IVOZALL Concentrate for solution for infusion Ref.[49843] Active ingredients: Clofarabine

Ivozall is a potent antineoplastic agent with potentially significant haematological and non-haematological adverse reactions (see section 4.8).

The following parameters should be closely monitored in patients undergoing treatment with clofarabine:

• Complete blood and platelet counts should be obtained at regular intervals, more frequently in patients who develop cytopaenias.
• Renal and hepatic function prior to, during active treatment and following therapy. Clofarabine should be discontinued immediately if substantial increases in creatinine, liver enzymes and/or bilirubin are observed.
• Respiratory status, blood pressure, fluid balance and weight throughout and immediately after the 5 day clofarabine administration period.

Blood and lymphatic disorders

Suppression of bone marrow should be anticipated. This is usually reversible and appears to be dose-dependent. Severe bone marrow suppression, including neutropaenia, anaemia and thrombocytopaenia have been observed in patients treated with clofarabine. Haemorrhage, including cerebral, gastrointestinal and pulmonary haemorrhage, has been reported and may be fatal. The majority of the cases were associated with thrombocytopaenia (see section 4.8).

In addition, at initiation of treatment, most patients in the clinical studies had haematological impairment as a manifestation of leukaemia. Because of the pre-existing immuno-compromised condition of these patients and prolonged neutropaenia that can result from treatment with clofarabine, patients are at increased risk for severe opportunistic infections, including severe sepsis, with potentially fatal outcomes. Patients should be monitored for signs and symptoms of infection and treated promptly.

Occurrences of enterocolitis, including neutropaenic colitis, caecitis, and C. difficile colitis, have been reported during treatment with clofarabine. This has occurred more frequently within 30 days of treatment, and in the setting of combination chemotherapy. Enterocolitis may lead to necrosis, perforation or sepsis complications and may be associated with fatal outcome (see section 4.8). Patients should be monitored for signs and symptoms of enterocolitis.

Skin and subcutaneous disorders

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases, have been reported (see section 4.8). Clofarabine must be discontinued for exfoliative or bullous rash, or if SJS or TEN is suspected.

Neoplasms benign and malignant (including cysts and polyps) and Immune systems disorders Administration of clofarabine results in a rapid reduction in peripheral leukaemia cells. Patients undergoing treatment with clofarabine should be evaluated and monitored for signs and symptoms of tumour lysis syndrome and cytokine release (e.g. tachypnoea, tachycardia, hypotension, pulmonary oedema) that could develop into Systemic Inflammatory Response Syndrome (SIRS), capillary leak syndrome and/or organ dysfunction (see section 4.8).

• Prophylactic administration of allopurinol should be considered if hyperuricemia (tumour lysis) is expected.
• Patients should receive intravenous fluids throughout the 5 day clofarabine administration period to reduce the effects of tumour lysis and other events.
• The use of prophylactic steroids (e.g., 100 mg/m² hydrocortisone on Days 1 through 3) may be of benefit in preventing signs or symptoms of SIRS or capillary leak.

Clofarabine should be discontinued immediately if patients show early signs or symptoms of SIRS, capillary leak syndrome or substantial organ dysfunction and appropriate supportive measures instituted. In addition, clofarabine treatment should be discontinued if the patient develops hypotension for any reason during the 5 days of administration. Further treatment with clofarabine, generally at a lower dose, can be considered when patients are stabilised and organ function has returned to baseline.

The majority of patients who respond to clofarabine achieve a response after 1 or 2 treatment cycles (see section 5.1). Therefore, the potential benefit and risks associated with continued therapy in patients who do not show haematological and/or clinical improvement after 2 treatment cycles should be assessed by the treating physician.

Cardiac disorders

Patients with cardiac disease and those taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine (see sections 4.5 and 4.8).

Renal and urinary disorders

There is no clinical study experience in paediatric patients with renal insufficiency (defined in clinical studies as serum creatinine ≥2 x ULN for age) and clofarabine is predominately excreted via the kidneys. Pharmacokinetic data indicate that clofarabine may accumulate in patients with decreased creatinine clearance (see section 5.2). Therefore, clofarabine should be used with caution in patients with mild to moderate renal insufficiency (see section 4.2 for dose adjustments). The safety profile of clofarabine has not been established in patients with severe renal insufficiency or patients receiving renal replacement therapy (see section 4.3). The concomitant use of medicinal products that have been associated with renal toxicity and those eliminated by tubular secretion such as NSAIDs, amphotericin B, methotrexate, aminosides, organoplatines, foscarnet, pentamidine, cyclosporin, tacrolimus, acyclovir and valganciclovir, should be avoided particularly during the 5 day clofarabine administration period; preference should be given to those medicinal products that are not known to be nephrotoxic (see sections 4.5 and 4.8). Renal failure or acute renal failure have been observed as a consequence of infections, sepsis and tumour lysis syndrome (see section 4.8). Patients should be monitored for renal toxicity and clofarabine should be discontinued as necessary.

