Chemical formula: C₁₀H₁₁ClFN₅O₃ Molecular mass: 303.677 g/mol PubChem compound: 119182
Clofarabine interacts in the following cases:
Patients with moderate renal impairment (creatinine clearance 30 - <60 ml/min) require a 50% dose reduction.
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. 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 impairment or patients receiving renal replacement therapy. 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. Renal failure or acute renal failure have been observed as a consequence of infections, sepsis and tumour lysis syndrome. 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 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.
Clofarabine should be used with caution in patients with mild to moderate hepatic impairment.
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. The concomitant use of medicinal products that have been associated with hepatic toxicity should be avoided wherever possible. 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.
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.
Patients taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine.
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.
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. As the effect of clofarabine treatment on human fertility is unknown, reproductive planning should be discussed with patients as appropriate.
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.
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. 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.
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. 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. Patients should be monitored for signs and symptoms of enterocolitis.
If the ANC does not recover by 6 weeks from the start of a treatment cycle, a bone marrow aspirate/biopsy should be performed to determine possible refractory disease. If persistent leukaemia is not evident, it is recommended that the dose for the next cycle be reduced by 25% of the previous dose following recovery of ANC to ≥0.75 × 109/l. Should patients experience an ANC <0.5 × 109/l for more than 4 weeks from the start of the last cycle, it is recommended that the dose for the next cycle be reduced by 25%.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases, have been reported. Clofarabine must be discontinued for exfoliative or bullous rash, or if SJS or TEN is suspected.
If a patient develops a clinically significant infection, clofarabine treatment may be withheld until the infection is clinically controlled. At this time, treatment may be reinitiated at the full dose. In the event of a second clinically significant infection, clofarabine treatment should be withheld until the infection is clinically controlled and may be reinitiated at a 25% dose reduction.
There are no data on the use of clofarabine in pregnant women. Studies in animals have shown reproductive toxicity including teratogenicity. Clofarabine may cause serious birth defects when administered during pregnancy.
Therefore, clofarabine 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, they should be informed of the possible hazard to the foetus.
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 clofarabine.
Females of childbearing potential and sexually active males must use effective methods of contraception during treatment.
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. 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.
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.
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 list below. Adverse reactions reported during the post-marketing period are also included in the list 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:
Common: Septic shock*, sepsis, bacteraemia, pneumonia, herpes zoster, herpes simplex, oral candidiasis
Frequency not known: C. difficile colitis
Common: Tumour lysis syndrome*
Very common: Febrile neutropaenia
Common: Neutropaenia
Common: Hypersensitivity
Common: Anorexia, decreased appetite, dehydration
Frequency not known: hyponatremia
Very common: Anxiety
Common: Agitation, restlessness, mental status change
Very common: Headache
Common: Somnolence, peripheral neuropathy, paraesthesia, dizziness, tremor
Common: Hypoacusis
Common: Pericardial effusion*, tachycardia*
Very common: Flushing*
Common: Hypotension*, capillary leak syndrome, haematoma
Common: Respiratory distress, epistaxis, dyspnoea, tachypnoea, cough
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
Common: Hyperbilirubinaemia, jaundice, venoocclusive disease, increases in alanine (ALT)* and aspartate (AST)* aminotransferases, hepatic failure
Uncommon: Hepatitis General disorders and administration site conditions
Very common: Fatigue, pyrexia, mucosal inflammation
Common: Multi-organ failure, systemic inflammatory response syndrome*, pain, chills, irritability, oedema, peripheral oedema, feeling hot, feeling abnormal
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)
Common: Pain in extremity, myalgia, bone pain, chest wall pain, arthralgia, neck and back pain
Common: Haematuria*, Renal failure, acute renal failure
Common: Weight decreased
Common: Contusion
* = see below
** All adverse reactions occurring at least twice (i.e., 2 or more reactions (1.7%)) are included in this list
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.
Sixty-four patients of 115 (55.7%) experienced at least one vascular disorders adverse event. Twentythree 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;). However, the majority of these hypotensive events were reported in patients who had confounding severe infections.
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%); 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.
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. 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 multiorgan failure.
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. 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).
The liver is a potential target organ for clofarabine toxicity and 25.2% of patients experienced at least one hepato-biliary disorders adverse event. 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.
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.
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). 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.
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.
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.
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