Apealea

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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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 
up to approximately 3.60 mg (0.157 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 
 
4.1 Therapeutic indications 
 
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/m2 body surface area (BSA) given as an intravenous 
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 × 109/L), febrile neutropenia or 
thrombocytopenia (platelet count < 100 × 109/L) during treatment should have the next treatment cycle 
delayed until neutrophil counts recover to ≥ 1.5 × 109/L and platelets recover to ≥ 100 × 109/L. For 
Apealea, dose reductions of initially 50 mg/m2 and additionally 25 mg/m2 should be considered for 
subsequent courses (see Table 1).  
 
In the case of febrile neutropenia or low platelet count (< 75 × 109/L), the dose of carboplatin should 
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. 
 



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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 

Observationa Delay of next cycle 
Apealea/carboplatin 

Apealea dose for subsequent courses 
(mg/m2)b 

Haematological toxicityb 

neutrophil count < 1.5 × 109/L 
or 
platelet count < 100 × 109/L 
or 
febrile neutropenia 

Withhold treatment until 
recovery 

Standard dose: 250 

Possible dose reductions: 

First dose level reduction:  200 

Second dose level reduction: 175 

Nervous system disorders 

grade ≥ 2 peripheral sensory 
neuropathy 
or 
grade ≥ 2 motor neuropathy 

Withhold treatment until 
recovery to < grade 2 

Dose reduction: 

First dose level reduction:  200 

Possible dose reduction: 

Second dose level reduction: 175 

All other adverse reactions 

Any grade 4 toxicity Discontinue treatment 

Any grade 3 toxicity except 
nausea, vomiting and 
diarrhoea 

Withhold treatment until 
symptoms resolve to 
grade ≤ 1 

Possible dose reductions: 

First dose level reduction:  200 

Second dose level reduction: 175 
a Grade of the adverse reaction is defined according to Common Terminology Criteria for Adverse 
Events (CTCAE). 
b The dose of carboplatin should be reduced by 1 AUC unit for treatment cycles following the 
occurrence of febrile neutropenia or low platelet count (< 75 × 109/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). 
 



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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 × 109/L. 
 
4.4 Special warnings and precautions for use 
 
Haematology 
 
Paclitaxel causes myelosuppression (primarily neutropenia). Neutropenia is a dose-dependent and 
dose-limiting adverse reaction. 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 × 109/L and platelets recover to ≥ 100 × 109/L. Patients with low 
neutrophil count 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). 
 



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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 



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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 up to approximately 1.6 g sodium per dose 
(0.9 g/m2 BSA; 3.6 mg per mL), equivalent to 80% 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 



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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) and adverse reactions from post-marketing 
experience. The latter ones may be attributed to paclitaxel regardless of the treatment regimen. 
 



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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, 
malignant and unspecified 
(incl. cysts and polyps) 

Uncommon: Metastatic pain 

Blood and lymphatic 
system disorders 

Very common: Neutropeniaa 

Common: Febrile neutropeniaa, leukopeniaa, 
thrombocytopeniaa, granulocytopenia, anaemiaa 

Uncommon: Disseminated intravascular coagulationa, 
pancytopenia, haematotoxicity, coagulopathy 

Immune system disorders Common: Hypersensitivity 

Uncommon: Anaphylactic shock, drug hypersensitivity 

Metabolism and nutrition 
disorders 

Very common: Anorexia 

Uncommon: Hyponatraemia, hypokalaemia, hypomagnesaemia, 
dehydration, decreased appetite 

Psychiatric disorders Uncommon: Depression, insomnia, anxiety 

Nervous system disorders Very common: Peripheral sensory neuropathya,b, 
neuropathy peripherala,b 

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: Vision blurred, eye irritation, ocular discomfort, 
lacrimation increased 

Ear and labyrinth 
disorders 

Uncommon: Vertigo, deafness, inner ear disorder, tinnitus 

Cardiac disorders Common: Angina pectoris, tachycardia 

Uncommon: Cardiac arrest, cardiac failure chronic, cyanosis, 
atrial fibrillation, sinus tachycardia, palpitations, 
sinus bradycardia 

