Chemical formula: C₁₀H₁₂ClN₅O₃ Molecular mass: 285.687 g/mol PubChem compound: 20279
Cladribine interacts in the following cases:
Corticosteroids have been shown to enhance the risk for severe infections when used in combination with cladribine and should not be given concomitantly with cladribine.
Since interactions with medicinal products undergoing intracellular phosphorylation, such as antiviral agents, or with inhibitors of adenosine uptake may be expected, their concomitant use with cladribine is not recommended.
Due to the similar intracellular metabolism, cross-resistance with other nucleoside analogues, such as fludarabine or 2'-deoxycoformycin may occur. Therefore, simultaneous administration of nucleoside analogues with cladribine is not advisable.
In mice, there were no effects on fertility or the reproductive function of offspring. However, testicular effects were observed in mice and monkeys.
As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected. Therefore, male patients must take precautions to prevent pregnancy of their partner during cladribine treatment and for at least 6 months after the last dose.
Like other nucleoside analogues, treatment with cladribine is associated with myelosuppression and profound and prolonged immunosuppression. Treatment with these agents is associated with the occurrence of second malignancies. Secondary malignancies are expected to occur in patients with hairy cell leukaemia. Their frequency varies widely, ranging from 2% to 21%. The peak risk is at 2 years after diagnosis with a median between 40 and 66 months. The cumulative frequencies of second malignancy are 5%, 10-12% and 13-14% following 5, 10 and 15 years respectively after diagnosis of hairy cell leukaemia.
Following cladribine, the incidence of second malignancies ranges from 0% to 9.5% after a median observation period of 2.8 to 8.5 years. The frequency of second malignancy following treatment with cladribine was 3.4% in all 232 hairy cell leukaemia patients treated, during a 10-year period. The highest incidence of second malignancy with cladribine was 6.5% after a median follow-up of 8.4 years. Therefore, patients treated with cladribine should be regularly monitored.
In patients with a high tumour burden, prophylactic allopurinol therapy to control serum levels of uric acid, together with adequate or increased hydration, should be commenced 24 hours before the start of chemotherapy. A daily oral dose of 100 mg of allopurinol is recommended for a period of 2 weeks. In case of an accumulation of the serum uric acid above the normal range, the dose of allopurinol may be increased to 300 mg/day.
Cases of PML, including fatal cases, have been reported with cladribine. PML was reported 6 months to several years after treatment with cladribine. An association with prolonged lymphopenia has been reported in several of these cases. Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural signs or symptoms.
Suggested evaluation for PML includes neurology consultation, magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction (PCR) or a brain biopsy with testing for JCV. A negative JCV PCR does not exclude PML. Additional follow-up and evaluation may be warranted if no alternative diagnosis can be established. Patients with suspected PML should not receive further treatment with cladribine.
During the first month following treatment, myelosuppression is most notable and red blood cell or platelet transfusions may be required. Patients with symptoms of bone marrow depression should be treated with caution, since further suppression of bone marrow function should be anticipated. Therapeutic risks and benefits should be carefully evaluated in patients with active or suspected infections. The risk of severe myelotoxicity and long-lasting immunosuppression is increased in patients with a disease-related bone marrow infiltration or a previous myelosuppressive treatment. Dose reduction and regular monitoring of the patient is required in such cases. Pancytopenia is normally reversible and the intensity of bone marrow aplasia is dose-dependent. An increased incidence of opportunistic infections is expected during, and for 6 months following, therapy with cladribine.
Careful and regular monitoring of peripheral blood counts is essential during, and for 2 to 4 months following, treatment with cladribine to detect potential adverse reactions and consequent complications (anaemia, neutropenia, thrombocytopenia, infections, haemolysis or bleedings), and to survey haematologic recovery. Fever of unknown origin frequently occurs in patients treated for hairy cell leukaemia and is manifested predominantly during the first 4 weeks of therapy. The origin of febrile events should be investigated by appropriate laboratory and radiologic tests.
Less than a third of febrile events are associated with a documented infection. In case of fever related to infections or agranulocytosis, an antibiotic treatment is indicated.
Based on human experience with other substances inhibiting DNA synthesis, cladribine could cause congenital malformations when administered during pregnancy. Studies in animals have shown reproductive toxicity.
