LUMOXITI Powder for concentrate solution for solution for infusion Ref.[28035] Active ingredients:

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Haemolytic uraemic syndrome (HUS)

HUS has been reported in patients treated with Lumoxiti and is characterized by the triad of microangiopathic haemolytic anaemia, thrombocytopenia, and progressive renal failure (see section 4.8).

Lumoxiti should be avoided in patients with prior history of severe thrombotic microangiopathy (TMA) or HUS. Prophylactic fluids are recommended during treatment with Lumoxiti (see section 4.2). In Study 1053, patients with a platelet count ≥100,000/mm³ received low-dose acetylsalicylic acid on Days 1 through 8 of each 28-day cycle for prophylaxis of renal insufficiency.

Blood chemistry and complete blood counts should be monitored prior to each dose and as clinically indicated during treatment. Monitoring mid-cycle is also recommended. Diagnosis of HUS should be considered in patients who develop haemolytic anaemia, worsening or sudden onset of thrombocytopenia, worsening of renal function, elevation of bilirubin and/or LDH, and have evidence of haemolysis based on peripheral blood smear schistocytes (see section 4.2).

The events of HUS may be life-threatening if treatment is delayed with increased risk of progressive renal failure requiring dialysis. If HUS is suspected appropriate supportive measures including fluid repletion and haemodynamic monitoring should be initiated, and hospitalisation as clinically indicated should be considered. For Grade 2 HUS, treatment with Lumoxiti should be withheld until resolution, and permanently discontinued for Grade ≥3 HUS (see section 4.2).

Capillary leak syndrome (CLS)

CLS has been reported among patients treated with Lumoxiti and is characterized by hypoalbuminaemia, hypotension, symptoms of fluid overload and haemoconcentration (see section 4.8).

Patient weight and blood pressure should be monitored prior to each Lumoxiti infusion and as clinically indicated during treatment. Patients should be assessed for signs and symptoms of CLS including weight gain (≥10% from Day 1 of current cycle), hypotension, peripheral oedema, shortness of breath or cough, and pulmonary oedema and/or serosal effusions. In addition, the following changes in laboratory parameters may help identify CLS: hypoalbuminemia, elevated haematocrit, leucocytosis and thrombocytosis (see section 4.2).

CLS may be life-threatening or fatal if treatment is delayed. Patients should be advised to seek immediate medical attention should signs or symptoms of CLS occur at any time. Patients who develop CLS should receive appropriate supportive measures, including concomitant oral or intravenous corticosteroids, and hospitalisation as clinically indicated. For Grade 2 CLS, treatment with Lumoxiti should be withheld until resolution, and permanently discontinued for Grade ≥3 CLS (see section 4.2).

Renal function monitoring

Patients who experience HUS, those ≥65 years of age, or those with baseline renal impairment may be at increased risk for worsening of renal function following treatment with Lumoxiti (see section 4.8). Treatment with Lumoxiti is not recommended in patients with pre-existing severe renal impairment (creatinine clearance ≤29 mL/min).

Renal function should be monitored prior to each infusion of Lumoxiti, and as clinically indicated throughout treatment. Lumoxiti dosing should be delayed in patients with Grade ≥3 elevations in creatinine, or upon worsening from baseline by 2 or more grades (see section 4.2).

Infusion related reactions

If a severe infusion related reaction occurs, the Lumoxiti infusion should be interrupted and appropriate medical management initiated. An oral or intravenous corticosteroid should be administered approximately 30 minutes before resuming, or before the next Lumoxiti infusion(s). See section 4.2 for information on premedication to reduce risk of infusion related reactions.

Lumoxiti contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially ‘sodium-free’.

No interaction studies have been performed. Moxetumomab pasudotox is a recombinant immunotoxin that binds specifically to CD22+ B cells. Based on the mechanism of action of moxetumomab pasudotox, no pharmacokinetic or pharmacodynamic interactions are expected.

Women of childbearing potential / contraception

Women of childbearing potential should use effective contraception during treatment with moxetumomab pasudotox and for at least 30 days after the last dose.

Pregnancy

There are no human or animal data to assess the risk of moxetumomab pasudotox use during pregnancy. Based on its mechanism of action and observed adverse findings of moxetumomab pasudotox in non-pregnant female monkeys including body weight loss, moxetumomab pasudotox may be expected to cause maternal and embryofetal toxicity when administered to a pregnant woman. Moxetumomab pasudotox should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus.

Breast-feeding

There is no information regarding the presence of moxetumomab pasudotox in human milk, the absorption and effects on the breast-fed child, or the effects on milk production. A risk to the breast-fed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Lumoxiti therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No adverse findings of moxetumomab pasudotox were observed on reproductive organ weights or reproductive organ histopathology following dosing of sexually mature monkeys. There are no data available to directly determine the potential effects on human fertility (see section 5.3).

