Pixuvri

1 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Pixuvri 29 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One vial contains pixantrone dimaleate equivalent to 29 mg pixantrone  
 
After reconstitution, each ml of concentrate contains pixantrone dimaleate equivalent to 5.8 mg 
pixantrone. 
 
Excipient with known effect: 
One vial contains 39 mg sodium. 
Upon reconstitution and dilution, this medicinal product contains approximately 1g (43 mmol) sodium 
per dose, equivalent to 50% of the WHO recommended maximum daily intake of 2 g sodium for an 
adult. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
Dark blue lyophilised powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Pixuvri is indicated as monotherapy for the treatment of adult patients with multiply relapsed or 
refractory aggressive Non-Hodgkin B-cell Lymphomas (NHL). The benefit of pixantrone treatment has 
not been established in patients when used as fifth line or greater chemotherapy in patients who are 
refractory to last therapy. 
 
4.2 Posology and method of administration 
 
Pixuvri must be administered by physicians who are familiar with the use of antineoplastic agents and 
have the facilities for regular monitoring of clinical, haematological, and biochemical parameters during 
and after treatment (see section 6.6). 
 
Posology 
 
The recommended dose is 50 mg/m2 of pixantrone on days 1, 8, and 15 of each 28-day cycle for up to 
6 cycles.  
Please note: 
In the EU recommended dose refers to the base of the active substance (pixantrone). Calculation of the 
individual dose to be administered to a patient must be based on the strength of the reconstituted 
solution that contains 5.8mg/ml pixantrone and the dose recommendation of 50 mg/m2. In some trials 
and publications, the recommended dose is based on the salt form (pixantrone dimaleate) 
However, the dose has to be adjusted before the start of each cycle based on nadir haematologic counts 
or maximum toxicity from the preceding cycle of therapy. The amount of Pixuvri in milligrams that is to 
be administered to a patient should be determined on the basis of the patient’s body surface area (BSA). 
The BSA should be determined using the institutional standard for BSA calculation and should use a 
weight measured on day 1 of every cycle. 
 
Some caution is advised in obese patients as data on BSA- based dosing is very limited for this group. 
 
Dose modification guidelines  



 

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Dose modification and the timing of subsequent doses should be determined by clinical judgement 
depending on the degree and duration of myelosuppression. For subsequent courses, the prior dose can 
usually be repeated if white blood cell and platelet counts have returned to acceptable levels. 
 
If on day 1 of any cycle the Absolute Neutrophil Count (ANC) is < 1.0 x 109/l or platelet count is 
< 75 x 109/l it is recommended to delay treatment until ANC recovers to ≥ 1.0 x 109/l and platelet count 
to ≥ 75 x 109/l. 
 
Table 1 and Table 2 are recommended as guides to dosage adjustments for days 8 and 15 of the 28- day 
cycles. 
 

Table 1 
Dose modifications for hematologic toxicity on days 8 and 15 of any cycle 

Grade Platelet count ANC count Dose modification 

1-2 LLN* – 50 x 109/l LLN – 1.0 x 109/l No change in dose or schedule. 

3 < 50 – 25 x 109/l < 1.0 – 0.5 x 109/l Delay treatment until recovery to platelet count ≥ 50 x 109/l and ANC** ≥ 1.0 x 109/l. 

4 < 25 x 109/l < 0.5 x 109/l 
Delay treatment until recovery to platelet count 
≥ 50 x 109/l and ANC** ≥ 1.0 x 109/l. 
Reduce the dose by 20%.

* LLN: Lower Limit of the Normal range 
** ANC: Absolute Neutrophil Count 
 
 

Table 2 
Treatment modifications for non-hematologic toxicities 

Toxicity Modification  
Any grade 3 or 4 drug-related non cardiac 
toxicity other than nausea or vomiting  

Delay treatment until recovery to grade 1. 
Reduce the dose by 20%.

Any grade 3 or 4 NYHA* cardiovascular 
toxicity or persistent LVEF** decline  

Delay treatment and monitor until 
recovery.Consider discontinuation for persistent 
decline in LVEF** of ≥ 15% of baseline value. 

* NYHA: New York Heart Association 
** LVEF: Left Ventricular Ejection Fraction
 
Special populations 
Paediatric population 
The safety and efficacy of Pixuvri in children aged < 18 years has not yet been established. No data are 
available.  
 
Elderly 
No specific dose adjustment is required in elderly patients (aged ≥ 65 years). 
 
Renal impairment 
The safety and efficacy of Pixuvri has not been established in patients with impaired renal function. 
Patients with serum creatinine > 2 x Upper Limit of the Normal range (ULN) were excluded from the 
randomised studies. Thus, Pixuvri should be used with caution in patients with renal impairment. 
 
Patients with impaired hepatic function 
The safety and efficacy of Pixuvri in patients with impaired hepatic function has not been established. 
Pixuvri should be used with caution in patients with mild or moderate liver impairment. Pixuvri is not 
recommended for use in patients with severe excretory hepatic impairment, (see section 4.3). 
 
Patients with poor performance status 
There is currently no information on the safety and efficacy of patients with poor performance status 
(ECOG > 2). Caution should be exercised when treating such patients. 
 



 

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Method of administration 
 
Pixuvri is for intravenous use only. The safety of intrathecal use has not been established. 
 
Pixuvri is intended for administration as a slow intravenous infusion using an in-line filter (over a 
minimum of 60 minutes) only after reconstitution with 5 ml sodium chloride 9 mg/ml (0.9%) solution 
for injection and after further dilution with sodium chloride 9 mg/ml (0.9%) solution for injection to a 
final volume of 250 ml. 
 
For instructions on reconstitution and dilution of the medicinal product before administration, see 
section 6.6. 
 
4.3 Contraindications 
 
- Hypersensitivity to pixantrone dimaleate, or to any of the excipients listed in section 6.1 
- Immunisation with live virus vaccines 
- Profound bone marrow suppression 
- Severe abnormal hepatic function. 
 
4.4 Special warnings and precautions for use 
 
All initial treatment with Pixuvri should be preceded by a careful baseline assessment of blood counts, 
serum levels of total bilirubin, serum levels of total creatinine, and cardiac function as measured by left 
ventricular ejection fraction (LVEF). 
 
Myelosuppression 
Severe myelosuppression may occur. Patients treated with Pixuvri are likely to experience 
myelosuppression (neutropenia, leukopenia, anaemia, thrombocytopenia, and lymphopenia) with the 
predominant manifestation being neutropenia. With the recommended dose and schedule, neutropenia is 
usually transient, reaching its nadir on days 15-22 following administration on days 1, 8, and 15 with 
recovery usually occurring by day 28.  
 