Cladribine injection should not be given during pregnancy. Women of childbearing potential must use effective contraception during treatment with cladribine and for 6 months after the last cladribine dose. If cladribine injection is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus.
Cladribine is teratogenic in mice and rabbits. A significant increase in foetal variations was observed in mice receiving 1.5 mg/kg/day (4.5 mg/m², a dose approximately equivalent to the recommended dose in humans of 3.6 mg/m²). Increased resorptions, reduced litter size, and increased foetal malformations were observed when mice received 3.0 mg/kg/day (9 mg/m²). Foetal death and malformations were observed in rabbits that received 3.0 mg/kg/day (33.0 mg/m²). No adverse foetal effects were seen in mice at 0.5 mg/kg/day (1.5 mg/m²) or in rabbits at 1.0 mg/kg/day (11.0 mg/m²).
Cladribine is contraindicated in pregnant women.
It is not known whether cladribine is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed infants, breast-feeding is contraindicated during treatment with cladribine and for 1 week after the last oral dose and 6 months after the last intravenous dose.
Before initiation of treatment both in year 1 and year 2, women of childbearing potential and males who could potentially father a child should be counselled regarding the potential for serious risk to the foetus and the need for effective contraception.
In women of childbearing potential, pregnancy must be excluded before the initiation of cladribine in year 1 and year 2, and prevented by use of effective contraception during cladribine treatment and for at least 6 months after the last dose. Women using systemically acting hormonal contraceptives should add a barrier method during cladribine treatment and for at least 4 weeks after the last dose in each treatment year. Women who become pregnant under therapy with cladribine should discontinue treatment.
As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected. Therefore, male patients must take precautions to prevent pregnancy of their partner during cladribine treatment and for at least 6 months after the last dose.
In mice, there were no effects on fertility or the reproductive function of offspring. However, testicular effects were observed in mice and monkeys.
As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected. Therefore, male patients must take precautions to prevent pregnancy of their partner during cladribine treatment and for at least 6 months after the last dose (see above).
Cladribine has no or negligible influence on the ability to drive and use machines.
Very common adverse reactions observed during the three most relevant clinical trials with cladribine in 279 patients treated for various indications and in 62 patients with hairy cell leukaemia (HCL) were myelosuppression, especially severe neutropenia (41% (113/279), HCL 98% (61/62)), severe thrombocytopenia (21% (58/279), HCL 50% (31/62)) and severe anaemia (14% (21/150), HCL 55% (34/62)), as well as severe immunosuppression/lymphopenia (63% (176/279), HCL 95% (59/62)), infections (39% (110/279), HCL 58% (36/62)) and fever (up to 64%).
Culture-negative fever following treatment with cladribine occurs in 10-40% of patients with hairy cell leukaemia and is rarely observed in patients with other neoplastic disorders. Skin rashes (2-31%) are mainly described in patients with other concomitantly administered medicinal products known to cause rash (antibiotics and/or allopurinol). Gastrointestinal adverse reactions like nausea (5-28%), vomiting (1-13%), and diarrhoea (3-12%) as well as fatigue (2-48%), headache (1-23%), and decreased appetite (1-22%) have been reported during treatment with cladribine. Cladribine is unlikely to cause alopecia; mild and transient alopecia for a few days was observed in 4/523 patients during the treatment, but could not clearly be associated with cladribine.
Adverse reactions that have been reported are listed below by frequency category and system organ class. The frequencies are defined as follows: 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 the available data). For severity, please see text below the list.
