Adverse reactions : תופעות לוואי

4.8   Undesirable effects

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 neutropenia (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
Infections and infestations                Common: Septic shock*, sepsis, bacteraemia, pneumonia, herpes zoster, herpes simplex, oral candidiasis
Frequency not known: C. difficile colitis
Neoplasms benign and malignant             Common: Tumour lysis syndrome* (including cysts and polyps)
Blood and lymphatic system disorders       Very common: Febrile neutropenia Common: Neutropenia
Immune system disorders                    Common: Hypersensitivity
Metabolism and nutrition disorders         Common: Anorexia, decreased appetite, dehydration Frequency not known: Hyponatremia
Psychiatric disorders                      Very common: Anxiety
Common: Agitation, restlessness, mental status change
Nervous system disorders                   Very common: Headache
Common: Somnolence, peripheral neuropathy,
paraesthesia, dizziness, tremor
Ear and labyrinth disorders                Common: Hypoacusis
Cardiac disorders                          Common: Pericardial effusion*, tachycardia* Vascular disorders                         Very common: Flushing*
Common: Hypotension*, capillary leak syndrome,
hematoma
Respiratory, thoracic and mediastinal      Common: Respiratory distress, epistaxis, dyspnoea, disorders                                  tachypnoea, cough
Gastrointestinal disorders                 Very common: Vomiting, nausea, diarrhoea Common: Mouth haemorrhage, gingival bleeding,
haematemesis, abdominal pain, stomatitis, upper abdominal pain, proctalgia, mouth ulceration
Frequency not known: Pancreatitis, elevations in serum amylase and lipase, enterocolitis, neutropaenic colitis,
caecitis
Hepato-biliary disorders                   Common: Hyperbilirubinaemia, jaundice, veno- occlusive disease, increases in alanine (ALT)* and aspartate (AST)* aminotransferases, hepatic failure
Uncommon: hepatitis

General disorders and administration site     Very common: Fatigue, pyrexia, mucosal inflammation conditions                                    Common: Multi-organ failure, systemic inflammatory response syndrome*, pain, chills, irritability, oedema,
peripheral oedema, feeling hot, feeling abnormal
Skin and subcutaneous tissue disorders        Very common: Palmar-plantar erythrodysaesthesia syndrome, pruritus
Common: Maculo-papular rash, petechiae, erythema,
pruritic rash, skin exfoliation, generalised rash, alopecia,
skin hyperpigmentation, generalised erythema, erythematous rash, dry skin, hyperhidrosis
Frequency not known: Stevens Johnson Syndrome
(SJS), Toxic Epidermal Necrolysis (TEN)
Musculoskeletal, connective tissue and        Common: Pain in extremity, myalgia, bone pain, chest bone disorders                                wall pain, arthralgia, neck and back pain Renal and urinary disorders                   Common: Haematuria*
Common: Renal failure, acute renal failure
Investigations                                Common: Weight decreased Injury, poisoning and procedural              Common: Contusion complications
* = see below
**All adverse reactions occurring at least twice (i.e., 2 or more events (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. Hemorrhage, including cerebral, gastrointestinal and pulmonaryhemorrhage, 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 event. 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 event. 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 events were reported in the first 2 cycles.

Pericardial effusion and pericarditis were reported as an adverse event 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 event.
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 events 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 event (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 event 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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/