Careful monitoring of blood counts is required, including leukocyte, red blood cells, platelet, and 
absolute neutrophil counts. Recombinant hematopoietic growth factors may be used according to 
institutional or European Society for Medical Oncology (ESMO) guidelines. The dose modifications 
should be considered (see section 4.2). 
 
Cardiotoxicity 
Changes in cardiac function including decreased LVEF or fatal congestive heart failure (CHF) may 
occur during or after treatment with Pixuvri.  
 
Active or dormant cardiovascular disease, prior therapy with anthracyclines or anthracenediones, prior 
or concurrent radiotherapy to the mediastinal area, or concurrent use of other cardiotoxic medicinal 
products may increase the risk of cardiac toxicity. Cardiac toxicity with Pixuvri may occur whether or 
not cardiac risk factors are present. 
 
Patients with cardiac disease or risk factors such as a baseline LVEF value of < 45% by multigated 
radionuclide (MUGA) scan, clinically significant cardiovascular abnormalities (equal to New York 
Heart Association [NYHA] grade 3 or 4), myocardial infarction within the last 6 months, severe 
arrhythmia, uncontrolled hypertension, uncontrolled angina, or prior cumulative doses of doxorubicin or 
equivalent exceeding 450 mg/m2 should receive careful risk versus benefit consideration before 
receiving treatment with Pixuvri. 
 
Cardiac function should be monitored before initiation and during the treatment with Pixuvri . If cardiac 
toxicity is demonstrated during treatment, the risk versus benefit of continued therapy with Pixuvri must 
be evaluated. 
 
Secondary malignancy 



 

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The development of haematological malignancies such as secondary acute myeloid leukaemia (AML) or 
myelodysplastic syndrome (MDS) is a recognised risk associated with anthracycline treatment and other 
topoisomerase II inhibitors. The occurrence of secondary cancers, including AML and MDS, may occur 
during or after treatment with Pixuvri. 
 
Infection 
Infections, including pneumonia, cellulitis, bronchitis, and sepsis have been reported during clinical 
trials (see section 4.8). Infections have been associated with hospitalisation, septic shock, and death. 
Patients with neutropenia are more susceptible to infections, although, in the clinical studies there was 
no increased incidence of atypical, difficult-to-treat infections, such as systemic mycotic infections or 
infections with opportunistic organisms such as Pneumocystis jiroveci. 
 
Pixuvri should not be administered to patients with an active, severe infection or in patients with a 
history of recurring or chronic infections or with underlying conditions which may further predispose 
them to serious infection.  
 
Tumour lysis syndrome 
Pixantrone may induce hyperuricaemia as a consequence of the extensive purine catabolism that 
accompanies drug-induced rapid lysis of neoplastic cells (tumour lysis syndrome) and can lead to 
electrolyte imbalances, which can result in kidney damage. Blood uric acid levels, potassium, calcium 
phosphate, and creatinine should be evaluated after treatment in patients at high risk for tumour lysis 
(elevated LDH, high tumour volume, high baseline uric acid or serum phosphate levels). Hydration, 
urine alkalinisation, and prophylaxis with allopurinol or other agents to prevent hyperuricaemia may 
minimise potential complications of tumour lysis syndrome. 
 
Immunisation 
Immunisation may be ineffective when given during Pixuvri therapy. Immunisation with live virus 
vaccines is contraindicated due to the immunosuppression associated with Pixuvri therapy (see 
section 4.3). 
 
Extravasation  
If extravasation occurs the administration should be stopped immediately and restarted in another vein. 
The non-vesicant properties of Pixuvri minimise the risk of local reaction following extravasation.  
 
Prevention of photosensitivity reactions 
Photosensitivity is a potential risk based on in vitro and in vivo non-clinical data. One case of 
photosensitivity reaction has been reported in the clinical trial program considered as non-serious and 
with outcome recovered. As a precaution, patients should be advised to follow sun protection strategies, 
including wearing sun protective clothing and using sunscreen. Since most medicinal product-induced 
photosensitivity reactions are caused by wavelengths within the UV-A range, sunscreen that strongly 
absorbs UV-A is recommended. 
 
Patients on a sodium restricted diet 
This medicinal product contains approximately 1000 mg (43 mmol) sodium per dose after dilution. To 
be taken into consideration by patients on a controlled sodium diet. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No drug interactions have been reported in human subjects and no drug-drug interaction studies in 
humans have been performed. 
 
In vitro inhibition studies 
In vitro studies with the most common human cytochrome P450 isoforms (including CYP1A2, 2B6, 
2C8, 2C9, 2C19, 2D6, and 3A4) have shown a possible mixed-type inhibition of CYP1A2 and CYP2C8 
that may be of clinical relevance. No other significant clinically relevant interactions with CYPP450s 
were observed.  
 
Theophylline: when co-administering the narrow-therapeutic index medicinal product theophylline, 
which is primarily metabolised by CYP1A2, there is a theoretical concern that this substrate may 



 

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increase in concentration resulting in theophylline toxicity. Theophylline levels should be carefully 
monitored in the weeks immediately following initiation of Pixuvri concurrent therapy. 
 
Warfarin is partially metabolised by CYP1A2, therefore, a theoretical concern exists with regard to 
co-administration of this medicinal product and the effect inhibition of its metabolism might have on its 
intended action. Coagulation parameters, specifically international normalised ratio (INR), should be 
monitored in the days immediately following the initiation of Pixuvri concurrent therapy. 
 
Amitriptyline, haloperidol, clozapine, ondansetron and propranolol are metabolised by CYP1A2, and 
therefore, a theoretical concern exists that co-administration of Pixuvri may increase blood levels of this 
medicinal product. 
 
Although a risk to inhibition of pixantrone towards CYP2C8 could not be ascertained, caution should be 
observed when co-administering substances that are primarily metabolised via CYP2C8, such as 
repaglinide, rosiglitazone, or paclitaxel e.g. by careful monitoring for side effects. 
 
Based on in vitro studies, pixantrone was found to be a substrate for the membrane transport proteins 
P-gp/BRCP and OCT1 and agents which inhibit these transporters have the potential to decrease hepatic 
uptake and excretion efficiency of pixantrone. Blood counts should be closely monitored when 
co-administered with agents which inhibit such transporters such as cyclosporine A or tacrolimus, 
commonly used to control chronic graft-versus-host disease, and the anti-HIV agents ritonavir, 
saquinavir, or nelfinavir. 
 
In addition, caution should be taken when pixantrone is continuously co-administered with efflux 
transport inducers such as rifampicin, carbamazepin and glucocorticoids, as pixantrone excretion might 
be increased with a consequent decrease of systemic exposure. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
Women of childbearing potential and their partners should be advised to avoid pregnancies. 
 
Women and men must use effective contraception during and up to 6 months after treatment. 
 