Very common: infections* (e.g. pneumonia*, septicaemia*)
Common: second malignancies*
Rare: tumour lysis syndrome*
Very common: pancytopenia/myelosuppression*, neutropenia, thrombocytopenia, anemia, lymphopenia
Uncommon: haemolytic anaemia*
Rare: hypereosinophilia
Very rare: amyloidosis
Very common: immunosuppression*
Rare: graft-versus-host disease*
Very common: decreased appetite
Uncommon: cachexia
Very common: headache, dizziness
Common: insomnia, anxiety
Uncommon: somnolence, paraesthesia, lethargy, polyneuropathy, confusion, ataxia
Rare: apoplexy, neurological disturbances in speech and swallowing
Very rare: depression, epileptic seizure
Uncommon: conjunctivitis
Very rare: blepharitis
Common: tachycardia, heart murmur, hypotension, epistaxis, myocardial ischemia*
Rare: Cardiac failure, atrial fibrillation, cardiac decompensation
Very common: purpura
Common: petechiae, haemorrhages*
Uncommon: phlebitis
Very common: abnormal breath sounds, abnormal chest sounds, cough
Common: shortness of breath, pulmonary interstitial infiltrates mostly due to infectious aetiology, mucositis
Uncommon: pharyngitis
Very rare: lung embolism
Very common: nausea, vomiting, constipation, diarrhoea
Common: gastrointestinal pain, flatulence
Rare: ileus
Common: reversible, mostly mild increases in bilirubin and transaminases
Rare: hepatic failure
Very rare: cholecystitis
Very common: rash, localised exanthema, diaphoresis
Common: pruritus, skin pain, erythema, urticaria
Rare: Stevens-Johnson syndrome/Lyell syndrome
Common: myalgia, arthralgia, arthritis, bone pain
Rare: renal failure
Very common: injection site reactions, fever, fatigue, chills, asthenia
Common: oedema, malaise, pain
* see descriptive section below.
Non-haematological adverse reactions are generally mild to moderate in severity. Treatment of nausea with antiemetics is usually not necessary. Adverse reactions related to skin and subcutaneous tissue are mostly mild or moderate and transient, usually resolving within a cycle interval of 30 days.
Since patients with an active hairy cell leukaemia mostly present with low blood counts, especially low neutrophil counts, more than 90% of the cases have transient severe neutropenias (<1.0 × 109/l). The use of haematopoietic growth factors neither improves the recovery of neutrophil counts nor decreases the incidence of fever. Severe thrombocytopenias (<50 × 109/l) are observed in about 20% to 30% of all patients. Lymphocytopenia lasting for several months and immunosuppression with an increased risk of infections are expected. The recovery of cytotoxic T-lymphocytes and natural killer cells occurs within 3 to 12 months. A complete recovery of T-helper cells and B-lymphocytes is delayed for up to 2 years. Cladribine induces a severe and prolonged reduction of CD4+ and CD8+ T-lymphocytes. At present there exists no experience on possible long-term consequences of this immunosuppression.
Severe long-term lymphocytopenias have been reported rarely which, however, could not be associated with late infectious complications. Very common severe complications, in some cases with fatal outcome, are opportunistic infections (e.g. Pneumocystis carinii, Toxoplasma gondii, listeria, candida, herpes viruses, cytomegalovirus and atypical mycobacteria). Forty percent of the patients who were treated with cladribine at a dose of 0.7 mg/kg body weight per cycle suffered from infections. These were on average more severe than the infections manifested in 27% of all patients receiving a reduced dose of 0.5 mg/kg body weight per cycle. Forty-three percent of patients with hairy cell leukaemia experienced infectious complications at standard dose regimen. One third of these infections have to be considered as severe (e.g. septicaemia, pneumonia). At least 10 cases with acute autoimmune haemolytic anaemia have been reported. All patients were successfully treated with corticosteroids.
Serious adverse reactions like ileus, severe hepatic failure, renal failure, cardiac failure, atrial fibrillation, cardiac decompensation, apoplexy, neurological disturbances in speech and swallowing, tumour lysis syndrome with acute renal failure, transfusion-related graft-versus-host disease, Stevens-Johnson syndrome/Lyell syndrome (toxic epidermal necrolysis), haemolytic anaemia, hypereosinophilia (with erythematous skin rash, pruritus, and facial oedema) are rare.
The majority of deaths related to the medicinal product are due to infectious complications. Further rare cases with fatal outcome, reported in association with cladribine chemotherapy, were second malignancy, cerebro- and cardiovascular infarctions, graft-versus-host disease caused by multiple transfusions of non-irradiated blood, as well as tumour lysis syndrome with hyperuricaemia, metabolic acidosis, and acute renal failure.