Lumoxiti has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The overall safety profile of Lumoxiti is based on data from 80 patients from Study 1053 (a Phase 3 study).

The most common adverse drug reactions (ADRs) (≥20%) of any grade were oedema (52.5%), nausea (35.0%), infusion related reactions (25.0%), hypoalbuminemia (21.3%), and increased transaminases (21.3%). The most common Grade 3 or 4 ADR was HUS (6.3%).

Adverse reactions resulting in permanent discontinuation of Lumoxiti occurred in 10.0% of patients. The most common adverse reaction leading to Lumoxiti discontinuation was HUS (5.0%). The adverse reaction that most commonly resulted in dose delays was increased serum creatinine (2.5%).

Tabulated list of adverse reactions

ADRs are listed according to system organ class (SOC) in MedDRA. Within each SOC, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, ADRs are presented in order of decreasing seriousness. Frequency category for each ADR is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from available data).

Table 4. Adverse drug reactions in patients with HCL treated with Lumoxiti (n=80):

^a Hypoalbuminaemia: includes preferred terms (PTs) of ‘hypoalbuminaemia’ and 'blood albumin decreased'
^b Oedema: includes all PTs of ‘oedema peripheral,’ ‘oedema,’ ‘localized oedema,’ ‘face oedema,’ ‘periorbita oedema,’ and ‘peripheral swelling’ Medicinal product no longer authorised
^c Transaminases increased: includes ‘aspartate aminotransferase increased’ and/or 'alanine aminotransferase increased'
^d Infusion related reactions: includes all events regardless of relatedness, as reported by investigator or as retrospectively defined by co-occurrence of 2 or more events of headache, dizziness, hypotension, myalgia, pyrexia, chills, nausea, and/or vomiting on the day of study drug infusion

Description of selected adverse reactions

HUS

In Study 1053 in patients with HCL treated with Lumoxiti, HUS occurred in 8.8% of patients, including Grade 3 in 5.0% and Grade 4 in 1.3%.

The median time to first onset of HUS was 33 days (range: 9-92), and may occur during any cycle of treatment with Lumoxiti. Most cases of HUS occurred in the first 9 days (range: 1-16) of a treatment cycle. The median time to resolution of HUS was 23.5 days (range: 2-44). All cases resolved, including those who discontinued Lumoxiti.

The median end of treatment creatinine clearance (as estimated by Cockcroft-Gault) was higher among patients without HUS (89 mL/min, range 42-195) compared with patients with HUS (76 mL/min, range 19-96).

For clinical management of HUS, see section 4.4.

CLS

In Study 1053 in patients with HCL treated with Lumoxiti, CLS occurred in 8.8% of patients, the majority were Grade 2. There were 2.5% Grade 4 events.

The median time to onset of CLS was 37 days (range: 5-92), and may occur during any cycle of treatment. Most cases of CLS occurred in the first 9 days (range: 1-24) of a treatment cycle. All CLS resolved, with a median time to resolution of 36 days (range: 10-53).

For clinical management of CLS, see section 4.4.

Increase in serum creatinine

In Study 1053, increases in creatinine up to a maximum of 3-times the upper limit of normal were reported in 11.3% of patients. At the end of treatment, serum creatinine levels were within normal limits for the majority (82.5%) of patients. Serum creatinine levels remained elevated above Grade 2 in 5% of patients, two of these patients had Grade 3 or 4 HUS.

Infusion related reactions

Infusion-related reactions as reported by investigator or retrospectively defined as two or more symptoms of headache, dizziness, hypotension, myalgia, pyrexia, chills, nausea, and/or vomiting on the day of treatment with study drug occurred in 25% of patients, including Grade 3 in 2.5% of patients. Infusion related reactions may occur during any cycle of treatment with Lumoxiti (see section 4.2).

Special populations

Elderly

In Study 1053, 39% of patients treated with Lumoxiti were 65 years of age or older. Patients ≥65 years of age had lower median creatinine clearance at baseline and at the end of treatment compared with patients <65 years of age (78 and 69 mL/min versus 114 and 98 mL/min, respectively).

Immunogenicity

In Study 1053, 88% (70/80) of patients were positive for ADA (before or after treatment). Fifty-eight percent (45/77) of patients tested positive for anti-drug antibodies (ADAs) prior to any treatment with moxetumomab pasudotox, and 66% (49/74) of patients tested positive for ADAs whilst on treatment. Neutralising antibodies against moxetumomab pasudotox were detected in 84% of patients (67/80) at any time. No clinically relevant effects of ADA on safety were identified. See Immunogenicity in section 5.2.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

No incompatibilities between Lumoxiti and 9 mg/mL (0.9%) sodium chloride in polyvinylchloride or polyolefin intravenous bags have been observed.

Do not co-administer other medicinal products through the same intravenous line.