Pregnancy  
There are no data from the use of pixantrone in pregnant women. Studies in animals have shown 
reproductive toxicity (see section 5.3).  
 
Pixuvri is not recommended during pregnancy and in women of childbearing potential not using 
contraception. 
 
Breast-feeding 
It is unknown whether Pixuvri/metabolites are excreted in human milk.  
 
A risk to the newborn/infants cannot be excluded. 
 
Breast-feeding should be discontinued during treatment with Pixuvri. 
 
Fertility 
After repeated administrations of Pixuvri at doses as low as 0,1 mg/kg/day, a dose-dependent testicular 
atrophy was detected in the dogs. This effect has not been evaluated in humans. As with other agents in 
the general class of deoxyribonucleic acid (DNA) damaging agents, Pixuvri may be associated with 
fertility impairment. Whilst the effect on fertility has not been ascertained, a precaution will be to advise 
male patients to use contraceptive methods (preferably barrier) during treatment and for a period of 
6 months post-treatment to allow new sperm to mature. To avoid the risk of long term infertility, sperm 
banking should be considered. 
 
4.7 Effects on ability to drive and use machines 
 



 

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It is not known whether Pixuvri has an effect on the ability to drive a car or use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most common toxicity is bone marrow suppression, particularly of the neutrophil lineage. Although 
the incidence of severe marrow suppression with clinical consequences is relatively low, patients have 
been treated with Pixuvri were closely monitored by frequent blood counts, particularly for neutropenia. 
The incidence of severe infections was low and opportunistic infections associated with 
immunocompromise were not seen. Although the occurrence of cardiac toxicity manifested by CHF 
appears to be lower than that would be expected with related medicinal products such as anthracyclines, 
monitoring of LVEF either by MUGA scans or ECHO is recommended to assess subclinical 
cardiotoxicity. Experience with pixantrone is limited to patients with LVEF ≥ 45% with most patients 
having values ≥ 50%. Experience administering Pixuvri to patients with more significant cardiac 
compromise is limited and should only be undertaken in the context of a clinical trial. Other toxicities 
such as nausea, vomiting, and diarrhoea were generally infrequent, mild, reversible, manageable, and 
expected in patients treated with cytotoxic agents. Effects on hepatic or renal function were minimal. 
 
Tabulated list of adverse reactions 
Adverse drug reactions (ADR) reported with Pixuvri are from final data from all completed single agent 
studies (n=197). ADRs are listed in Table 3 below by MedDRA system organ class and by frequency: 
very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), 
rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from available 
data). Within each frequency grouping, undesirable effects are presented in order of decreasing 
seriousness. 
 

Table 3 
Adverse drug reactions reported related to  

Pixuvri in completed Pixuvri single agent studies by frequency 
System Organ Class Frequency Undesirable effect 

Infections and infestations 

Common Neutropenic infection, respiratory tract infection, infection, sepsis

Uncommon 

Bronchitis, candidiasis, cellulitis, herpes zoster, 
meningitis, nail infection, oral fungal infection, oral 
herpes, pneumonia, salmonella gastroenteritis, septic 
shock 

Neoplasms benign, malignant 
and unspecified (incl. cysts and 
polyps) 

Uncommon 
Neoplasm progression 
Secondary malignancy (including reports of AML and 
MDS)

Blood and lymphatic system 
disorders* 

Very 
common 

Neutropenia, leukopenia, lymphopenia, anaemia, 
thrombocytopenia 

Common Febrile neutropenia, blood disorder 

Uncommon  Bone marrow failure, eosinophilia 

Immune system disorders Uncommon  Hypersensitivity to the medicinal product 

Metabolism and nutrition 
disorders 

Common  Anorexia, hypophosphataemia 

Uncommon  Hyperuricaemia, hypocalcaemia, hyponatraemia,  

Psychiatric disorders Uncommon  Anxiety, insomnia, sleep disorder 

Nervous system disorders 
Common  Taste disturbances, paraesthesia, headache, somnolence
Uncommon Dizziness, lethargy  

Eye disorders 
Common  Conjunctivitis 

Uncommon  Dry eye, keratitis 



 

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Table 3 
Adverse drug reactions reported related to  

Pixuvri in completed Pixuvri single agent studies by frequency 
System Organ Class Frequency Undesirable effect 

Ear and labyrinth disorders Uncommon  Vertigo 

Cardiac disorders* 
Common Left ventricular dysfunction, cardiac disorder, cardiac failure congestive, bundle branch block, tachycardia
Uncommon  Arrhythmia  

Vascular disorders 
Common  Pallor, vein discolouration, hypotension 

Uncommon  Vein disorder  

Respiratory, thoracic and 
mediastinal disorders 

Common  Dyspnoea, cough 

Uncommon Pleural effusion, pneumonitis, rhinorrhoea  

Gastrointestinal disorders 

Very 
common Nausea, vomiting  

Common  Stomatitis, diarrhoea, constipation, abdominal pain, dry mouth, dyspepsia, 
Uncommon  Esophagitis, oral paresthesia, rectal haemorrhage 

Hepatobiliary disorders Uncommon  Hyperbilirubinaemia, hepatotoxicity 

Skin and subcutaneous tissue 
disorders* 

Very 
common Skin discolouration, alopecia  

Common Erythema, nail disorder, pruritus 

Uncommon  Night sweats, petechiae, rash macular, skin ulcer  

Musculoskeletal and connective 
tissue disorders 

Common  Bone pain 

Uncommon 
Arthralgia, arthritis, back pain, muscular weakness, 
musculoskeletal chest pain, musculoskeletal stiffness, 
neck pain, pain in extremity

Renal and urinary disorders 

Very 
common Chromaturia  

Common  Proteinuria, haematuria  

Uncommon  Oliguria 
Reproductive system and breast 
disorders Uncommon Spontaneous penile erection 

General disorders and 
administration site conditions 

Very 
common Asthenia  

Common  Fatigue, mucosal inflammation, pyrexia, chest pain, oedema 
Uncommon  Chills, injection site coldness, local reaction  

Investigations 

Common  
Alanine aminotransferase increased, aspartate 
aminotransferase increased, blood alkaline 
phosphatase increased, blood creatinine increased

Uncommon 
Bilirubin urine, blood phosphorus increased, blood 
urea increased, gamma-glutamyltransferase increased, 
neutrophil count increased, weight decreased 

* ADRs discussed below 
 
Description of selected adverse reactions 
Hematologic toxicities and complications of neutropenia 
Hematologic toxicities have been the most frequent toxicity observed but they have, in general, been 
easily managed with granulocyte-colony stimulating factor (G-CSF) and transfusion support as needed. 
While grade 3-4 neutropenia occurred in randomised trials more frequently among Pixuvri recipients, 
they were uncomplicated in the majority of cases, noncumulative and associated with a low incidence of 



