cladribine: prescribing information – dosing, contraindications, interactions, side effects

LITAK is indicated for the treatment of hairy cell leukaemia.

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 The recommended dose is directly withdrawn by a syringe and injected as a subcutaneous bolus injection without dilution.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.

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.

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, lymphopenia Uncommon: haemolytic anaemia * Rare: hypereosinophilia Very rare: amyloidosis Immune system disorders Very common: immunosuppression * Rare: graft-versus-host disease * Metabolism and nutrition disorders Very common: decreased appetite Uncommon: cachexia Nervous system disorders 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 Eye disorders Uncommon: conjunctivitis Very rare: blepharitis Cardiac disorders Common: tachycardia, heart murmur, hypotension, epistaxis, myocardial ischemia * Rare: Cardiac failure, atrial fibrillation, cardiac decompensation Vascular disorders Very common: purpura Common: petechiae, haemorrhages * Uncommon: phlebitis Respiratory, thoracic and mediastinal disorders 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 Gastrointestinal disorders Very common: nausea, vomiting, constipation, diarrhoea Common: gastrointestinal pain, flatulence Rare: ileus Hepato-biliary disorders Common: reversible, mostly mild increases in bilirubin and transaminases Rare: hepatic failure Very rare: cholecystitis Skin and subcutaneous tissue disorders Very common: rash, localised exanthema, diaphoresis Common: pruritus, skin pain, erythema, urticaria Rare: 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, asthenia Common: 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 national reporting system listed in Appendix V.

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).

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.

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).

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.

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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Purine analogues, ATC code: L01BB04

Cladribine is a purine nucleoside analogue acting as an antimetabolite. The single substitution of hydrogen for chlorine at position 2 distinguishes cladribine from its natural counterpart 2'-deoxyadenosine and renders the molecule resistant to deamination by adenosine deaminase.

Mechanism of action
Cladribine is a prodrug which is taken up rapidly in cells after parenteral administration, and is phosphorylated intracellularly to the active nucleotide 2-chlorodeoxyadenosine-5'-triphosphate (CdATP) by deoxycytidine kinase (dCK). An accumulation of active CdATP is observed predominantly in cells with a high dCK activity and a low deoxynucleotidase activity, particularly in lymphocytes and in other haematopoietic cells. The cytotoxicity of cladribine is dose-dependent.
Non-haematologic tissues seem to be unaffected, explaining the low incidence of non-haematopoietic toxicity of cladribine

Unlike other nucleoside analogues, cladribine is toxic in rapidly proliferating cells as well as in resting cells. No cytotoxic effect of cladribine could be observed in cell lines of solid tumours. The mechanism of action of cladribine is attributed to the incorporation of CdATP into DNA strands: the synthesis of new DNA in dividing cells is blocked and the DNA repair mechanism is inhibited, resulting in an accumulation of DNA strand breaks and a decrease of NAD (nicotinamide adenine dinucleotide) and ATP concentration, even in resting cells. Furthermore, CdATP inhibits ribonucleotide reductase, the enzyme responsible for the conversion of ribonucleotides into deoxyribonucleotides. Cell death occurs from energy depletion and apoptosis.

Clinical efficacy
In the clinical trial using LITAK subcutaneously, 63 patients with hairy cell leukaemia (33 newly diagnosed patients and 30 patients with relapsed or progressive disease) were treated. The overall response rate was 97% with long-lasting remission, with 73% of patients staying in complete remission after four years follow-up time.

Absorption
Cladribine shows complete bioavailability after parenteral administration; the mean area under the plasma concentration versus time curve (AUC) is comparable after continuous or intermittent 2-hour intravenous infusion and after subcutaneous injection.

Distribution
After subcutaneous bolus injection of a 0.14 mg/kg cladribine dose, a Cmax of 91 ng/ml is reached on average after 20 minutes only. In another study using a dose of 0.10 mg/kg body weight/day, the maximum plasma concentration Cmax after continuous intravenous infusion was 5.1 ng/ml (tmax: 12 hours) compared to 51 ng/ml after subcutaneous bolus injection (tmax: 25 minutes).