Vascular disorders 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 



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System Organ Class Frequency Preferred term 

Respiratory, thoracic and 
mediastinal disorders 

Common: 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: Diarrhoeaa, nauseaa, vomitinga 

Common: 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: Hepatitis, liver disorder 

Skin and subcutaneous 
tissue disorders 

Very common: Alopeciaa 

Common: 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 

Not known: Palmar-plantar erythrodysesthesia syndromec 

Musculoskeletal and 
connective tissue disorders 

Very common: Arthralgiaa, myalgiaa 

Common: Back pain, bone pain, musculoskeletal pain, 
muscular weakness, pain in extremity 

Uncommon: Haemarthrosis, musculoskeletal discomfort, 
sensation of heaviness 

Renal and urinary 
disorders 

Uncommon: Azotaemia 

Reproductive system and 
breast disorders 

Uncommon: Vaginal haemorrhage, pelvic pain, breast pain 

General disorders and 
administration site 
conditions 

Very common: Astheniaa, fatiguea, infusion site reactiona,d 

Common: 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. 
b Can persist beyond 6 months of paclitaxel discontinuation.c 
c As reported in the post-marketing surveillance of paclitaxel. 
d Includes the following preferred terms: infusion site pain, infusion site phlebitis, 
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. 



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Description of selected adverse reactions 
 
In the pivotal clinical study, patients were either treated with Apealea (paclitaxel micellar) at a dose of 
250 mg/m2 in combination with carboplatin or with solvent-based paclitaxel at a dose of 175 mg/m2 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 × 109/L before the next 
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. 
Further, it has been demonstrated that peripheral neuropathies can persist beyond 6 months of 
paclitaxel discontinuation. 
 
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. 
 



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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. 
 
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, such as pain, phlebitis, and erythema, were seen in 12% of patients (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/m2 
in a 3-week regimen to weekly doses of 250 mg/m2 for various indications. Based on the combined 
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%), 
infusion site reactiona (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 
 
5.1 Pharmacodynamic properties 
 
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 



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mitotic cellular functions. In addition, paclitaxel induces microtubule bundle formation throughout the 
cell cycle and induces microtubule aster formation during mitosis. 
 
Clinical efficacy and safety 
 
An open, randomised, multicentre study was conducted in 789 women with recurrent epithelial 
ovarian cancer, primary peritoneal cancer and fallopian tube cancer to compare Apealea (paclitaxel 
micellar) in combination with carboplatin with solvent-based paclitaxel in combination with 
carboplatin. Patients were treated every three weeks for six cycles, either with Apealea 250 mg/m2 
given as a 1-hour intravenous infusion (N = 391) or with solvent-based paclitaxel 175 mg/m2 given as 
a 3-hour infusion (N = 391). The paclitaxel infusion was followed by carboplatin after an interval of 
30 minutes in both treatment arms.  
 
Patients were stratified based on relapse (first or second) and CA125 values. The proportions of 
patients treated at first or second relapse were then 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 (N = 391) 
Paclitaxel (solvent-based) 

(N = 391) 

Type of 
premedication Overall Paclitaxel Carboplatin Overall Paclitaxel Carboplatin 

Corticosteroids 43% 6% 39% 99% 97% 15% 

Antihistamines 19% 4% 16% 85% 85% 9% 

H2 antagonists 5% 2% 2% 90% 90% 1% 

Antiemetics and 
antinauseants 87% 8% 81% 92% 38% 63% 

 
In the study, 35% of the patients in the paclitaxel micellar group and 30% of the patients in the 
solvent-based paclitaxel group, 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 as the primary endpoint was evaluated by blinded assessment of computerised tomography 
images using Response Evaluation Criteria in Solid Tumours (RECIST) 1.0. 
 



