4.1. Therapeutic indications

LITAK is indicated for the treatment of hairy cell leukaemia.

4.2. Posology and method of administration

Therapy with LITAK should be initiated by a qualified physician with experience in cancer chemotherapy.

Posology

The recommended posology for hairy cell leukaemia is a single course of LITAK given by subcutaneous bolus injection at a daily dose of 0.14 mg/kg body weight for 5 consecutive days.

Deviations from the posology indicated above are not advised.

Elderly

Experience with patients older than 65 years is limited. Elderly patients should be treated by individual assessment and careful monitoring of the blood counts and of the renal and hepatic function. The risk requires assessment on a case‑by‑case basis (see section 4.4).

Renal and hepatic impairment

There are no data on the use of LITAK in patients with renal or hepatic impairment. LITAK is contraindicated in patients with moderate to severe renal impairment (creatinine clearance ≤ 50 ml/min) or with moderate to severe hepatic impairment (Child‑Pugh score > 6) (see sections 4.3, 4.4 and 5.2).

Paediatric population

LITAK is contraindicated in patients less than 18 years of age (see section 4.3).

Method of administration

LITAK is supplied as a ready‑to‑use solution for injection. The recommended dose is directly withdrawn by a syringe and injected as a subcutaneous bolus injection without dilution. LITAK should be inspected visually for particulate matter and discoloration prior to administration. LITAK should warm up to room temperature prior to administration.

Self-administration by the patient

LITAK can be self‑administered by the patient. Patients should be instructed and trained appropriately. Detailed instructions are contained in the Package Leaflet.

4.3. Contraindications

Hypersensitivity to the active substance or any of the excipients listed in section 6.1.

Pregnancy and lactation.

Patients less than 18 years of age.

Moderate to severe renal impairment (creatinine clearance ≤ 50 ml/min) or moderate to severe hepatic impairment (Child‑Pugh score > 6) (see also section 4.4).

Concomitant use of other myelosuppressive medicinal products.

4.4. Special warnings and precautions for use

Cladribine is an antineoplastic and immunosuppressive substance that can induce considerable toxic adverse reactions, such as myelo‑ and immunosuppression, long‑lasting lymphocytopenia, and opportunistic infections. Patients undergoing treatment with cladribine should be closely monitored for signs of haematologic and non‑haematologic toxicities.

Particular caution is advised and risks/benefits should be carefully evaluated if administration of cladribine is considered in patients with increased infection risk, manifested bone marrow failure or infiltration, myelosuppressive pre‑treatments, as well as in patients with suspected or manifested renal and hepatic insufficiency. Patients with active infection should be treated for the underlying condition prior to receiving therapy with cladribine. Although anti‑infective prophylaxis is not generally recommended, it may be beneficial for patients immunocompromised prior to therapy with cladribine or for patients with a pre‑existing agranulocytosis.

If severe toxicity occurs, the physician should consider delaying or discontinuing the therapy with the medicinal product until serious complications resolve. In case of infections, antibiotic treatment should be initiated as required.

It is recommended that patients receiving cladribine should receive irradiated cellular blood components/products to prevent transfusion‑related graft‑versus‑host disease (Ta‑GVHD).

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.

Secondary malignancies

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 LITAK was 3.4% in all 232 hairy cell leukaemia patients treated, during a 10‑year period. The highest incidence of second malignancy with LITAK was 6.5% after a median follow‑up of 8.4 years. Therefore, patients treated with cladribine should be regularly monitored.

Haematologic toxicity

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.

Renal and hepatic impairment

There are no data on the use of LITAK in patients with renal or hepatic impairment. Clinical experience is very limited and safety of LITAK in these patients is not well established (see sections 4.3 and 5.2).

Careful treatment is required in patients with known or suspected renal or hepatic impairment. For all patients treated with LITAK, periodic assessment of renal and hepatic function is advised as clinically indicated.

Elderly

Elderly patients should be treated by individual assessment and careful monitoring of the blood counts and of the renal and hepatic function. The risk requires assessment on a case‑by‑case basis (see section 4.2).

Prevention of tumour lysis syndrome

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.

Fertility

Men being treated with cladribine should be advised not to father a child up to 6 months after treatment and to seek advice of cryoconservation of sperm prior to treatment because of the possibility of infertility due to therapy with cladribine (see sections 4.6 and 5.3).

4.5. Interaction with other medicinal products and other forms of interaction

Due to a potential increase of haematological toxicity and bone marrow suppression, cladribine must not be used concomitantly with other myelosuppressive medicinal products. An influence of cladribine on the activity of other antineoplastic agents has not been observed in vitro (e.g. doxorubicin, vincristine, cytarabine, cyclophosphamide) and in vivo. However, an in vitro study revealed cross‑resistance between cladribine and nitrogen mustard (chlormethine); for cytarabine, one author has described an in vivo cross‑reaction without loss of activity.

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.

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

Cladribine causes serious birth defects when administered during pregnancy. Animal studies and in vitro studies with human cell lines demonstrated the teratogenicity and mutagenicity of cladribine. Cladribine is contraindicated in pregnancy.