It was observed that the frequency and severity of adverse reactions, in particular infection, myelosuppression (neutropenia) and hepatotoxicity, are increased when clofarabine is used in in combination. In this regard, patients should be closely monitored when clofarabine is used in combined regimens.

Patients receiving clofarabine may experience vomiting and diarrhoea; they should, therefore, be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, fainting spells, or decreased urine output. Prophylactic anti-emetic medicinal products should be considered.

Hepato biliary disorders

There is no experience in patients with hepatic impairment (serum bilirubin >1.5 x ULN plus AST and ALT >5 x ULN) and the liver is a potential target organ for toxicity. Therefore, clofarabine should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.2 and 4.3). The concomitant use of medicinal products that have been associated with hepatic toxicity should be avoided wherever possible (see sections 4.5 and 4.8).

If a patient experiences a hematologic toxicity of Grade 4 neutropaenia (ANC <0.5 × 10⁹/l) lasting ≥4 weeks, then the dose should be reduced by 25% for the next cycle.

Any patient who experiences a severe non-hematologic toxicity (US NCI CTC Grade 3 toxicity) on a third occasion, a severe toxicity that does not recover within 14 days (excluding nausea/vomiting) or a life-threatening or disabling non-infectious non-hematologic toxicity (US NCI CTC Grade 4 toxicity) should be withdrawn from treatment with clofarabine (see section 4.2).

Patients who have previously received a hematopoietic stem cell transplant (HSCT) may be at higher risk for hepatotoxicity suggestive of veno-occlusive disease (VOD) following treatment with clofarabine (40 mg/m²) when used in combination with etoposide (100 mg/m²) and cyclophosphamide (440 mg/m²). In the post-marketing period, following treatment with clofarabine, serious hepatotoxic adverse reactions of VOD in paediatric and adult patients have been associated with a fatal outcome. Cases of hepatitis and hepatic failure, including fatal outcomes, have been reported with clofarabine treatment (see section 4.8).

Most patients received conditioning regimens that included busulfan, melphalan, and/or the combination of cyclophosphamide and total body irradiation. Severe hepatotoxic events have been reported in a Phase ½ combination study of clofarabine in paediatric patients with relapsed or refractory acute leukaemia.

There are currently limited data on the safety and efficacy of clofarabine when administered for more than 3 treatment cycles.

Excipient with known effect

Each vial of Ivozall contains 70.77 mg of sodium. This is equivalent to 3.08 mmol (or 70.77 mg) of sodium which is equivalent to 3.53% of the WHO recommended maximum daily intake of 2 g sodium for an adult and should be taken into consideration for patients on a controlled sodium diet.

No interaction studies have been performed. However, there are no known clinically significant interactions with other medicinal products or laboratory tests.

Clofarabine is not detectably metabolised by the cytochrome P450 (CYP) enzyme system. Therefore, it is unlikely to interact with active substances which inhibit or induce cytochrome P450 enzymes. In addition, clofarabine is unlikely to inhibit any of the major 5 human CYP isoforms (1A2, 2C9, 2C19, 2D6 and 3A4) or to induce 2 of these isoforms (1A2 and 3A4) at the plasma concentrations achieved following intravenous infusion of 52 mg/m²/day. As a result, it is not expected to affect the metabolism of active substances which are known substrates for these enzymes.

Clofarabine is predominately excreted via the kidneys. Thus, the concomitant use of medicinal products that have been associated with renal toxicity and those eliminated by tubular secretion such as NSAIDs, amphotericin B, methotrexate, aminosides, organoplatines, foscarnet, pentamidine, cyclosporin, tacrolimus, acyclovir and valganciclovir, should be avoided particularly during the 5 day clofarabine administration period (see sections 4.4, 4.8 and 5.2).

The liver is a potential target organ for toxicity. Thus, the concomitant use of medicinal products that have been associated with hepatic toxicity should be avoided wherever possible (see sections 4.4 and 4.8).