The safety of cladribine was evaluated in 576 cladribine-treated patients with hairy cell leukaemia (HCL) (studies K90-091 and L91-048, n=576). These subjects received at least 1 injection of cladribine and provided safety data. Based on pooled safety data from the HCL clinical trials, the most commonly reported (i.e., ≥10% incidence) adverse drug reactions (ADRs) were: pyrexia (33%), fatigue (31%), nausea (22%), rash (16%), headache (14%), and administration site reaction (11%).
Including the above-mentioned ADRs, following list displays ADRs that have been reported with the use of cladribine in HCL-treated patients from clinical trial experiences or from the consolidated (not indication specific) listing of post-marketing experiences.
The displayed frequency categories use the following convention: 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).
Adverse Drug Reactions from HCL Clinical Trials and Post-marketing:
Common: Septic shocka
Uncommon: Opportunistic infectionsa
Common: Secondary malignanciesal, Primary haematological malignanciesa1
Common: Haemolytic anaemiaa,b, Anaemia, Febrile neutropenia
Uncommon: Bone marrow suppression with prolonged pancytopeniaa, Aplastic anaemiaa, Hypereosinophiliaa, Myelodysplastic syndromea
Common: Hypersensitivitya
Uncommon: Tumour lysis syndromea
Common: Confusiona,c, Anxiety, Insomnia
Very common: Headache
Common: Dizziness
Uncommon: Depressed level of consciousnessa, Neurological toxicitya,d
Common: Conjunctivitisa
Common: Tachycardia, Myocardial ischaemia
Rare: Heart failure, Arrhythmia
Common: Pulmonary interstitial infiltratesa,e, Breath sounds abnormal, Cough, Dyspnoeaf, Rales
Very common: Nausea
Common: Abdominal paing, Constipation, Diarrhoea, Flatulence, Vomiting
Uncommon: Increases in bilirubina, Increases in transaminasesa
Very common: Rashh
Common: Urticariaa, Ecchymosis, Hyperhidrosis, Petechiae, Pruritus
Uncommon: Stevens-Johnson syndromea
Common: Arthralgia, Myalgia, Paini
Common: Renal failurea,j
Very common: Administration site reactionk, Fatigue, Pyrexia
Common: Asthenia, Chills, Decreased Appetite, Malaise, Muscular weakness, Oedema peripheral
Common: Contusion
a Events reported as ADRs during the post-marketing experience.
b Haemolytic anaemia includes autoimmune haemolytic anaemia
c Confusion includes disorientation
d Neurological toxicity includes peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, and paraparesis
e Pulmonary interstitial infiltrates includes lung infiltration, interstitial lung disease, pneumonitis and pulmonary fibrosis
f Dyspnoea includes dyspnoea, dyspnoea exertional, and wheezing
g Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain (lower and upper)
h Rash includes erythema, rash, and rash (macular, macula-papular, papular, pruritic, pustular, and erythematous)
i Pain includes pain, back pain, chest pain, arthritis pain, bone pain, and pain in extremity
j Renal failure includes renal failure acute and renal impairment
k Administration site reaction includes administration site reaction, catheter site (cellulitis, erythema, haemorrhage, and pain), and infusion site reaction (erythema, oedema, and pain)
l Due to the prolonged immunosuppression associated with the use of nucleoside analogues like cladribine, secondary malignancies are a potential risk. Primary haematological malignancies are also a risk factor for secondary malignancies.
The following safety data are based on a subset of 124 patients with HCL that were enrolled in the pivotal study (K90-091). In the first month, severe neutropenia was noted in 70% of patients and infection in 31% of patients. Fever was noted in 72% of patients. Most non-haematologic adverse experiences were mild to moderate in severity.
Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics. In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine.
The majority of rashes were mild.
Myelosuppression was frequently observed during the first month after starting treatment with cladribine injection. Neutropenia (ANC less than 500 × 106/L) was noted in 69% of patients, compared with 25% in whom it was present initially. Severe anaemia (haemoglobin less than 8.5 g/dL) occurred in 41% of patients, compared with 12% initially and thrombocytopenia (platelets less than 20 × 109/L) occurred in 15% of patients, compared to 5% in whom it was noted initially. Forty three percent (43%) of patients received transfusions with red blood cells (RBCs) and 13% received transfusions with platelets during month 1.
Treatment with cladribine is associated with prolonged depression of CD4 lymphocyte counts and transient suppression of CD8 lymphocyte counts. In a follow-up of 78 of the 124 patients enrolled in the clinical trials, prior to treatment the CD4 count was 766/µl. The mean CD4 count nadir, which occurred 4 to 6 months following treatment, was 272/µl. Fifteen months after treatment, the mean CD4 count remained below 500/µl. Although CD8 counts decreased initially, increasing counts were observed after 9 months. The clinical significance of the prolonged CD4 lymphopenia is unclear.
Prolonged bone marrow hypocellularity (<35%) was observed. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or cladribine injection toxicity.
Fever was a frequently observed adverse event during the first month of study.
During the first month, 12% of patients experienced severe fever (ie greater than or equal to 40°C). Of the 124 patients treated, 11 were noted to have a documented infection in the month prior to treatment. In the month following treatment, 31% of patients had a documented infection: 13.7% of patients had bacterial infection, 6.5% had viral and 6.5% had fungal infections. Seventy percent (70%) of these patients were treated empirically with antibiotics.
During the first month, serious, including fatal, infections (eg septicaemia, pneumonia) were reported in 7% of all patients; the remainder were mild or moderate. During the second month, the overall rate of documented infection was 8%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding cladribine therapy. Of the 124 hairy cell leukaemia patients entered in the two trials, there were 6 deaths following treatment; one death was due to infection, two to underlying cardiac disease, and two to persistent hairy cell leukaemia with infectious complications. One patient died of progressive disease after receiving additional treatment with another chemotherapeutic agent.
The safety of cladribine was evaluated in 266 cladribine-treated patients with B-cell chronic lymphocytic leukaemia (CLL) noted in the CLL clinical trial dataset (studies L91-999 and L091-048, n=266). These subjects received at least 1 injection of cladribine and provided safety data. Based on pooled safety data from the CLL clinical trials, the most commonly reported (i.e. ≥10% incidence) ADRs were: pyrexia (28%), fatigue (22%), administration site reaction (21%), and headache (11%).
Including the above-mentioned ADRs, following list displays ADRs that have been reported with the use of cladribine in CLL-treated patients from clinical trial experiences or from the consolidated (not indication specific) listing of post-marketing experiences.
The displayed frequency categories use the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100).
Adverse Drug Reactions from CCL Clinical Trials and Post-marketing:
Common: Septic shocka, Bacteraemia, Cellulitis, Localised infection, Pneumonia
Uncommon: Opportunistic infectionsa, Herpes infections (Herpesretinitis, Herpes zoster) have been observed months and up to years after therapy with cladribinea.
Common: Secondary malignanciesa,k, Primary haematological malignanciesa,k
Common: Haemolytic anaemiaa,b, Anaemia, Thrombocytopenia (with bleeding or petechiae)
__Uncommon:__Bone marrow suppression with prolonged pancytopeniaa, Aplastic anaemiaa, Hypereosinophiliaa, Myelodysplastic syndromea
Common: Hypersensitivitya
__Uncommon:__Tumour lysis syndromea
Common: Confusiona,c
Very common: Headache
__Uncommon:__Depressed level of consciousnessa, Neurological toxicitya,d
Common: Conjunctivitisa
Common: Phlebitis
Common: Pulmonary interstitial infiltratesa,e, Breath sounds abnormal, Cough, Dyspnoeaf, Rales
Common: Diarrhoea, Nausea, Vomiting
__Uncommon:__Increases in bilirubina, Increases in transaminasesa
Common: Urticariaa, Hyperhidrosis, Purpura, Rashg
__Uncommon:__Stevens-Johnson syndromea
Common: Painh
Common: Renal failurea,i
Very common: Administration site reactionj, Fatigue, Pyrexia
Common: Asthenia, Crepitations, Localised oedema, Muscular weakness, Oedema, Oedema peripheral
a Events reported as ADRs during the post-marketing experience.
b Haemolytic anaemia includes autoimmune haemolytic anaemia
c Confusion includes disorientation
d Neurological toxicity includes peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, and paraparesis
e Pulmonary interstitial infiltrates includes lung infiltration, interstitial lung disease, pneumonitis and pulmonary fibrosis
f Dyspnoea includes dyspnoea and dyspnoea exertional
g Rash includes rash (macula-papular, pruritic, and pustular) and erythema
h Pain includes pain, arthralgia, back pain, bone pain, musculoskeletal pain, and pain in extremity
i Renal failure includes renal failure acute and renal impairment
j Administration site reaction includes administration site reaction, catheter site (erythema and infection), and infusion site (cellulitis, erythema, irritation, oedema, pain, infection, and phlebitis)
k Due to the prolonged immunosuppression associated with the use of nucleoside analogues like cladribine, secondary malignancies are a potential risk. Primary haematological malignancies are also a risk factor for secondary malignancies.
Patients with CLL treated with cladribine injection were more severely myelosuppressed prior to therapy than HCL patients; increased myelosuppression was observed during Cycle 1 and Cycle 2 of therapy, reaching a nadir during Cycle 2. The percentage of patients having a haemoglobin level below 8.5 g/dL was 16.9% at baseline, 37.9% in Cycle 1, and 46.1% in Cycle 2. The percentage of patients with platelet counts below 20 × 109/L was 4.0% at baseline, 20.2% during Cycle 1, and 22.5% during Cycle 2. Absolute neutrophil count was below 500 × 106/L in 18.5% of patients at baseline, 56.5% in Cycle 1, 61.8% in Cycle 2, 59.3% in Cycle 3 and 55.9% in Cycle 4. There appeared to be no cumulative toxicity upon administration of multiple cycles of therapy. Marked blood chemistry abnormalities noted during the study were pre-existing, or were isolated abnormalities which resolved, or were associated with death due to the underlying disease.
During Cycle 1, 23.6% of patients experienced pyrexia, and 32.5% experienced at least one documented infection. Infections that occurred in 5% or more of the patients during Cycle 1 were: respiratory infection/inflammation (8.9%), pneumonia (7.3%), bacterial infection (5.6%), and viral skin infections (5.7%). In Cycles 2 through 9, 71.3% of the patients had at least one infection. Infections that occurred in 10% or more of patients were: pneumonia (28.7%), bacterial infection (21.8%), viral skin infection (20.8%), upper respiratory infection (12.9%), other intestinal infection/inflammation (12.9%), oral candidiasis (11.9%), urinary tract infection (11.9%), and other skin infections (11.9%). Overall, 72.4% of the patients had at least one infection during therapy with cladribine injection. Of these, 32.6% had been administered concomitant immunosuppressive therapy (prednisone).
In a Phase 1 study with 31 patients in which cladribine injection was administered at high doses (4 to 9 times that recommended for hairy cell leukaemia) for 7-14 days in conjunction with cyclophosphamide and total body irradiation as preparation for bone marrow transplantation, acute nephrotoxicity, delayed onset neurotoxicity, severe bone marrow suppression with neutropenia, anaemia, and thrombocytopenia and gastro-intestinal symptoms were reported.
Six patients (19%) developed manifestations of acute renal dysfunction/insufficiency (eg acidosis, anuria, elevated serum creatinine, etc) within 7 to 13 days after starting treatment with cladribine, 5 of the affected patients required dialysis. Renal insufficiency was reversible in 2 of these patients. Evidence of tubular damage was noted at autopsy in 2 (of 4) patients whose renal function had not recovered at the time of death. Several of these patients had also been treated with other medications having known nephrotoxic potential.
Eleven patients (35%) experienced delayed onset neurological toxicity. In the majority, this was characterised by progressive irreversible motor weakness, of the upper and/or lower extremities (paraparesis/quadraparesis), noted 35 to 84 days after starting high dose therapy.
Non-invasive neurological testing was consistent with demyelinating disease.
While the use of cladribine cannot be recommended in indications other than hairy cell leukaemia or chronic lymphocytic leukaemia, nor can subcutaneous administration be recommended, data are available from the following investigations which were designed to evaluate the potential efficacy of the drug in the treatment of multiple sclerosis.
In two studies which employed the intravenous route, cladribine was infused in doses ranging from 0.087 to 0.1 mg/kg/day for seven days, with this regimen being repeated for a total of 4 to 6 months. Cumulative doses achieved thus ranged from 2.8 to 3.65 mg/kg. Additionally, in three studies which utilized the subcutaneous route, cladribine was administered in doses ranging from 0.07 to 0.14 mg/kg/day for 5 days, with this regimen being repeated for a total of 2 to 6 months. Cumulative total doses administered thus ranged from 0.7 to 2.1 mg/kg.
The safety profile established based on these trials reflects the drug’s expected lymphocytotoxic and bone marrow-suppressing effects and is consistent with the safety profile attributable to the intravenous route of administration in the currently recommended indications of HCL and CLL.
In these trials, most of the frequently reported adverse events, including serious adverse events, were events typically associated with the underlying disease. Most occurred with comparable frequency in placebo- and cladribine-treated subjects. Inflammation and/or pain at the injection site were seen with subcutaneous injection of the study drug. Subjects treated with cladribine had a higher incidence of upper respiratory tract infection, purpura, hypertonia and muscle weakness than did subjects treated with placebo, with the between-group difference in the incidence of muscle weakness due primarily to results obtained by a single investigator. With the exception of a higher incidence of thrombocytopenia after re-treatment (8%) compared to initial treatment (4%), there were no notable differences in the adverse events profile associated with an initial cladribine treatment versus re-treatment among the 78 subjects who received more than one cladribine treatment course.
Less common, but clinically important adverse events, included those associated with myelosuppression and compromised immune function (pneumonia, aplastic anaemia, pancytopenia, thrombocytopenia, herpes simplex, and herpes zoster infections) and these occurred either exclusively or with increased incidence and severity in subjects who received a cumulative cladribine dose of 2.8 mg/kg or higher, particularly when the total dose was administered in an interval as short as four months.
Safety and effectiveness in children have not been established. [In a Phase I study of 1-21 year old patients with leukemia, cladribine injection was given by continuous intravenous infusion in doses ranging from 3 to 10.7 mg/m²/day for 5 days (one-half to twice the recommended dose for hairy cell leukemia). The dose-limiting toxicity was severe myelosuppression with profound neutropenia and thrombocytopenia. At the highest dose, 3 of 7 patients developed irreversible myelosuppression and fatal systemic bacterial or fungal infections. No unique toxicities were noted.]
The most clinically relevant adverse reactions reported in MS patients who received cladribine at the recommended cumulative dose of 3.5 mg/kg over 2 years in clinical studies were lymphopenia and herpes zoster. The incidence of herpes zoster was higher during the period of grade 3 or 4 lymphopenia (<500 to 200 cells/mm³ or <200 cells/mm³) compared to the time when the patients were not experiencing grade 3 or 4 lymphopenia.
Adverse reactions described in the list below are derived from pooled data from clinical studies in MS in which oral cladribine was used as monotherapy at a cumulative dose of 3.5 mg/kg. The safety database from these studies comprises 923 patients.
The following definitions apply to the frequency terminology used hereafter:
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)
Frequency not known (cannot be estimated from the available data)
Common: Oral herpes, dermatomal herpes zoster.
Very rare: Tuberculosis.
Very common:: Lymphopenia.
Common: Decrease in neutrophil count.
Common: Rash, alopecia.
In clinical studies, 20% to 25% of the patients treated with a cumulative dose of cladribine 3.5 mg/kg over 2 years as monotherapy developed transient grade 3 or 4 lymphopenia. Grade 4 lymphopenia was seen in less than 1% of the patients. The largest proportion of patients with grade 3 or 4 lymphopenia was seen 2 months after the first cladribine dose in each year (4.0% and 11.3% of patients with grade 3 lymphopenia in year 1 and year 2, 0% and 0.4% of patients with grade 4 lymphopenia in year 1 and year 2). It is expected that most patients recover to either normal lymphocyte counts or grade 1 lymphopenia within 9 months.
To decrease the risk for severe lymphopenia, lymphocyte counts must be determined before, during and after cladribine treatment and strict criteria for initiating and continuing cladribine treatment must be followed.
In clinical studies and long-term follow-up of patients treated with a cumulative dose of 3.5 mg/kg oral cladribine, events of malignancies were observed more frequently in cladribine-treated patients (10 events in 3,414 patient-years [0.29 events per 100 patient-years]) compared to patients who received placebo (3 events in 2,022 patient-years [0.15 events per 100 patient-years]).
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