Women of childbearing potential must use effective contraception during treatment with cladribine and for 6 months after the last cladribine dose. In case of pregnancy during therapy with cladribine, the woman should be informed about the potential hazard to the foetus.

Breast-feeding

Limited data from case reports have shown that cladribine is excreted in human milk. The quantity is not yet well established. Because of the potential for serious adverse reactions in nursing infants, lactation is contraindicated during treatment with cladribine and for 6 months after the last cladribine dose.

Fertility

The effects of cladribine on fertility have not been studied in animals. However, a toxicity study conducted with cynomolgus monkeys has shown that cladribine suppresses maturation of rapidly generating cells, including testicular cells. The effect on human fertility is unknown. Antineoplastic agents, such as cladribine, which interfere with DNA, RNA and protein synthesis, might be expected to have adverse effects on human gametogenesis (see section 5.3).

Men being treated with cladribine should be advised not to father a child up to 6 months after treatment and to seek advice of cryoconservation of sperm prior to treatment because of the possibility of infertility due to therapy with cladribine (see section 4.4).

4.7. Effects on ability to drive and use machines

LITAK has a major influence on the ability to drive and use machines. In case certain adverse reactions with a potential impact on performance occur (e.g. dizziness, very common, or drowsiness, which may occur due to anaemia, which is very common), patients should be advised not to drive or use machines.

4.8. Undesirable effects

Summary of the safety profile

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.

Tabulated list of adverse reactions

Adverse reactions that have been reported are listed in the table 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 table.

Infections and infestations

Very common: infections * (e.g. pneumonia *, septicaemia *)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Common: second malignancies *Rare: tumour lysis syndrome *

Blood and lymphatic system disorders

Very common: pancytopenia/myelosuppression *, neutropenia, thrombocytopenia, anemia, lymphopeniaUncommon: haemolytic anaemia *Rare: hypereosinophiliaVery rare: amyloidosis

Immune system disorders

Very common: immunosuppression *Rare: graft‑versus‑host disease *

Metabolism and nutrition disorders

Very common: decreased appetiteUncommon: cachexia

Nervous system disorders

Very common: headache, dizzinessCommon: insomnia, anxietyUncommon: somnolence, paraesthesia, lethargy, polyneuropathy, confusion, ataxiaRare: apoplexy, neurological disturbances in speech and swallowingVery rare: depression, epileptic seizure

Eye disorders

Uncommon: conjunctivitisVery rare: blepharitis

Cardiac disorders

Common: tachycardia, heart murmur, hypotension, epistaxis, myocardial ischemia *Rare: Cardiac failure, atrial fibrillation, cardiac decompensation

Vascular disorders

Very common: purpuraCommon: petechiae, haemorrhages *Uncommon: phlebitis

Respiratory, thoracic and mediastinal disorders

Very common: abnormal breath sounds, abnormal chest sounds, coughCommon: shortness of breath, pulmonary interstitial infiltrates mostly due to infectious aetiology, mucositisUncommon: pharyngitisVery rare: lung embolism

Gastrointestinal disorders

Very common: nausea, vomiting, constipation, diarrhoeaCommon: gastrointestinal pain, flatulenceRare: ileus

Hepato‑biliary disorders

Common: reversible, mostly mild increases in bilirubin and transaminasesRare: hepatic failureVery rare: cholecystitis

Skin and subcutaneous tissue disorders

Very common: rash, localised exanthema, diaphoresisCommon: pruritus, skin pain, erythema, urticariaRare: Stevens‑Johnson syndrome/Lyell syndrome

Musculoskeletal and connective tissue disorders

Common: myalgia, arthralgia, arthritis, bone pain

Renal and urinary disorders

Rare: renal failure

General disorders and administration site conditions

Very common: injection site reactions, fever, fatigue, chills, astheniaCommon: oedema, malaise, pain

* see descriptive section below.

Description of selected adverse reactions

Non-haematological adverse reactions

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.

Blood counts

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 x 109/l). The use of haematopoietic growth factors neither improves the recovery of neutrophil counts nor decreases the incidence of fever. Severe thrombocytopenias (< 50 x 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.

Infections

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 LITAK 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.

Rare serious adverse reactions

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.

Fatal outcome

The majority of deaths related to the medicinal product are due to infectious complications. Further rare cases with fatal outcome, reported in association with LITAK 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.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Frequently observed symptoms of overdose are nausea, vomiting, diarrhoea, severe bone marrow depression (including anaemia, thrombocytopenia, leukopenia, and agranulocytosis), acute renal insufficiency, as well as irreversible neurologic toxicity (paraparesis/quadriparesis), Guillain‑Barré syndrome, and Brown‑Séquard syndrome. Acute, irreversible neuro‑ and nephrotoxicity have been described in individual patients treated at a dose which was ≥ 4 times higher than the recommended regimen for hairy cell leukaemia.

No specific antidote exists. Immediate discontinuation of therapy, careful observation, and initiation of appropriate supportive measures (blood transfusions, dialysis, haemofiltration, anti‑infectious therapy, etc.) are the indicated treatment of overdose of cladribine. Patients who have received an overdose of cladribine should be monitored haematologically for at least four weeks.