13 

There was no statistically significant difference in PFS or OS between the two treatment arms. A 
non-inferiority analysis was conducted for PFS in the per-protocol (PP) population 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 ratio being less than 1.2. The 
non-inferiority criterion was met for OS in the PP population with the upper bound limit of the 
one-sided 97.5% CI for the associated hazard ratio being less than 1.185 (Table 4; Figures 1 and 2). In 
the intention-to-treat (ITT) population (n = 789), 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. Thereby, non-inferiority was shown in the ITT 
population for PFS, 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. Non-inferiority analyses on PFS and OS in a randomised trial in patients with recurrent 
epithelial ovarian cancer, primary peritoneal cancer and fallopian tube cancer (PP population)a 

 
Apealea 

Q3W 250 mg/m2 + carboplatin 
(N = 311) 

Solvent-based paclitaxel 
Q3W 175 mg/m2 + carboplatin 

(N = 333) 

Progression free survival (independent review) 

Death or progression, n (%) 239 (77%) 270 (81%) 

Median time to death or disease 
progression [months] (95% CI) 10.3 (10.1;10.7) 10.1 (9.9;10.2) 

Hazard ratio (95% CI) 0.86 (0.72;1.03) 

Overall survival 

Number of deaths, n (%) 179 (58%) 206 (62%) 

Median time to death [months] 
(95% CI) 25.7 (22.9;28.1) 24.8 (21.7;27.1) 

Hazard ratio (95% CI) 0.95 (0.78;1.16) 
a Primary population in non-inferiority analysis was predefined as the PP population 
 
Figure 1. Kaplan-Meier curve of PFS (PP population) 

 

 

 

 

Pr
ob

ab
ilit

y 
of

 p
ro

gr
es

si
on

-fr
ee

 s
ur

vi
va

l 

 

 

Months  

Apealea:   
solvent-based paclitaxel:   

 Number at risk  

  Patients Events 
 Apealea: 311 239 
 solvent-based paclitaxel: 333 270 

 



14 

Figure 2. Kaplan-Meier curve of OS (PP population) 

 
 
Post-hoc subgroup analysis by relapse  
Additional subgroup analyses were conducted to investigate efficacy by relapse (first and second) in 
the PP and the ITT population. PFS and OS results in the PP population are summarised in Figures 3 
and 4. 
 
Figure 3. Forest plot for PFS by relapse (PP population) 

  Apealea  Solvent-based paclitaxel   

Relapse 
 

n Events 
(%) 

Median 
months 
(95% CI) 

 

n Events 
(%) 

Median 
months 
(95% CI) 

 
non-inferiority 
margin (1.2) 

 

Hazard Ratio 
(95% CI) 

 

        

 

 

All 
 

 
 
 
 
 
 311 239 

(77%) 
10.3 

(10.1;10.7) 
 

333 270 
(81%) 

10.1 
(9.9;10.2) 0.86 (0.72;1.03) 

 
 

   
 

    
First 

 
 
 
 
 
 
 
 
 

240 180 
(75%) 

10.3 
(10.2;11.3) 

 

257 209 
(81%) 

10.1 
(9.8;10.3) 0.82 (0.67;1.00) 

 
 

   
 

    
Second 

 
 
 
 
 
 
 71 59 

(83%) 
9.9 

(8.6;10.6) 
 

76 61 
(80%) 

10.1 
(9.7;10.4) 1.01 (0.69;1.46) 

       

 

       

favours 
Apealea   

favours 
solvent-based paclitaxel 

 

 

 

 

Pr
ob

ab
ilit

y 
of

 s
ur

vi
va

l 

 

 

Months  

Apealea:   
solvent-based paclitaxel:   
 Number at risk  

  Patients Events 
 Apealea: 311 179 
 solvent-based paclitaxel: 333 206 

 



15 

Figure 4. Forest plot for OS by relapse (PP population) 

  Apealea  Solvent-based paclitaxel   

Relapse 
 

n Events 
(%) 

Median 
months 
(95% CI) 

 

n Events 
(%) 

Median 
months 
(95% CI) 

 
non-inferiority 
margin (1.185) 

 

Hazard Ratio 
(95% CI) 

 

        

 

 

All 
 

 
 
 
 
 
 311 179 

(58%) 
25.7 

(22.9;28.1) 
 

333 206 
(62%) 

24.8 
(21.7;27.1) 0.95 (0.78;1.16) 

 
 

   
 

    
First 

 
 
 
 
 
 
 
 
 

240 139 
(58%) 

26.1 
(23.0;28.4) 

 

257 162 
(63%) 