 

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febrile neutropenia or infections, none leading to fatal outcome. Importantly, growth factor support was 
not routinely required and transfusions with red blood cells and platelets were uncommon. (See 
section 4.4) 
 
Cardiac toxicity 
In the study PIX 301, decreased ejection fraction occurred in 13 patients (19.1%) in the Pixuvri group. 
In 11 Pixuvri-treated patients, these events were grade 1-2 and in 2 patients they were grade 3; these 
events were transient and not Pixuvri dose related. Cardiac failure events (MedDRA terms cardiac 
failure, cardiac failure acute and cardiac failure congestive) occurred in 6 patients (8.8%) treated with 
Pixuvri (2 patients with grade 1-2, 1 patient with grade 3, and 3 patients, 2 considered as unrelated, with 
grade 5). Three Pixuvri patients (4.4%) had tachycardia, arrhythmia, sinus tachycardia, supraventricular 
tachycardia or bradycardia. Most patients had received prior doxorubicin or equivalent at dose of up to 
450 mg/m². 
A baseline cardiac evaluation with a MUGA scan or an ECHO is recommended, especially in patients 
with risk factors for increased cardiac toxicity. Repeated MUGA scan or ECHO determinations of 
LVEF should be considered in patients with risk factors such as high cumulative exposure to prior 
anthracyclines or significant pre-existing cardiac disease. (See section 4.4) 
 
Other common toxicities 
Skin discolouration and chromaturia are known related effects of Pixuvri administration due to the 
colour of the compound (blue). The skin discolouration generally disappears over a few days to weeks 
as the medicinal product is cleared. 
 
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 system listed in 
Appendix V. 
 
4.9 Overdose 
 
In the clinical trial program, there has been one report of overdose with Pixuvri with no reported 
concomitant adverse events. 
 
Single doses of pixantrone up to 158 mg/m2 have been given in dose-escalation clinical trials without 
evidence of dose-related toxicity. 
 
If overdose occurs, supportive management is recommended. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, anthracyclines, and related substances.  
ATC code: L01DB11 
 
Mechanism of action 
The active substance of Pixuvri is pixantrone , a cytotoxic aza-anthracenedione. 
 
Unlike approved anthracyclines (doxorubicin and others) and anthracenediones (mitoxantrone), 
pixantrone is only a weak inhibitor of topoisomerase II. Moreover, unlike anthracyclines or 
anthracenediones, pixantrone directly alkylates DNA forming stable DNA adducts and cross-strand 
breaks. Furthermore, because it incorporates a nitrogen heteroatom into the ring structure and does not 
have ketone groups, pixantrone has less potential for generating reactive oxygen species, binding iron, 
and forming alcohol metabolites that are felt to cause the cardiac toxicity of anthracyclines. Due to this 
unique structure, pixantrone produced minimal cardiotoxicity in animal models compared with 
doxorubicin or mitoxantrone. 
 

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A comprehensive retrospective population PK/PD analysis of Phase 1 trials and combination regimens 
(Phase 1/2) demonstrated that progression-free survival and Grade 2-3 neutropenia were related to 
Pixuvri exposure. 
 
Clinical efficacy and safety 
The safety and efficacy of Pixuvri as single-agent therapy were evaluated in a multicentre, randomised, 
active controlled trial in patients with relapsed or refractory aggressive NHL after receiving at least two 
prior therapies. This study randomised 140 patients (1:1) to treatment with either Pixuvri or to an 
investigator chosen single-agent chemotherapy on the comparator arm. Patient demographics and 
baseline disease characteristics were well balanced between the treatment groups, and no statistically 
significant differences were noted. For the study overall, patient median age was 59, 61% were male, 
64% were Caucasian, 76% had Ann Arbor stage III/IV disease at baseline, 74% had a baseline 
International Prognostic Index (IPI) score ≥ 2, and 60% had received ≥ 3 prior chemotherapies. Mantle 
cell lymphoma patients were not included in the pivotal study. Patients in PIX 301 were required to 
have been sensitive to prior anthracycline therapy (confirmed or unconfirmed CR or PR). 
 
There is limited data in patients previously treated with rituximab (38 patients in the Pixuvri arm and 
39 patients in the comparator arm). 
Tumour response was assessed by a blinded independent central review panel according to the 
international workshop to standardise response criteria for NHL. Patients treated with Pixuvri showed a 
significantly higher rate of complete responses and unconfirmed complete responses (CR/CRu), and a 
higher objective response rate (ORR), compared to the comparator group (see Table 4). 
 
 

Table 4 
Summary of response per independent assessment panel (ITT population) 

 
End-of-Treatment End-of-Study 
Pixuvri 
(n=70) 

Comparator 
(n=70) P-value 

Pixuvri 
(n=70) 

Comparator 
(n=70) P-value 

CR/CRu 14 (20.0%) 4 (5.7%) 0.021 17 (24.3%) 5 (7.1%) 0.009 

CR 8 (11.4%) 0 (0%) 
 

11 (15.7%) 0 (0.0%) 
 

CRu 6 (8.6%) 4 (5.7%) 6 (8.6%) 5 (7.1%) 
ORR (CR, Cru, and 
PR) 26 (37.1%) 10 (14.3%) 0.003 28 (40.0%) 10 (14.3%) 0.001 

The Fisher exact test was used to compare proportions in the Pixuvri and comparator chemotherapeutic 
groups. 
 
Patients treated with Pixuvri demonstrated 40% improvement in progression-free-survival compared to 
patients treated with comparator agents with 2.7 months longer median PFS ( hazard ratio (HR)=0.60, 
logrank p=0.005) (see Figure 1 below). 
 
The median overall survival for patients treated with Pixuvri was 2.6 months longer compared to 
patients treated with comparator (HR=0.79, logrank p=0.25) (see Figure 2 below). 
 
 
 
 
 
 
 
 
 
 
 
 



 

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Figure 1 
PIX301 Progression-free survival - end of study 

Pr
og

re
ss

io
n 

Fr
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 S
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vi
va

l P
ro

ba
bi

lit
y 

 

 
 Time from Randomization (Months) 

 
 

Figure 2 
PIX 301 Overall survival–end of study 

O
ve

ra
ll 

Su
rv

iv
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 P
ro

ba
bi

lit
y 

 

 

 
 Time from Randomization (Months) 

 
 
The results in the rituximab pretreated patients still showed superior treatment benefit with Pixuvri over 
the comparator for overall response rate (31.6% with Pixuvri versus 17.9% with the comparator) and 
median progression-free survival (3.3 months with Pixuvri versus 2.5 months with the comparator). 
However, the benefit of Pixuvri has not been established when used as fifth line or greater in patients 
refractory to last therapy, and there is very limited data in this group of patients. 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with Pixuvri 
in all subsets of the paediatric population in treatment of non-Hodgkin lymphoma.  (see section 4.2 for 
information on paediatric use). 
 