Patients taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine (see sections 4.4 and 4.8).

Contraception in males and females

Females of childbearing potential and sexually active males must use effective methods of contraception during treatment.

Pregnancy

There are no data on the use of clofarabine in pregnant women. Studies in animals have shown reproductive toxicity including teratogenicity (see section 5.3). Clofarabine may cause serious birth defects when administered during pregnancy. Therefore, Ivozall should not be used during pregnancy, especially not during the first trimester, unless clearly necessary (i.e. only if the potential benefit to the mother outweighs the risk to the foetus). If a patient becomes pregnant during treatment with clofarabine, she should be informed of the possible hazard to the foetus.

Breast-feeding

It is unknown whether clofarabine or its metabolites are excreted in human breast milk. The excretion of clofarabine in milk has not been studied in animals. However, because of the potential for serious adverse reactions in nursing infants, breastfeeding should be discontinued prior to, during and following treatment with Ivozall (see section 4.3).

Fertility

Dose related toxicities on male reproductive organs have been observed in mice, rats and dogs, and toxicities on female reproductive organs have been observed in mice (see section 5.3). As the effect of clofarabine treatment on human fertility is unknown, reproductive planning should be discussed with patients as appropriate.

No studies on the effects of clofarabine on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as dizziness, light-headedness or fainting spells during treatment and told not to drive or operate machines in such circumstances.

Summary of the safety profile

Nearly all patients (98%) experienced at least one adverse event considered by the study investigator to be related to clofarabine. Those most frequently reported were nausea (61% of patients), vomiting (59%), febrile neutropaenia (35%), headache (24%), rash (21%), diarrhoea (20%), pruritus (20%), pyrexia (19%), palmar-plantar erythrodysaesthesia syndrome (15%), fatigue (14%), anxiety (12%), mucosal inflammation (11%), and flushing (11%). Sixty-eight patients (59%) experienced at least one serious clofarabine-related adverse event. One patient discontinued treatment due to grade 4 hyperbilirubinaemia considered as related to clofarabine after receiving 52 mg/m²/day clofarabine.

Three patients died of adverse events considered by the study investigator to be related to treatment with clofarabine: one patient died from respiratory distress, hepatocellular damage, and capillary leak syndrome; one patient from VRE sepsis and multi-organ failure; and one patient from septic shock and multi-organ failure.

Tabulated list of adverse reactions

The information provided is based on data generated from clinical trials in which 115 patients (>1 and ≤21 years old) with either ALL or acute myeloid leukaemia (AML) received at least one dose of clofarabine at the recommended dose of 52 mg/m² daily x 5.

Adverse reactions are listed by system organ class and 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) and very rare (<1/10,000)) in the table below. Adverse reactions reported during the post-marketing period are also included in the table under the frequency category “not known” (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Patients with advanced stages of ALL or AML may have confounding medical conditions that make causality of adverse events difficult to assess due to the variety of symptoms related to the underlying disease, its progression and the co-administration of numerous medicinal products.

Adverse reactions considered to be related to clofarabine reported at frequencies ≥1/1,000 (i.e. in >1/115 patients) in clinical trials and post-marketing:

^* = see below
^** All adverse reactions occurring at least twice (i.e., 2 or more reactions (1.7%)) are included in this table.

Description of selected adverse reactions

Blood and lymphatic system disorders

The most frequent haematological laboratory abnormalities observed in patients treated with clofarabine were anaemia (83.3%; 95/114); leucopaenia (87.7%; 100/114); lymphopaenia (82.3%; 93/113), neutropaenia (63.7%; 72/113), and thrombocytopaenia (80.7%; 92/114).The majority of these events were of grade ≥ 3.

During the post-marketing period prolonged cytopaenias (thrombocytopaenia, anaemia, neutropaenia and leukopaenia) and bone marrow failure have been reported. Bleeding events have been observed in the setting of thrombocytopaenia. Haemorrhage, including cerebral, gastrointestinal and pulmonary haemorrhage, has been reported and may be associated with a fatal outcome (see section 4.4).

Vascular disorders

Sixty-four patients of 115 (55.7%) experienced at least one vascular disorders adverse reaction. Twenty-three patients out of 115 experienced a vascular disorder considered to be related to clofarabine, the most frequently reported being flushing (13 events; not serious) and hypotension (5 events; all of which were considered to be serious; see section 4.4). However, the majority of these hypotensive events were reported in patients who had confounding severe infections.