23.6 
(21.3;27.1) 0.92 (0.73;1.16) 

 
 

   
 

    
Second 

 
 
 
 
 
 
 71 40 

(56%) 
23.2 

(18.3;28.9) 
 

76 44 
(58%) 

24.8 
(19.2;30.0) 1.07 (0.68;1.68) 

       

 

       

favours 
Apealea   

favours 
solvent-based paclitaxel 

 

In the ITT population, the hazard ratios for PFS in the subgroups of patients with first relapse and 
second relapse were 0.80 (95% CI: 0.66;0.97) and 1.04 (95% CI: 0.74;1.47), respectively. The hazard 
ratios for OS in patients with first and second relapse were 0.98 (95% CI: 0.79;1.21) and 1.18 
(95% CI: 0.79;1.75), respectively. Thus, the results in the subgroup of patients with first relapse are 
consistent with the results in the overall population and in addition, there was an indication of PFS 
benefit for Apealea. 
 
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/m2). In addition, a study with a crossover design compared total and unbound paclitaxel 
concentrations in plasma after a 1-hour infusion of Apealea 260 mg/m2 with those after a 1-hour 
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/m2. Dose-linearity could not be ascertained since a large inter-individual variability was 
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 



16 

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 
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 
terminal elimination phase of about 155 L/m2 corresponding to about 280 L for an average patient 
with a body surface area of 1.8 m2. Thus, only about 1% of the paclitaxel in the body is located in 
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). 
 



17 

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 
with increasing body size. The model indicated that a 0.2 m2 increase in BSA would lead to a 9% 
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 
 
6.1 List of 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 (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 
 
3 years. 
 
After reconstitution 
 
Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C in lactated 
and acetated Ringer’s solution and for 4 hours at 2 °C to 8 °C in sodium chloride 9 mg/mL (0.9%) 
solution 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. 
 



18 

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. 
 
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 Apealea using one of the following commercially available solutions for 
reconstitution: 

- sodium chloride 9 mg/mL (0.9%) solution suitable for infusion; 
- lactated Ringer’s solution suitable for infusion; 
- acetated Ringer’s solution suitable for infusion. 

 
The pH of lactated or acetated Ringer’s solution 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) 
Ca2+ 1.0–3.5* 
Mg2+ 0.0–2.5* 

* Solutions containing both Ca2+ and Mg2+ should have a total (combined) concentration of Ca2+ and 
Mg2+ within the range of 1.0 to 3.5 mmol/L. 
 
Apealea should be reconstituted using either one of the three suitable solutions for reconstitution and 
according to the following steps: 
 



19 

a. Take the desired number of vials from the refrigerator. The powder should be greenish-yellow 
to yellow. In case of discolouration (orange), discard the vial. To reach room temperature, let 
the vials stand protected from light for approximately 15 to 20 minutes not above 25 °C. 

b. Due to negative pressure in the vial, pressure must be equilibrated by a needle or a spike before 
and during injection of the solution for reconstitution. Using a sterile syringe, inject 60 mL of 
solution for reconstitution per vial. The solution should be injected during approximately one 
minute towards the inner wall of the vial and not directly onto the powder as this will result in 
foaming. 

c. Swirl the vial in an upright position for approximately 20 seconds. To keep the generation of 
foam to a minimum, do not shake the vial. 

d. Protect from light and allow the vial to stand for three to five minutes. 
e. Swirl the vial again in upright position for approximately 20 seconds, then gently invert it five 

times. Do not shake.  
f. Continue to swirl the vial until the powder is completely dissolved., Alternatively, the vial may 

be placed on a shaker and rotated for up to 20 minutes, while being protected from light (orbital 
shake pattern; 200–250 rpm). Steps c and to f should not be more than 30 minutes. 

g. The solution should be clear and greenish-yellow without visible particles or precipitates. If 
particles, precipitates, discolouration (orange) or opalescence are observed, the solution should 
be discarded. 

h. Inject the required amount of reconstituted Apealea into an empty, sterile ethylene-vinyl acetate 
(EVA) bag. Ensure that the solution is clear and place a light-protective bag over the EVA 
infusion bag. 

