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

Dose modification and the timing of subsequent doses should be determined by clinical judgment 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 haematologic 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-haematologic 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.

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 haematopoietic 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

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 programme 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 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 ciclosporin 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, carbamazepine 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

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

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 paraesthesia, 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-glutamyl transferase increased, neutrophil count increased, weight decreased

* ADRs discussed below

Description of selected adverse reactions

Haematologic toxicities and complications of neutropenia

Haematologic 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)

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In the clinical trial programme, 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.