Cardiac disorders

Fifty percent of patients experienced at least one cardiac disorders adverse reaction. Eleven events in 115 patients were considered to be related to clofarabine, none of which were serious and the most frequently reported cardiac disorder was tachycardia (35%) (see section 4.4); 6.1% (7/115) patient’s tachycardia were considered to be related to clofarabine. Most of the cardiac adverse reactions were reported in the first 2 cycles.

Pericardial effusion and pericarditis were reported as an adverse reaction in 9% (10/115) of patients. Three of these events were subsequently assessed as being related to clofarabine: pericardial effusion (2 events; 1 of which was serious) and pericarditis (1 event; not serious). In the majority of patients (8/10), the pericardial effusion and pericarditis were deemed to be asymptomatic and of little or no clinical significance on echocardiographic assessment. However, the pericardial effusion was clinically significant in 2 patients with some associated haemodynamic compromise.

Infections and infestations

Forty-eight percent of patients had one or more ongoing infections prior to receiving treatment with clofarabine. A total of 83% of patients experienced at least 1 infection after clofarabine treatment, including fungal, viral and bacterial infections (see section 4.4). Twenty-one (18.3%) events were considered to be related to clofarabine of which catheter related infection (1 event), sepsis (2 events) and septic shock (2 events; 1 patient died (see above)) were considered to be serious.

During the post-marketing period, bacterial, fungal and viral infections have been reported and may be fatal. These infections may lead to septic shock, respiratory failure, renal failure, and/or multi-organ failure.

Renal and urinary disorders

Forty-one patients of 115 (35.7%) experienced at least one renal and urinary disorders adverse reaction. The most prevalent renal toxicity in paediatric patients was elevated creatinine. Grade 3 or 4 elevated creatinine occurred in 8% of patients. Nephrotoxic medicinal products, tumour lysis, and tumour lysis with hyperuricemia may contribute to renal toxicity (see sections 4.3 and 4.4).

Haematuria was observed in 13% of patients overall. Four renal adverse reactions in 115 patients were considered to be related to clofarabine, none of which were serious; haematuria (3 events) and acute renal failure (1 event) (see sections 4.3 and 4.4).

Hepato-biliary disorders

The liver is a potential target organ for clofarabine toxicity and 25.2% of patients experienced at least one hepato-biliary disorders adverse reaction (see sections 4.3 and 4.4). Six events were considered to be related to clofarabine of which acute cholecystitis (1 event), cholelithiasis (1 event), hepatocellular damage (1 event; patient died (see above)) and hyperbilirubinaemia (1 event; the patient discontinued therapy (see above)) were considered to be serious. Two paediatric reports (1.7%) of veno-occlusive disease (VOD) were considered related to study drug.

VOD cases reported during the post-marketing period in paediatric and adult patients have been associated with a fatal outcome (see section 4.4).

In addition, 50/113 patients receiving clofarabine had at least severely (at least US NCI CTC Grade 3) elevated ALT, 36/100 elevated AST and 15/114 elevated bilirubin levels. The majority of elevations in ALT and AST occurred within 10 days of clofarabine administration and returned to ≤ grade 2 within 15 days. Where follow-up data are available, the majority of bilirubin elevations returned to ≤ grade 2 within 10 days.

Systemic inflammatory response syndrome (SIRS) or capillary leak syndrome

SIRS, capillary leak syndrome (signs and symptoms of cytokine release, e.g., tachypnea, tachycardia, hypotension, pulmonary oedema) were reported as an adverse reaction in 5% (6/115) of paediatric patients (5 ALL, 1 AML) (see section 4.4). Thirteen events of tumour lysis syndrome, capillary leak syndrome or SIRS have been reported; SIRS (2 events; both were considered to be serious), capillary leak syndrome (4 events; 3 of which were considered serious and related) and tumour lysis syndrome (7 events; 6 of which were considered related and 3 of which were serious).

Capillary leak syndrome cases reported during the post-marketing period have been associated with a fatal outcome (See section 4.4).

Gastrointestinal disorders

Occurrences of enterocolitis, including neutropaenic colitis, caecitis, and C. difficile colitis have been reported during treatment with clofarabine. Enterocolitis may lead to necrosis, perforation or sepsis complications and may be associated with fatal outcome (see section 4.4).

Skin and subcutaneous disorders

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases, have been reported in patients who were receiving or had recently been treated with clofarabine. Other exfoliative conditions have also been reported.

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.