Intracellular concentration of cladribine exceeds its plasma concentration by 128 to 375 times.

The mean volume of distribution of cladribine is 9.2 l/kg. Plasma protein binding of cladribine is 25% on average, with a wide interindividual variation (5-50%).

Biotransformation
The prodrug cladribine is metabolised intracellularly, predominantly by deoxycytidine kinase, to 2-chlorodeoxyadenosine-5'-monophosphate, that is further phosphorylated to the diphosphate by nucleoside monophosphate kinase and to the active metabolite 2-chlorodeoxyadenosine-5'-triphosphate (CdATP) by nucleoside diphosphate kinase.

Elimination
Pharmacokinetic studies in humans showed that the plasma concentration curve of cladribine fits a 2- or 3-compartment model with α- and β-half-lives of on average 35 minutes and 6.7 hours, respectively. The biexponential decline of the serum concentration of cladribine after subcutaneous bolus injection is comparable to elimination parameters after 2-hour intravenous infusion with an initial and terminal half-life of approximately 2 hours and 11 hours, respectively. The intracellular retention time of cladribine nucleotides in vivo is clearly prolonged as compared to the retention time in the plasma: Half-lives t1/2 of initially 15 hours and subsequently more than 30 hours were measured in leukaemic cells.

MAVENCLAD is indicated for the treatment of adult patients with highly active relapsing multiple sclerosis (MS) as defined by clinical or imaging features (see section 5.1).

Treatment must be initiated and supervised by a physician experienced in the treatment of MS.

Posology

The recommended cumulative dose is 3.5 mg/kg body weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. If medically necessary (e.g. for recovery of lymphocytes), the treatment course in year 2 can be delayed for up to 6 months. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body weight.
For details, see Tables 1 and 2 below.

Following completion of the 2 treatment courses, no further cladribine treatment is required in years 3 and 4 (see section 5.1). Re-initiation of therapy after year 4 has not been studied.

Criteria for initiating and continuing therapy

Lymphocyte counts must be
- normal before initiating treatment in year 1,
- at least 800 cells/mm³ before initiating treatment in year 2.

If necessary, the treatment course in year 2 can be delayed for up to 6 months to allow for recovery of lymphocytes. If this recovery takes more than 6 months, the patient should not receive cladribine tablets anymore.

Distribution of dose

The distribution of the total dose over the 2 years of treatment is provided in Table 1. For some weight ranges the number of tablets may vary from one treatment week to the next. Use of oral cladribine in patients weighing less than 40 kg has not been investigated.

Table 1 Dose of cladribine per treatment week by patient weight in each treatment year Weight range Dose in mg (number of tablets) per treatment week kg Treatment week 1 Treatment week 2 40 to < 50 40 mg (4 tablets) 40 mg (4 tablets) 50 to < 60 50 mg (5 tablets) 50 mg (5 tablets) 60 to < 70 60 mg (6 tablets) 60 mg (6 tablets) 70 to < 80 70 mg (7 tablets) 70 mg (7 tablets) 80 to < 90 80 mg (8 tablets) 70 mg (7 tablets) 90 to < 100 90 mg (9 tablets) 80 mg (8 tablets) 100 to < 110 100 mg (10 tablets) 90 mg (9 tablets) 110 and above 100 mg (10 tablets) 100 mg (10 tablets)

Table 2 shows how the total number of tablets per treatment week is distributed over the individual days. It is recommended that the daily cladribine doses in each treatment week be taken at intervals of 24 hours at approximately the same time each day. If a daily dose consists of two tablets, both tablets are taken together as a single dose.

Table 2 Number of tablets per week day
Total number of tablets per week
Day 1
Day 2
Day 3
Day 4
Day 5

A missed dose must be taken as soon as remembered on the same day according to the treatment schedule.

A missed dose must not be taken together with the next scheduled dose on the following day. In the case of a missed dose, the patient must take the missed dose on the following day, and extend the number of days in that treatment week. If two consecutive doses are missed, the same rule applies, and the number of days in the treatment week is extended by two days.

Concomitant use of other oral medicinal products

It is recommended that administration of any other oral medicinal product be separated from that of MAVENCLAD by at least 3 hours during the limited number of days of cladribine administration (see section 4.5).

