Litak · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-093650 · has-adverse-reaction-information · PDF-Seite 6

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. 6 Infections and infestations Very common: infections * (e.g. pneumonia *, septicaemia *) Neoplasms benign, malignant Common: second malignancies * and unspecified (incl cysts and Rare: tumour lysis syndrome * polyps) Blood and lymphatic system Very common: pancytopenia/myelosuppression *, neutropenia, disorders thrombocytopenia, anemia, lymphopenia Uncommon: haemolytic anaemia * Rare: hypereosinophilia Very rare: amyloidosis Immune system disorders Very common: immunosuppression *

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HOS-093646 · has-contraindication-information · PDF-Seite 3

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.

HOS-093645 · has-indication-information · PDF-Seite 2

LITAK is indicated for the treatment of hairy cell leukaemia.

HOS-093648 · has-interaction-information · PDF-Seite 5

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.

HOS-093649 · has-pregnancy-information · PDF-Seite 5

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).

HOS-093647 · has-warning-information · PDF-Seite 3

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. 3 Secondary malignancies Like other nucleoside analogues, treatment with cladribine is associated with myelosupp

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