in your blood
painful severe swelling of deep skin layers, mainly in the face
skin discolouration, pigmentation disorder
skin inflammation with blisters
increased sweating, cold sweat
dry skin, nail disorder
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•
•
•
•
•
•
•
•
•
bleeding into a joint
sensation of heaviness in the legs
multi-organ failure which can lead to death
tissue swelling caused by excess fluid
hernia
feeling hot
low body temperature
vaginal bleeding
abnormally high levels of nitrogen-containing compounds in the blood
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist 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 Apealea
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 vial label and carton after EXP.
The expiry date refers to the last day of that month.
Unopened vials: Store in a refrigerator (2 °C – 8 °C). Keep the vial in the outer carton in order to
protect from light.
Once opened, Apealea is recommended to be used immediately.
Any unused medicine or waste material should be disposed of in accordance with local requirements.
Do not throw away any medicines via wastewater or household waste. These measures will help
protect the environment.
6.
Contents of the pack and other information
What Apealea contains
•
•
The active substance is paclitaxel. One vial contains 60 mg of paclitaxel. After preparation, each
millilitre of solution contains 1 mg of paclitaxel (micellar).
The other ingredients are:
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−
−
N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt
N-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt
sodium hydroxide (for pH adjustment)
See section 2 “Apealea contains sodium”.
What Apealea looks like and contents of the pack
Apealea is supplied as a greenish-yellow to yellow powder in a glass vial with a rubber stopper and
aluminium seal.
Each carton contains 1 glass vial with powder equivalent to 60 mg of paclitaxel.
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Marketing Authorisation Holder and Manufacturer
Oasmia Pharmaceutical AB
Vallongatan 1
SE-752 28 Uppsala
Sweden
Tel +46 18 50 54 40
e-mail: [email protected]
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 website:
http://www.ema.europa.eu.
---------------------------------------------------------------------------------------------------------------------------
The following information is intended for healthcare professionals only:
Administration precautions
Paclitaxel is an antineoplastic medicinal product and as with other potentially toxic compounds,
caution should be exercised in handling Apealea. The use of gloves, goggles and protective clothing is
recommended. If the solution 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. Apealea should only be prepared and administered by personnel appropriately
trained in the handling of cytotoxic agents. Pregnant and breast-feeding staff should not handle
Apealea. The reconstituted product should not be diluted.
Reconstitution of the medicinal product
Apealea is supplied as a sterile powder for reconstitution before use. After reconstitution, the solution
contains 1 mg/mL of paclitaxel formulated as micellar nanoparticles. The reconstituted solution for
infusion is a clear, greenish-yellow solution.
Protect from direct and/or bright light throughout the preparation process. The (reconstituted) product
can only withstand short-term handling in absence of light protection.
Only reconstitute using commercially available lactated or acetated Ringer’s solutions suitable for
infusion. The pH of the solution of reconstitution must be in the range of 5.0 to 7.5 and acceptable ion
concentrations of calcium and magnesium are listed below (Table 1).
Table 1. Acceptable ion concentrations for calcium and magnesium in lactated and acetated
Ringer’s solutions suitable for reconstitution
Ion
Range (mmol/L)
1.0–3.5*
Ca
2+
Mg
2+
0.0–2.5*
* Solutions containing both Mg
2+
and Ca
2+
should have a total (combined) concentration of Mg and
2+
Ca
2+
within the range of 1.0 to 3.5 mmol/L.
1.
Take the desired number of vials from the refrigerator. The powder should be greenish-yellow
to yellow. In case of discolouration (orange-reddish), discard the vial. To reach room
temperature, let the vials stand protected from light for approximately 20 to 30 minutes not
above 25 °C.
2.
Due to negative pressure in the vial, pressure must be equilibrated by a needle or a spike before
injection of the solution for reconstitution. Using a sterile syringe, inject 60 mL of solution for
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reconstitution per vial. The solution should be injected slowly, directed onto the inside wall of
the vial and not directly onto the powder as this will result in foaming.
Gently swirl the solution manually for 20 to 30 seconds, protect from light and allow the vial to
stand for three to five minutes.
Then the vial should gently and slowly be swirled and/or inverted until the powder is
completely dissolved. To avoid generation of foam, do not shake. In case of particulate matter,
the vial should be placed on a shaker and rotated for up to 15 minutes, while being protected
from light (orbital shake pattern; 200–250 rpm). Steps 3 and 4 should not be more than
30 minutes.
3.
4.
5.
6.
The solution should be clear and greenish-yellow without visible particles or precipitates. If
particles, precipitates or discolouration (orange-reddish) are observed, the solution should be
discarded.
Inject the appropriate amount of reconstituted Apealea into an empty, sterile ethylene-vinyl
acetate (EVA) bag. Place a light protective bag over the EVA infusion bag.
Shelf life after reconstitution
Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C when
protected from light. From a microbiological point of view, unless the method of opening and
reconstituting precludes the risks of microbial contamination, the product should be used immediately.
If not used immediately, in-use storage times and conditions are the responsibility of the user.
Intravenous administration
Compatibility with administration sets made of DEHP-free PVC (i.e. polyvinyl chloride without the
plasticizer di-(2-ethylhexyl) phthalate) has been demonstrated. However, compatibility with
DEHP-containing administration sets has not been demonstrated. Administration sets containing a
15 µm polyamide fluid filter should be used. It is important to flush the infusion set and
catheter/cannula before and after the administration using the solution for reconstitution in order to
avoid accidental administration into the surrounding tissue and to ensure administration of the
complete dose.
Disposal
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
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