Special populations

Renal impairment

No dedicated studies have been conducted in patients with renal impairment.

In patients with mild renal impairment (creatinine clearance 60 to 89 mL/min), no dose adjustment is considered necessary (see section 5.2).

Safety and efficacy in patients with moderate or severe renal impairment have not been established.
Therefore, cladribine is contraindicated in these patients (see section 4.3).

Hepatic impairment

No studies have been conducted in patients with hepatic impairment.

No dose adjustment is required in patients with mild hepatic impairment because the importance of hepatic function for the elimination of cladribine is considered negligible (see section 5.2).
In absence of data, the use of cladribine is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh score >6).

Elderly

Caution is recommended when cladribine is used in elderly patients, taking into account the potential greater frequency of decreased hepatic or renal function, concomitant diseases and other medicinal therapies.

Paediatric population

The safety and efficacy of MAVENCLAD in children below the age of 18 years have not been established. No data are available.

Method of administration

MAVENCLAD is for oral use. The tablets must be taken with water, and swallowed without chewing.
The tablets can be taken independent of food intake.

As the tablets are uncoated, they must be swallowed immediately once removed from the blister and not be left exposed on surfaces or handled for any period of time longer than that required for dosing.
If a tablet is left on a surface, or if a broken or fragmented tablet is released from the blister, the area must be thoroughly washed.

The patient's hands must be dry when handling the tablets and washed thoroughly afterwards.

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

Infection with human immunodeficiency virus (HIV).

Active chronic infection (tuberculosis or hepatitis).

Initiation of cladribine treatment in immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy (see section 4.5).

Active malignancy.

Moderate or severe renal impairment (creatinine clearance <60 mL/min) (see section 5.2).

Pregnancy and breast-feeding (see section 4.6).

Summary of the safety profile

The most clinically relevant adverse reactions are lymphopenia (25.6%) and herpes zoster (3.0%). 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 (see section 4.4).

Tabulated list of adverse reactions

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. Adverse reactions identified during post- marketing surveillance are indicated by an asterisk [*].

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) and frequency not known (cannot be estimated from the available data).

Infections and infestations

Common:
Oral herpes, dermatomal herpes zoster.
Very rare:
Tuberculosis (see section 4.4).

Blood and lymphatic system disorders

Very common:
Lymphopenia.
Common:
Decrease in neutrophil count.

Immune system disorders

Common:
Hypersensitivity* including pruritus, urticaria, rash and rare cases of angio-oedema.

Hepatobiliary disorders

Uncommon:
Liver Injury*.

Skin and subcutaneous tissue disorders

Common:
Rash, alopecia.

Description of selected adverse reactions

Lymphopenia

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 (see section 4.4) and strict criteria for initiating and continuing cladribine treatment must be followed (see section 4.2).

Malignancies

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]) (see section 4.4).

Hypersensitivity

In clinical studies of patients treated with a cumulative dose of 3.5 mg/kg oral cladribine, hypersensitivity events were observed more frequently in cladribine-treated patients (11.8%) compared to patients who received placebo (8.4%). Serious hypersensitivity events were observed in 0.3% of cladribine-treated patients and in no patients who received placebo. Hypersensitivity events led to treatment discontinuation in 0.4% of cladribine-treated patients and in 0.3% patients who received placebo.

Liver Injury

During post-marketing experience, uncommon events of liver injury, including serious cases and cases leading to discontinuation of treatment, were reported in temporal association with MAVENCLAD.
Transient elevations of serum transaminases were usually greater than 5-fold the upper limit of normal (ULN). Isolated cases of transient serum transaminase elevations up to 40-fold the ULN and / or symptomatic hepatitis with transient elevation of bilirubin and jaundice have been observed.
Time to onset varied, with most cases occurring within 8 weeks after the first treatment course (see section 4.4).

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 national reporting system listed in Appendix V.

Haematological monitoring

Cladribine's mode of action is closely linked to a reduction in lymphocyte count. The effect on lymphocyte count is dose-dependent. Decreases in neutrophil count, red blood cell count, haematocrit, haemoglobin or platelet count compared to baseline values have also been observed in clinical studies, although these parameters usually remain within normal limits.

Additive haematological adverse reactions may be expected if cladribine is administered prior to or concomitantly with other substances that affect the haematological profile (see section 4.5).

Lymphocyte counts must be determined
- before initiating treatment in year 1,
- before initiating treatment in year 2,
- 2 and 6 months after start of treatment in each treatment year. If the lymphocyte count is below 500 cells/mm³, it should be actively monitored until values increase again.

For treatment decisions based on the patient's lymphocyte counts, see section 4.2 and subsection 'Infections' below.

Infections

Cladribine can reduce the body's immune defence and may increase the likelihood of infections.
Serious, severe, and opportunistic infections - including events with fatal outcome - have been observed with MAVENCLAD treatment. HIV infection, active tuberculosis and active hepatitis must be excluded before initiation of cladribine (see section 4.3).

Latent infections may be activated, including tuberculosis or hepatitis. Therefore, screening for latent infections, in particular tuberculosis and hepatitis B and C, must be performed prior to initiation of therapy in year 1 and year 2. Initiation of MAVENCLAD should be delayed until the infection has been adequately treated.

A delay in initiation of cladribine should also be considered in patients with an acute infection until the infection is fully controlled.

Particular attention is recommended for patients who have no history of exposure to varicella zoster virus. Vaccination of antibody-negative patients is recommended prior to initiation of cladribine therapy. Initiation of treatment with MAVENCLAD should be postponed for 4 to 6 weeks to allow for the full effect of vaccination to occur.

The incidence of herpes zoster was increased in patients on cladribine. If lymphocyte counts drop below 200 cells/mm³, anti-herpes prophylaxis according to local standard practice should be considered during the time of grade 4 lymphopenia (see section 4.8).

Patients with lymphocyte counts below 500 cells/mm³ should be actively monitored for signs and symptoms suggestive of infections, in particular herpes zoster. If such signs and symptoms occur, anti- infective treatment should be initiated as clinically indicated. Interruption or delay of MAVENCLAD may be considered until proper resolution of the infection.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported for parenteral cladribine in patients treated for hairy cell leukaemia with a different treatment regimen.

Although no case of PML has been reported with cladribine tablets, a baseline magnetic resonance imaging (MRI) should be performed before initiating cladribine tablets treatment (usually within 3 months).

Malignancies

In clinical studies, events of malignancies were observed more frequently in cladribine-treated patients compared to patients who received placebo (see section 4.8).

MAVENCLAD is contraindicated in MS patients with active malignancies (see section 4.3). An individual benefit-risk evaluation should be performed before initiating treatment in patients with prior malignancy. Patients treated with cladribine should be advised to follow standard cancer screening guidelines.

Liver function

Liver injury, including serious cases, has been reported uncommonly in patients treated with MAVENCLAD.
Before initiating MAVENCLAD a comprehensive patient history regarding previous episodes of liver injury with other drugs or underlying liver disorders should be taken. Patients should have their serum aminotransferase, alkaline phosphatase, and total bilirubin levels assessed prior to initiation of therapy in year 1 and year 2. During treatment, liver enzyme and bilirubin monitoring should be obtained based on clinical signs and symptoms.

If a patient develops clinical signs, unexplained liver enzyme elevations or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), serum transaminases and total bilirubin should be measured promptly.
Treatment with MAVENCLAD should be interrupted or discontinued, as appropriate.

Contraception

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 (see section 4.6).

Women of childbearing potential must prevent pregnancy by use of effective contraception during cladribine treatment and for at least 6 months after the last dose (see section 4.5).

Male patients must take precautions to prevent pregnancy of their female partner during cladribine treatment and for at least 3 months after the last dose.

Blood transfusions

In patients who require blood transfusion, irradiation of cellular blood components is recommended prior to administration to prevent transfusion-related graft-versus-host disease. Consultation with a haematologist is advised.

Switching to and from cladribine treatment

In patients who have previously been treated with immunomodulatory or immunosuppressive medicinal products the mode of action and duration of effect of the other medicinal product should be considered prior to initiation of treatment. A potential additive effect on the immune system should also be considered when such medicinal products are used after treatment (see section 4.5).