 
5.2 Pharmacokinetic properties 
 
Absorption 

Comparator Agents 

Pixantrone 

 
 Pixantrone Comparator 
 N=70 N=70 

Event (PD or death) 58 (83%) 64 (91%)
Median PFS (months) 5.3 (2.3, 6.2) 2.6 (1.9, 3.5) 

 log rank p-value = 0.005
 HR = 0.60 (95% CI 0.42, 0.86)
 

Comparator Agents 

Pixantrone 

 
 Pixantrone Comparator 
 N=70 N=70 

Event (death) 47 (67%) 52 (74%) 
Median OS (95% CI) 10.2 (6.4, 15.7) 7.6 (5.4, 9.3) 

 log rank p-value = 0.251 
 HR = 0.79 (95% CI 0.53, 1.18) 
 



 

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Following intravenous administration, plasma concentrations of pixantrone reached the maximal 
concentration at the end of infusion and then declined poly-exponentially. The pharmacokinetics of 
Pixuvri was dose-independent in the 3 mg/m2 to105 mg/m2 dose range and no substantial differences 
were observed when the medicinal product was given as a single agent or in combination studies. 
Average exposures as single agent accounted for: 
 

Pixuvri Dose (mg/m2) 
 

Number of patients
 

AUC (0-24h) (ng.hr/ml ) 

33 
 

3 
 

982  115 

49 
 

6 
 

1727  474 

88 
 

2
 

3811
 
From an analysis of population PK data, for a target recorded dose of 50 mg/m2 of pixantrone the 
median 28-day cycle exposure was 6320 ng.hr/ml (90% CI, 5990-6800 ng.hr/ml), for 3 doses / 4 week 
cycle. 
 
Distribution 
Pixuvri has a large volume of distribution of 25.8 l and is approximately 50% bound to plasma proteins. 
 
Biotransformation  
Acetylated metabolites are the major biotransformation products of pixantrone. However, in vitro, 
conversion of pixantrone into the acetylated metabolites by either NAT1 or NAT2 was very limited. In 
human urine, the compound was mainly excreted unchanged, and very small amounts of phase I and 
phase II acetylated metabolites were found. Therefore, metabolism does not appear to be an important 
elimination pathway for pixantrone. Acetylated metabolites were pharmacologically inactive and 
metabolically stable. 
 
Elimination 
Pixantrone has a moderate to high total plasma clearance of 72.7 l/hr and a low renal excretion 
accounting for less than 10% of the administered dose in 0-24 hours. The terminal half-life ranged from 
14.5 to 44.8 hr with a mean of 23.3  8.0 (n=14, CV=34%) and a median of 21.2 hr. Due to the limited 
contribution of renal clearance, plasma clearance is mainly non-renal. Pixuvri may be metabolised in the 
liver and/or excreted in the bile. As metabolism appears to be limited, biliary excretion of unchanged 
pixantrone may be the major elimination pathway. Hepatic clearance approximates the hepatic plasma 
flow, suggesting a high hepatic extraction ratio and, therefore, efficient parent active substance 
elimination. Hepatic uptake of pixantrone is possibly mediated by OCT1 active transporters and biliary 
excretion by P-gp and BCRP. 
 
Pixantrone had only a weak or no capability to inhibit P-gp, BCRP, and BSEP transport mechanism in 
vitro.  
 
Pixantrone did inhibit OCT1-mediated metformin transport in vitro, but is not expected to inhibit OTC1 
in vivo at clinically relevant concentrations. 
 
Pixantrone was a poor inhibitor of OATP1B1 and OATP1B3 uptake transporters in vitro. 
 
Linearity/non-linearity 
Pharmacokinetics of pixantrone proved to be linear in a broad range of doses, from 3 
mg/m2 to 105 mg/m2. 
 
Pharmacokinetic/pharmacodynamic relationship(s) 
A relationship between plasma exposure to pixantrone and neutrophil count has been observed.  
 
5.3 Preclinical safety data 
 



 

13 
 

After a single intravenous administration of Pixuvri at 29 mg/kg and 38 mg/kg, immediate deaths were 
seen in mice (114 mg/m2, LD10). Decreases in white and red blood cells and alterations in bone 
marrow, spleen, kidney, and testes were observed. Similar findings were reported in rats, and in dogs at 
116 mg/m2. In dogs, tachycardia and electrocardiography (ECG) changes occurred immediately after 
treatment. 
 
In repeated-dose studies in mice, rats, and dogs, the main findings were myelotoxicity, nephrotoxicity 
(except dogs), and testicular damage. 
 
In dogs, Pixuvri given at 0.5 to 0.9 mg/kg for six cycles did not cause mortality or severe clinical signs, 
including ECG or body weight changes. Males were more sensitive to treatment, with respect to 
reduction in white blood cells and platelet count (reversible) and lymphoid depletion (spleen and 
thymus), as well as the marked toxicity to reproductive organs, as expected from a cytotoxic agent. 
Except for a transient increase in exposure in females after the third cycle, there were no marked 
differences in pharmacokinetic parameters. Males showed, however, slightly higher exposure than 
females. 
 
In dogs, the heart was not affected by treatment, as no ECG changes were seen at different treatment 
times, nor heart changes were detected at gross- and histopathology. Kidney function and histology 
were similarly not affected both in 4- and 26-week studies. 
 
The cardiotoxic potential of Pixuvri compared with equiactive doses of doxorubicin and mitoxantrone in 
treatment-naïve and doxorubicin-pre-treated mice was evaluated. Pixantrone dimaleate up to 27 mg/kg 
given twice a week for 4 weeks did not induce any cardiotoxic effects, while mitoxantrone, as expected, 
was cardiotoxic at all tested doses (0.6, 1.6, and 1.5 mg/kg). Slight nephropathy was induced by Pixuvri. 
Minimal cardiotoxicity of Pixuvri was also demonstrated with repeat treatment cycles at the same doses.  
 
Genotoxicity studies confirmed the potential for clastogenic effects in mammalian cells in vitro and in 
vivo. Pixuvri was mutagenic in the Ames test, increased the number of chromosomal aberrations in 
human lymphocytes, and increased the frequency of micronuclei in vivo.  
 
Pixuvri caused maternal and foetal toxicity in rats and rabbits, even at a dose as low as 1.8 mg/kg given 
on days 9-11 of pregnancy, higher doses resulting in abortions and total embryo resorption. 
Embryotoxicity was characterised by reduced mean foetal weight, foetal malformations and incomplete 
or delayed foetal ossification. No long-term animal studies have been performed to establish the 
carcinogenic potential of Pixuvri. No local tolerance study was conducted. 
 
