Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Les Laboratoires Servier, 50, rue Carnot, 92284, Suresnes cedex, France
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).
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).
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.
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.
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.
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 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).
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.
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.
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.
No drug interactions have been reported in human subjects and no drug-drug interaction studies in humans have been performed.
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 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.
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.
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.
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.
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.
It is not known whether Pixuvri has an effect on the ability to drive a car or use machines.
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.
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:
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
Uncommon: Neoplasm progression, Secondary malignancy (including reports of AML and MDS)
Very common: Neutropenia, leukopenia, lymphopenia, anaemia, thrombocytopenia
Common: Febrile neutropenia, blood disorder
Uncommon: Bone marrow failure, eosinophilia
Uncommon: Hypersensitivity to the medicinal product
Common: Anorexia, hypophosphataemia
Uncommon: Hyperuricaemia, hypocalcaemia, hyponatraemia,
Uncommon: Anxiety, insomnia, sleep disorder
Common: Taste disturbances, paraesthesia, headache, somnolence
Uncommon: Dizziness, lethargy
Common: Conjunctivitis
Uncommon: Dry eye, keratitis
Uncommon: Vertigo
Common: Left ventricular dysfunction, cardiac disorder, cardiac failure congestive, bundle branch block, tachycardia
Uncommon: Arrhythmia
Common: Pallor, vein discolouration, hypotension
Uncommon: Vein disorder
Common: Dyspnoea, cough
Uncommon: Pleural effusion, pneumonitis, rhinorrhoea
Very common: Nausea, vomiting
Common: Stomatitis, diarrhoea, constipation, abdominal pain, dry mouth, dyspepsia,
Uncommon: Esophagitis, oral paresthesia, rectal haemorrhage
Uncommon: Hyperbilirubinaemia, hepatotoxicity
Very common: Skin discolouration, alopecia
Common: Erythema, nail disorder, pruritus
Uncommon: Night sweats, petechiae, rash macular, skin ulcer
Common: Bone pain
Uncommon: Arthralgia, arthritis, back pain, muscular weakness, musculoskeletal chest pain, musculoskeletal stiffness, neck pain, pain in extremity
Very common: Chromaturia
Common: Proteinuria, haematuria
Uncommon: Oliguria
Uncommon: Spontaneous penile erection
Very common: Asthenia
Common: Fatigue, mucosal inflammation, pyrexia, chest pain, oedema
Uncommon: Chills, injection site coldness, local reaction
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
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 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)
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)
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 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.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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