When switching from another MS medicinal product, a baseline MRI should be performed (see subsection 'Infections' above).

Hepatic impairment

The use of cladribine is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh score >6) (see section 4.2).

Sorbitol

The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

This medicinal product contains hydroxypropylbetadex, which may be available for complex formation with other medicinal products, potentially leading to an increase in bioavailability of such a product (especially medicinal products with low solubility). Therefore, it is recommended that administration of any other oral medicinal product be separated from that of MAVENCLAD by at least 3 hours during the limited number of days of cladribine administration.

Immunosuppressive medicinal products

Initiation of cladribine treatment is contraindicated in immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy with, e.g., methotrexate, cyclophosphamide, cyclosporine or azathioprine, or chronic use of corticosteroids because of a risk of additive effects on the immune system (see section 4.3).

Acute short-term therapy with systemic corticosteroids can be administered during cladribine treatment.

Other disease-modifying medicinal products

The use of cladribine with interferon beta results in an increased risk of lymphopenia. Safety and efficacy of cladribine in combination with other disease-modifying treatments for MS have not been established. Concomitant treatment is not recommended.

Haematotoxic medicinal products

Because of the cladribine-induced reduction in lymphocyte count, additive haematological adverse reactions may be expected if cladribine is administered prior to or concomitantly with other substances that affect the haematological profile (e.g. carbamazepine). Careful monitoring of haematological parameters is recommended in such cases.

Live or live attenuated vaccines

Treatment should not be initiated within 4 to 6 weeks after vaccination with live or attenuated live vaccines because of a risk of active vaccine infection. Vaccination with live or attenuated live vaccines should be avoided during and after cladribine treatment as long as the patient's white blood cell counts are not within normal limits.

Potent ENT1, CNT3 and BCRP transporter inhibitors

At the level of cladribine absorption, the only conceivable interaction pathway of clinical relevance appears to be the breast cancer resistance protein (BCRP or ABCG2). Inhibition of BCRP in the gastrointestinal tract may increase the oral bioavailability and systemic exposure of cladribine. Known BCRP inhibitors, which may alter the pharmacokinetics of BCRP substrates by 20% in vivo, include eltrombopag.

In vitro studies indicate that cladribine is a substrate of the equilibrative nucleoside (ENT1) and concentrative nucleoside (CNT3) transport proteins. Accordingly, the bioavailability, intracellular distribution and renal elimination of cladribine may theoretically be altered by potent ENT1 and CNT3 transporter inhibitors such as dilazep, nifedipine, nimodipine, cilostazol, sulindac or reserpine.
However, net effects in terms of potential cladribine exposure alterations are difficult to predict.

Although the clinical relevance of such interactions is unknown, it is recommended that co- administration of potent ENT1, CNT3 or BCRP inhibitors be avoided during the 4- to 5-day cladribine treatment. If this is not possible, selection of alternative concomitant medicinal products with no, or minimal ENT1, CNT3 or BCRP transporter inhibiting properties should be considered. If this is not possible, dose reduction to the minimum mandatory dose of medicinal products containing these compounds, separation in the timing of administration and careful patient monitoring is recommended.

Potent BCRP and P-gp transporter inducers

The effects of potent inducers of the efflux transporters BCRP and P-glycoprotein (P-gp) on the bioavailability and disposition of cladribine have not been formally studied. A possible decrease in cladribine exposure should be considered if potent BCRP (e.g. corticosteroids) or P-gp (e.g.
rifampicin, St. John's Wort) transporter inducers are co-administered.

Hormonal contraceptives

Co-administration of cladribine with oral hormonal contraceptives (ethinylestradiol and levonorgestrel) showed no clinically relevant pharmacokinetic interaction with cladribine. Therefore, concomitant use of cladribine is not expected to decrease the efficacy of hormonal contraceptives (see section 4.6).

Contraception in males and females

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 MAVENCLAD 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 who become pregnant under therapy with MAVENCLAD should discontinue treatment.

As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected (see section 5.3). Therefore, male patients must take precautions to prevent pregnancy of their partner during cladribine treatment and for at least 3 months after the last dose.