Pixuvri has been shown to cause phototoxic effects on 3T3 cells in vitro. 
 
In a colony-forming units study in mice, the myelotoxicity of Pixuvri and mitoxantrone administered at 
their LD10 (pixantrone dimaleate 38 mg/kg and mitoxantrone 6.1 mg/kg) was similar. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium chloride 
Lactose monohydrate 
Sodium hydroxide (for pH adjustment) 
Hydrochloric acid (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 
 



 

14 
 

Unopened vial 
5 years 
 
Reconstituted and diluted solution 
Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (15°C to 
25°C) and daylight exposure in polyethylene (PE) standard infusion bags. 
 
From a microbiological point of view, the product should be used immediately. If not used immediately, 
in-use storage times and conditions prior to use are the responsibility of the user and would normally not 
be longer than 24 hours at 2°C to 8°C, unless reconstitution and dilution have taken place in controlled 
and validated aseptic conditions.  
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C to 8°C). 
 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  
 
Type I glass vial with grey butyl rubber stopper with aluminium seal and red plastic cap containing 50 
mg pixantrone dimaleate equivalent to 29 mg pixantrone.  
Pack size of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
Reconstitution and dilution 
Aseptically reconstitute each 29 mg vial with 5 ml of sodium chloride 9 mg/ml (0.9%) solution for 
injection. The lyophilised powder should completely dissolve in 60 seconds with agitation. This yields a 
dark blue solution with a pixantrone concentration of 5.8 mg/ml.  
 
Aseptically withdraw the volume needed for the required dose (based on 5.8 mg/ml concentration) and 
transfer to a 250 ml infusion bag of sodium chloride 9 mg/ml (0.9%) solution for injection. The final 
concentration of pixantrone in the infusion bag should be less than 580 microgram /ml based upon input 
of reconstituted medicinal product. Compatibility with other diluents has not been determined. After 
transferring, thoroughly mix the contents of the infusion bag. The mixture should be a clear and dark 
blue solution. 
 
Polyethersulfone 0.2 µm pore size in-line filters should be used during administration of the diluted 
Pixuvri solution.  
 
Pixuvri is a cytotoxic agent. Avoid contact with eyes and skin. Use gloves, masks, and protective 
eyewear when handling Pixuvri and during decontamination procedures. 
 
Special precautions for disposal 
Pixuvri is for single use only. Any unused medicinal product or waste material including materials used 
for reconstitution, dilution, and administration should be disposed of in accordance with local 
requirements applicable to cytotoxic agents. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France  



 

15 
 

 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
 EU/1/12/764/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
 Date of first authorisation: 10 May 2012 
 Date of latest renewal: 06 June 2019 
 
 
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



 

16 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 
 

D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 
USE OF THE MEDICINAL PRODUCT 



 

17 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturer(s) responsible for batch release 
 

Les Laboratoires Servier Industrie 
905 Route de Saran 
45520 Gidy  
France 

 
 

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. 

 
 



 

18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



 

19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 

20 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pixuvri 29 mg powder for concentrate for solution for infusion  
pixantrone  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains pixantrone dimaleate equivalent to 29 mg pixantrone. After reconstitution, each ml 
of concentrate contains pixantrone dimaleate equivalent to 5.8 mg pixantrone.  
 
 
3. LIST OF EXCIPIENTS 
 
Lactose monohydrate, sodium chloride, hydrochloric acid, sodium hydroxide. Contains sodium, see 
leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
Pack size of 1 vial. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Reconstitute and dilute before use.  
Read the package leaflet before use. 
For 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. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



 

21 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2C – 8C). 
Keep the vial in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 EU/1/12/764/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted.  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 



 

22 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
VIAL  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pixuvri 29 mg powder for concentrate for solution for infusion  
pixantrone  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains pixantrone dimaleate equivalent to 29 mg pixantrone. After reconstitution, each ml 
of concentrate contains pixantrone dimaleate equivalent to 5.8 mg pixantrone. 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose monohydrate, sodium chloride, hydrochloric acid, sodium hydroxide. Contains sodium, see 
leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Reconstitute and dilute before use.  
Read the package leaflet before use. 
For 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. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2C – 8C). 
Keep the vial in the outer carton in order to protect from light. 



 

23 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 EU/1/12/764/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted.  



 

24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 

25 

Package leaflet: Information for the user 
 

Pixuvri 29 mg powder for concentrate for solution for infusion 
pixantrone  

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

this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Pixuvri is and what it is used for 
2. What you need to know before you use Pixuvri 
3. How to use Pixuvri 
4. Possible side effects 
5. How to store Pixuvri 
6. Content of the pack and other information 
 
 
1. What Pixuvri is and what it is used for  
 
Pixuvri belongs to a pharmacotherapeutic group of medicines known as ‘antineoplastic agents’. These 
are used to treat cancer.  
 
Pixuvri is used for the treatment of adult patients with multiply relapsed or refractory aggressive 
Non-Hodgkin Lymphomas. Pixuvri kills cancer cells by binding to DNA, resulting in cell death. It is 
used for patients whose cancer does not respond or has returned after they have received other 
chemotherapy treatments. 
 
 
2. What you need to know before you use Pixuvri 
 
Do not use Pixuvri  
- if you are allergic to pixantrone dimaleate or any of the other ingredients of this medicine 

(listed in section 6). 
- if you have recently received a vaccine. 
- if you have been told that you have persistent, long-term low numbers of red blood cells, white 

blood cells, and platelets. 
- if you have very severe liver problems. 
 
Warnings and precautions 
Talk to your doctor before using Pixuvri: 
 
- if you have been told that your white blood cell count is very low. 
- if you have heart disease or uncontrolled high blood pressure, especially if you have ever been 

told you had heart failure or if you have had a heart attack within the last six months. 
- if you have an infection. 
- if you have ever been treated for cancer.  
- if you follow a specific sodium restricted diet. 
- if you are taking other medicines which could interact with Pixuvri (see ‘Taking other 

medicines’ below). 
 
Skin sensitivity to sunlight 



 

26 

During treatment with pixantrone, you should minimize or avoid exposure to natural or artificial 
sunlight (tanning beds or UVA/B treatment). If you will be exposed to sunlight, you should wear sun- 
protective clothing and use sunscreen that strongly absorbs UV-A. 
 
Children and adolescents 
Do not give this medicine to children under the age of 18 years because there is no information about 
Pixuvri treatment in children and adolescents. 
 
Other medicines and Pixuvri 
Tell your doctor if you are taking, have recently taken or might take any other medicines. This is 
extremely important as using more than one medicine at the same time can strengthen or weaken their 
effect. Pixuvri must not be used with other medicines unless your doctor has told you it is safe to do 
so. 
In particular, make sure to tell your doctor if you are currently using, or have recently used, any of the 
following medicines: 
 
Tell your doctor if you take medicines such as:  
 

- Warfarin to prevent blood clot formation 
- Theophylline to treat lung conditions like emphysema or asthma 
- Amitriptyline to treat depression 
- Olanzapine, Clozapine to treat schizophrenia or maniac depression 
- Haloperidol to treat anxiety and sleeplessness 
- Ondansetron to prevent nausea and vomiting during chemotherapy 
- Propranolol to treat high blood pressure 

 

 
 
 
 
 

 
Pixuvri with food and drink 
You do not have to change your diet after treatment with Pixuvri unless instructed by your doctor. 
 
Pregnancy, breast-feeding and fertility 
Pixuvri must not be given to pregnant women as it may cause harm to unborn babies. If you are 
pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your 
doctor for advice before taking this medicine.  
 
Adequate contraceptive precautions must be used when receiving Pixuvri and for up to 6 months after 
treatment. This applies to women who can become pregnant and men receiving Pixuvri who may be 
able to father a child. 
 
Do not breast-feed while you are being treated with Pixuvri.  
 
Driving and using machines 
It is not known whether Pixuvri has an effect on your ability to drive a car or use machines. 
 
Pixuvri contains sodium 
Upon reconstitution and dilution, this medecine contains approximately 1g (43 mmol) sodium (main 
component of cooking salt)  per dose. This is equivalent to 50% of the recommended maximum daily 
dietary intake of sodium for an adult.  
 
 
3. How to use Pixuvri 
 
How much of Pixuvri is given 
The amounts (dose) of Pixuvri that will be given to you will depend on your body surface area in 
square meters (m2). This is determined by your height and weight. The results of blood tests and your 
medical condition will also be taken into account. The recommended dose is 50 mg/m2. If necessary, 
your doctor will adjust the dose during treatment. 



 

27 

 
Your doctor will carry out some tests before you are given Pixuvri. 
 
How often Pixuvri is given 
Pixuvri is given on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles.  
 
Before the infusion is administered you may be given medicines to prevent or reduce possible 
reactions to Pixuvri, such as medicines to prevent sickness. 
 
How Pixuvri is given 
Pixuvri is given through a drip into a vein (by intravenous infusion). This will be done by a nurse or 
doctor. 
 
How long the infusion will take 
This will take approximately one hour unless otherwise stated. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Infusion reactions 
Pain/redness of the injection site may occur rarely during infusion of Pixuvri. Tell the person giving 
you the infusion immediately if you feel pain or if the injection site gets red. The infusion may need 
to be slowed down or stopped. When these symptoms go away or improve, the infusion can be 
continued. 
 
Pixuvri has a deep blue colour and for several days after receiving Pixuvri, your skin and eyes may 
develop a bluish discolouration, and your urine may have a bluish discolouration. The skin 
discolouration generally disappears over a few days to weeks as the drug is cleared. 
 
Infections 
Tell your doctor if you get any symptoms of an infection (for example, fever, chills, trouble 
breathing, cough, sores in your mouth, trouble swallowing, or severe diarrhoea) after Pixuvri 
treatment. You might get infections more easily after you have been given Pixuvri.  
 
Heart  
There is a possibility that your heart pumping function could decrease as a result of the treatment or 
you might even develop a serious condition called heart failure, especially if your heart function was 
already compromised at the beginning of the treatment with Pixuvri. Your doctor will monitor your 
heart function if there is any sign or symptom of your heart being affected.  
 
Tell your doctor if you think you have any of the following reactions 
 
Very common: may affect more than 1 in 10 people 
- nausea, vomiting 
- skin discolouration  
- thinning or loss of hair 
- abnormal colouration of the urine 
- physical weakness  
- low number of white blood cells, low number of red blood cells (anaemia), and low number of 

platelets in the blood (may require transfusion). 
 

Common: may affect up to 1 in 10 people 
- infection such as lung infection, skin infections, infections with low white blood cells, thrush 
- fever 
- severe blood infection (sepsis) 



 

28 

- taste disturbances 
- abnormal sensations of the skin such as numbness, tingling, pricking (paraesthesia) 
- headache 
- sleepiness 
- tiredness 
- inflammation of the eyes (conjunctivitis) 
- diarrhoea 
- pain in the abdomen 
- inflammation and/or ulceration of the throat and the mouth 
- dry mouth, constipation, indigestion, loss of appetite 
- skin changes such as redness and itching of the skin, nail changes  
- damage to the heart, decrease in heart’s ability to pump blood, blockage of electrical signals in 

your heart, uneven or fast heartbeat.  
- low blood pressure 
- vein discolouration, pale skin 
- shortness of breath, cough 
- blood in urine 
- excess protein in urine 
- swelling of legs or ankles or other parts of the body 
- bone pain  
- chest pain 
- low levels of phosphate in the blood 
- abnormal blood test for liver or kidney function. 
 
Uncommon: may affect up to 1 in 100 people 
- severe infections such as septic shock, bronchitis, pneumonia, candidiasis, cellulitis, meningitis, 

gastroenteritis 
- viral infections such as shingles or reactivation of other virus such as herpes in the mouth  
- nervousness, sleeplessness 
- loss of energy 
- dizziness, vertigo 
- dryness of the eye 
- numbness of the mouth 
- infection of the cornea 
- allergy to the medicine 
- decrease in blood calcium and sodium level; increase in blood uric acid level 
- inflammation or fluid accumulation around the lungs 
- runny nose 
- bleeding such as gut bleed, purple spots on body due to broken blood vessels 
- vein irritation 
- night sweats  
- irregular heartbeat 
- spontaneous erection 
- skin rash and/or ulceration 
- pain, swelling, weakness, stiffness in joints or muscles 
- decreased urinary output 
- loss of weight 
- increased bilirubin in blood or urine 
- inflammation of the gullet 
- pain in neck, back, extremities 
- nail infection 
- neoplasm (tumour) progression 
- new cancers of the bone marrow or blood, such as acute myeloid leukaemia (AML) or 

myelodysplastic syndrome (MDS) 
- liver damage 
- bone marrow failure  
- increased eosinophils in blood. 



 

29 

 
Reporting of side effects 
If you get any side effects, talk to your doctor. 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 Pixuvri  
 
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. 
 
Store in a refrigerator (2C to 8C). 
Keep the vial in the outer carton in order to protect from light. 
 
Pixuvri does not contain anything to prevent the growth of bacteria and it is, therefore, recommended 
that it be used immediately after reconstitution. If not used immediately, in-use storage times and 
conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 
2C to 8C. 
 
Reconstituted pixantrone solution is stable for up to 24 hours at room temperature (15C to 25C) in 
standard infusion bags.  
 