 
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 
 
Date of first authorisation: 20 November 2018 
 
 
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. 



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 



21 

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 (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 

• At the request of the European Medicines Agency; 
 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



24 

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. 
 
 



25 

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. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



26 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



27 

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. 
 
 



28 

8. EXPIRY DATE 
 
EXP 
 
 
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. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 



29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



30 

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. What Apealea is and what it is used for 
2. What you need to know before you are given Apealea 
3. How Apealea is given 
4. Possible side effects 
5. How to store Apealea 
6. 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 × 109/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 



31 

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. 
 



32 

Apealea contains sodium 
 
After reconstitution, this medicine contains approximately up to 1.6 g sodium (component of cooking 
salt) per dose. This is equivalent to 80% 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/m2 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. 

 
* Can persist beyond 6 months of paclitaxel discontinuation. 
 
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 



33 

• breathing difficulties, nasal congestion 
• abdominal pain, constipation, wind 
• 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 



34 

• increased sweating, cold sweat 
• dry skin, nail disorder 
• 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 

 
Frequency not known (cannot be estimated from the available data): 
• redness and swelling of the palms of your hands or soles of your feet which may cause your 

skin to peel 
 
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: 

− 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”. 
 



35 

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. 
 
Marketing Authorisation Holder and Manufacturer 
 
Oasmia Pharmaceutical AB 
Vallongatan 1 
SE-752 28 Uppsala 
Sweden 
Tel +46 18 50 54 40 
e-mail: med-info@oasmia.com 
 
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 Apealea using one of the following commercially available solutions for 
reconstitution: 

- sodium chloride 9 mg/mL (0.9%) solution suitable for infusion; 
- lactated Ringer’s solution suitable for infusion; 
- acetated Ringer’s solution suitable for infusion. 

 
The pH of lactated or acetated Ringer’s solution must be in the range of 5.0 to 7.5 and acceptable ion 
concentrations of calcium and magnesium are listed below (Table 1). 
 



36 

Table 1. Acceptable ion concentrations for calcium and magnesium in lactated and acetated 
Ringer’s solutions suitable for reconstitution 

Ion Range (mmol/L) 
Ca2+ 1.0–3.5* 
Mg2+ 0.0–2.5* 

* Solutions containing both Ca2+ and Mg2+ should have a total (combined) concentration of Ca2+ and 
Mg2+ within the range of 1.0 to 3.5 mmol/L. 
 
Apealea should be reconstituted using either one of the three suitable solutions for reconstitution and 
according to the following steps: 
 
1. Take the desired number of vials from the refrigerator. The powder should be greenish-yellow 

to yellow. In case of discolouration (orange), discard the vial. To reach room temperature, let 
the vials stand protected from light for approximately 15 to 20 minutes not above 25 °C. 

2. Due to negative pressure in the vial, pressure must be equilibrated by a needle or a spike before 
and during injection of the solution for reconstitution. Using a sterile syringe, inject 60 mL of 
solution for reconstitution per vial. The solution should be injected during approximately one 
minute towards the inner wall of the vial and not directly onto the powder as this will result in 
foaming. 

3. Swirl the vial in an upright position for approximately for 20 seconds. To keep the generation of 
foam to a minimum, do not shake the vial. 

4. Protect from light and allow the vial to stand for three to five minutes. 
5. Swirl the vial again in upright position for approximately 20 seconds, then gently invert it five 

times. Do not shake. 
6. Continue to swirl the vial until the powder is completely dissolved. Alternatively, the vial may 

be placed on a shaker and rotated for up to 20 minutes, while being protected from light (orbital 
shake pattern; 200–250 rpm). Steps 3 to 6 should not be more than 30 minutes. 

7. The solution should be clear and greenish-yellow without visible particles or precipitates. If 
particles, precipitates, discolouration (orange) or opalescence are observed, the solution should 
be discarded. 

8. Inject the required amount of reconstituted Apealea into an empty, sterile ethylene-vinyl acetate 
(EVA) bag. Ensure that the solution is clear and 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 in lactated 
and acetated Ringer’s solution and for 4 hours at 2 °C to 8 °C in sodium chloride 9 mg/mL (0.9%) 
solution 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. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET