Cladribine

Registered South African indications:

• Hairy cell leukaemia

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Males of reproductive potential
• Renal impairment
• Hepatic impairment
• Elderly
• Coombs' positive patients
• Patients whose disease has progressed while treated with fludaribine
• Active infection
• High tumour burden
• Patients at risk for the development of hyperuricaemia as a result of tumour breakdown 
• Prolonged lymphopenia
• Severe bone marrow impairment of any aetiology
• High doses of treatment
• Primary haematological malignancies 
• Haematological malignancies having a high tumour burden
• Children
• Sodium controlled diet
• May impair ability to drive or operate machinery

Forms avail. in SA and covered in this monograph: inj

Used for the treatment of

• Primary or secondary treatment of hairy cell leukaemia 
• B-cell chronic lymphocytic leukaemia
  - Who have not responded to, or whose disease has progressed during or after, treatment with at least one standard alkylating-agent-containing regimen

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Consult specialist for dosages and regimens

Not established for use in children

Pregnancy

• Caution; positive evidence of risk in animal studies
• There are no adequate and well-controlled studies in pregnant women
• Cladribine injection is teratogenic in mice and rabbits. A significant increase in foetal variations was observed in mice receiving 1.5mg/kg/day (4.5mg/m², a dose approximately equivalent to the recommended dose in humans of 3.6mg/m²). Increased resorptions, reduced litter size, and increased foetal malformations were observed in mice when receiving 3.0mg/kg/day (9mg/m²). Foetal death and malformations were observed in rabbits that received 3.0mg/kg/day (33.0mg/m²). No adverse foetal effects were seen in mice at 0.5mg/kg/day (1.5mg/m²) or in rabbits at 1.0mg/kg/day (11.0mg/m²)
• 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 medication, the patient should be apprised of the potential hazard to the foetus

Breastfeeding

• Caution; not recommended
• It is not known whether cladribine is excreted in human milk. Because it may be excreted in human milk and because there is potential for serious adverse reactions in breastfeeding infants, breastfeeding should not be undertaken during treatment with cladribine injection and for 6 months after the last dose of cladribine injection

Fertility

• When administered intravenously to Cynomolgus monkeys, cladribine has been shown to cause suppression of rapidly generating cells, including testicular cells
• Men being treated with cladribine injection should be advised to not father a child up to 6 months after the last cladribine dose. Family planning should be discussed with patients as appropriate

Renal Impairment

• Caution; no information available
  There is inadequate data on dosing of patients with renal insufficiency. Until more information is available, caution is advised when administering cladribine to patients with known or suspected renal insufficiency. As with other potent chemotherapeutic agents, monitoring of renal function should be performed as clinically indicated, especially in patients with underlying kidney dysfunction. Physicians should consider delaying or discontinuing therapy if renal toxicity occurs

Hepatic Impairment

• Caution; no information available
  There is inadequate data on dosing of patients with hepatic insufficiency. Until more information is available, caution is advised when administering cladribine to patients with known or suspected hepatic insufficiency. As with other potent chemotherapeutic agents, monitoring of hepatic function should be performed as clinically indicated, especially in patients with underlying liver dysfunction

Elderly

• Caution; no dose adjustment recommended
  Elderly patients should be treated by individual assessment and careful monitoring of blood counts and renal and hepatic function. The risk requires assessment on a case-by-case basis

Porphyria Information

• Probably not porphyrinogenic (PNP) 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Confusion
• Disorientation
• Anxiety
• Insomnia
• Headache
• Dizziness
• Depressed level of consciousness
• Neurological toxicity
  - Peripheral sensory neuropathy
  - Motor neuropathy (paralysis)
  - Polyneuropathy
  - Paraparesis
  - Quadraparesis
• Fatigue
• Progressive multifocal leukoencephalopathy

Cardiovascular Disorders

• Tachycardia
• Myocardial ischaemia
• Cardiac failure
• Arrhythmia
• Phlebitis

Respiratory Disorders

• Pneumonia
• Pulmonary interstitial infiltrates
  - Lung infiltration
  - Interstitial lung disease
  - Pneumonitis
  - Pulmonary fibrosis
• Abnormal breath sounds
• Cough
• Dyspnoea
  - Exertional dyspnoea
  - Wheezing
• Rales
• Crepitations

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain
• Constipation
• Diarrhoea
• Flatulence

Hepatobiliary Disorders

• Increases in bilirubin
• Increases in transaminases

Genitourinary Disorders

• Renal failure
• Renal dysfunction/insufficiency
  - Acidosis
  - Anuria
  - Increased blood creatinine
  - Tubular damage

Endocrine and Metabolic Disorders

• Decreased appetite
• Tumour lysis syndrome

Musculoskeletal Disorders

• Arthralgia
• Myalgia
• Pain
  - Back pain
  - Chest pain
  - Arthritis pain
  - Bone pain
  - Pain in extremity
• Muscular weakness

Skin and Subcutaneous Tissue Disorders

• Rash
  - Erythema
  - Macular rash
  - Macular-papular rash
  - Papular rash
  - Pruritic rash
  - Pustular rash
  - Erythematous rash
• Urticaria
• Ecchymosis
• Hyperhidrosis
• Petechiae
• Pruritus
• Stevens-Johnson syndrome
• Administration site reaction
• Catheter site reaction
  - Cellulitis
  -Erythema
  - Haemorrhage
  - Pain
• Infusion site reaction
  - Erythema
  - Oedema
  - Pain

Immune, Blood and Lymphatic System Disorders

• Haemolytic anaemia
• Autoimmune haemolytic anaemia
• Anaemia
• Febrile neutropenia
• Thrombocytopenia with bleeding or petechiae
• Neutropenia
• Bone marrow suppression with prolonged pancytopenia
• Aplastic anaemia
• Hypereosinophilia
• Myelodysplastic syndrome
• Hypersensitivity
• Immunosuppression
• Secondary malignancies
• Primary haematological malignancies
• Septic shock
• Bacteraemia
• Herpes infections
  - Herpes retinitis
  - Herpes zoster
• Opportunistic infections
  - Respiratory infection/inflammation
  - Pneumonia
  - Bacterial infection
  - Viral skin infections
  - Oral candidiasis
  - Urinary tract infection
  - Other skin infections
• Fever
• Chills
• Peripheral oedema
• Localised oedema
• Contusion
• Prolonged decrease of CD4 lymphocyte counts
• Transient suppression of CD8 lymphocyte counts
• Prolonged bone marrow hypocellularity

Sensory Disorders

• Conjunctivitis

• Myelosuppression agents
• Immunosuppressive agents
• Live attenuated vaccines
• Antiviral agents
• Inhibitors of adenosine uptake 
• Didanosine
• Tenofovir
• Adefovir
• Nucleoside analogues
• Fludrabine
• 2'-deoxycoformycin

• Full blood count with differential
• Renal function
• Hepatic function
• Bone marrow biopsy

None routine. Specific cases may require:

• Pregnancy test
• Evaluation for progressive multifocal leukoencephalopathy
  - Magnetic resonance imaging (MRI)
  - Cerebrospinal fluid analysis
  - Polymerase chain reaction (PCR)
  - Brain biopsy
  (see additional prescribing points)

Progressive multifocal leukoencephalopathy (PML)

• 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

Cladribine is a synthetic antineoplastic agent. The selective toxicity cladribine towards certain normal and malignant lymphocyte and monocyte populations is based on the relative activities of deoxycytidine kinase, deoxynucleotidase and adenosine deaminase. It is postulated that cells with high deoxycytidine kinase and low deoxynucleotidase activities will be selectively killed by cladribine as toxic deoxynucleotides accumulate intracellularly. Cells containing high concentrations of deoxynucleotides are unable to properly repair single-strand DNA breaks. Cladribine can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair.

Injection (per 5ml) 10mg

• Litak (Key Oncologics)