Pixuvri is for single use only. Any unused medicinal product or waste material, including materials 
used for reconstitution, dilution, and administration should be disposed of in accordance with local 
requirements. 
 
 
6. Contents of the pack and other information 
 
What Pixuvri contains  
The active substance is pixantrone. Each vial contains 50 mg pixantrone dimaleate (equivalent to 
29 mg pixantrone). The other ingredients are lactose monohydrate, sodium hydroxide, hydrochloric 
acid, and sodium chloride. 
 
What Pixuvri looks like and contents of the pack 
Pixuvri is a powder for concentrate for solution for infusion. It appears as a dark blue powder which 
comes in vials containing 29 mg of pixantrone. Pack size: 1 vial. 
 
Marketing Authorisation Holder 

Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France  

 
Manufacturer 
 Les Laboratoires Servier Industrie 
 905 Route de Saran 
 45520 Gidy 
 France 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 



 

30 

 
België/Belgique/Belgien 
S.A. Servier Benelux N.V. 
Tél/Tel: +32 (0)2 529 43 11 
 

Lietuva 
UAB “SERVIER PHARMA” 
Tel: +370 (5) 2 63 86 28 

България 
Сервие Медикал ЕООД 
Тел.: +359 2 921 57 00 
 

Luxembourg/Luxemburg 
S.A. Servier Benelux N.V. 
Tel: +32 (0)2 529 43 11 
 

Česká republika 
Servier s.r.o. 
Tel: +420 222 118 111 
 

Magyarország 
Servier Hungaria Kft. 
Tel: +36 1 238 7799 
 

Danmark 
Servier Danmark A/S 
Tlf: +45 36 44 22 60 
 

Malta 
V.J. Salomone Pharma Ltd  
Tel: + 356 21 22 01 74 
 

Deutschland 
Servier Deutschland GmbH 
Tel: +49 (0)89 57095 01 
 

Nederland 
Servier Nederland Farma B.V. 
Tel: + 31 (0)71 5246700 

Eesti 
Servier Laboratories OÜ  
Tel:+ 372 664 5040 
 

Norge 
Servier Danmark A/S 
Tlf: +45 36 44 22 60 

Eλλάδα 
ΣΕΡΒΙΕ ΕΛΛΑΣ ΦΑΡΜΑΚΕΥΤΙΚΗ ΕΠΕ 
Τηλ: + 30 210 939 1000 
 

Österreich 
Servier Austria GmbH 
Tel: +43 (1) 524 39 99 

España 
Laboratorios Servier S.L. 
Tel: + 34 91 748 96 30 
 

Polska 
Servier Polska Sp. z o.o. 
Tel: + 48 (0) 22 594 90 00 

France 
Les Laboratoires Servier 
Tél: + 33 (0)1 55 72 60 00 
 

Portugal 
Servier Portugal, Lda 
Tel: + 351 21 312 20 00 

Hrvatska 
Servier Pharma, d. o. o. 
Tel: + 385 (0)1 3016 222 
 

România 
Servier Pharma SRL 
Tel: + 4 021 528 52 80 
 

Ireland 
Servier Laboratories (Ireland) Ltd. 
Tel: + 353 (0)1 663 8110 
 

Slovenija 
Servier Pharma d. o. o.  
Tel: + 386 (0)1 563 48 11 

Ísland 
Servier Laboratories 
c/o Icepharma hf 
Sími: + 354 540 8000 
 

Slovenská republika 
Servier Slovensko spol. s r.o. 
Tel: + 421 2 5920 41 11 
 

Italia 
Servier Italia S.p.A. 
Tel: + 39 (06) 669081 
 

Suomi/Finland 
Servier Finland Oy 
P. /Tel: +358 (0)9 279 80 80 

Κύπρος 
CA Papaellinas Ltd. 
Τηλ: + 357 22 741 741 

Sverige 
Servier Sverige AB 
Tel : +46 (0)8 522 508 00 



 

31 

 
Latvija 
SIA Servier Latvia 
Tel: + 371 67502039 
 

United Kingdom 
Servier Laboratories Ltd 
Tel: +44 (0)1753 666409 

 
This leaflet was last revised in  
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu  
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
------------------------------------------------------------------------------------------------------------------------ 
 
The following information is intended for healthcare professionals only: 
 

Detailed instructions for users 
 

READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION  
 
Special precautions for use  
Pixuvri is an anticancer medicinal product that is harmful to cells; caution should be exercised in 
handling. Avoid contact with eyes and skin. Use gloves, masks, and protective eyewear when 
handling and during decontamination procedures. If Pixuvri (lyophilised powder or reconstituted 
liquid solution) contacts the skin, wash the skin immediately and flush the membranes thoroughly 
with water.  
 
Reconstitution/preparation for intravenous administration 
Each single-use vial of Pixuvri contains pixantrone dimaleate equivalent to 29 mg pixantrone. After 
reconstitution with 5 ml sodium chloride 9 mg/ml (0.9%) solution for injection, each ml of 
concentrate contains pixantrone dimaleate equivalent to 5.8 mg pixantrone. 
 
Using sterile procedures, reconstitute each 29 mg vial with 5 ml of sodium chloride 9 mg/ml (0.9%) 
solution for injection. The powder should completely dissolve in 60 seconds with agitation. This 
yields a dark blue solution with a pixantrone concentration of 5.8 mg/ml.  
 
Using sterile procedures, withdraw the volume needed for the required dose (based on 5.8 mg/ml 
concentration) and further dilute with sodium chloride 9 mg/ml (0.9%) solution for injection to a final 
volume of 250 ml. 
 
Compatibility with other diluents has not been determined. After transferring, thoroughly mix the 
contents of the infusion bag. The mixture should be a dark blue solution. 
Polyethersulfone 0.2 µm pore size in-line filters should be used during administration of the diluted 
Pixuvri solution. 
 
In-use storage conditions 
Pixuvri does not contain anything to prevent the growth of bacteria and it is therefore recommended 
that it be used immediately after reconstitution. If not used immediately, in-use storage times and 
conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 
2C to 8C. 
 
The reconstituted and diluted solution is stable for up to 24 hours at room temperature (15C to 25C) 
and daylight exposure in standard polyethylene (PE) infusion bags.  
 



 

32 

Special precautions for disposal and handling 
Pixuvri is a cytotoxic agent. Any unused product or waste material should be disposed of in 
accordance with local requirements. 
 
Devices and surfaces accidentally contaminated with Pixuvri must be treated with a solution of 
sodium hypochlorite (100 µl of water and 20 µl of sodium hypochlorite [7 ± 2% of available chlorine] 
for 0.58 mg of Pixuvri).  
 
Equipment such as vials, needles and syringes used for Pixuvri administration should be handled as 
toxic waste. 


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