Pregnancy

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 (see section 5.3).

MAVENCLAD is contraindicated in pregnant women (see section 4.3).

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 breast-fed infants, breast-feeding is contraindicated during treatment with MAVENCLAD and for 1 week after the last dose (see section 4.3).

Fertility

In mice, there were no effects on fertility or the reproductive function of offspring. However, testicular effects were observed in mice and monkeys (see section 5.3).

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 3 months after the last dose (see above).

MAVENCLAD has no or negligible influence on the ability to drive and use machines.

There is limited experience with overdose of oral cladribine. Lymphopenia is known to be dose- dependent (see sections 4.4 and 4.8).

Particularly close monitoring of haematological parameters is recommended in patients who have been exposed to an overdose of cladribine.

There is no known specific antidote to an overdose of cladribine. Treatment consists of careful observation and initiation of appropriate supportive measures. Discontinuation of MAVENCLAD may need to be considered. Because of the rapid and extensive intracellular and tissue distribution, haemodialysis is unlikely to eliminate cladribine to a significant extent.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants,
ATC code: L04AA40

Mechanism of action

Cladribine is a nucleoside analogue of deoxyadenosine. A chlorine substitution in the purine ring protects cladribine from degradation by adenosine deaminase, increasing the intracellular residence time of the cladribine prodrug. Subsequent phosphorylation of cladribine to its active triphosphate form, 2-chlorodeoxyadenosine triphosphate (Cd-ATP), is particularly efficiently achieved in lymphocytes, due to their constitutively high deoxycytidine kinase (DCK) and relatively low 5'-nucleotidase (5'-NTase) levels. A high DCK to 5'-NTase ratio favours the accumulation of Cd-ATP, making lymphocytes particularly susceptible to cell death. As a result of a lower DCK/5'-NTase ratio other bone marrow derived cells are less affected than lymphocytes. DCK is the rate limiting enzyme for conversion of the cladribine prodrug into its active triphosphate form, leading to selective depletion of dividing and non-dividing T and B cells.

The primary apoptosis-inducing mechanism of action of Cd-ATP has direct and indirect actions on DNA synthesis and mitochondrial function. In dividing cells, Cd-ATP interferes with DNA synthesis via inhibition of ribonucleotide reductase and competes with deoxyadenosine triphosphate for incorporation into DNA by DNA polymerases. In resting cells cladribine causes DNA single-strand breaks, rapid nicotinamide adenine dinucleotide consumption, ATP depletion and cell death. There is evidence that cladribine can also cause direct caspase-dependent and -independent apoptosis via the release of cytochrome c and apoptosis-inducing factor into the cytosol of non-dividing cells.

MS pathology involves a complex chain of events in which different immune cell types, including autoreactive T and B cells play a key role. The mechanism by which cladribine exerts its therapeutic effects in MS is not fully elucidated but its predominant effect on B and T lymphocytes is thought to interrupt the cascade of immune events central to MS.

Variations in the expression levels of DCK and 5'-NTases between immune cell subtypes may explain differences in immune cell sensitivity to cladribine. Because of these expression levels, cells of the innate immune system are less affected than cells of the adaptive immune system.

Pharmacodynamic effects

Cladribine has been shown to exert long-lasting effects by preferentially targeting lymphocytes and the autoimmune processes involved in the pathophysiology of MS.

Across studies, the largest proportion of patients with grade 3 or 4 lymphopenia (<500 to 200 cells/mm³ or <200 cells/mm³) was seen 2 months after the first cladribine dose in each year, indicating a time gap between cladribine plasma concentrations and the maximum haematological effect.

Cladribine is a prodrug that has to be phosphorylated intracellularly to become biologically active.
Cladribine pharmacokinetics were studied following oral and intravenous administration in MS patients and patients with malignancies, and in in vitro systems.

Absorption

Following oral administration, cladribine is rapidly absorbed. Administration of 10 mg cladribine resulted in a cladribine mean Cmax in the range of 22 to 29 ng/mL and corresponding mean AUC in the range of 80 to 101 ng•h/mL (arithmetic means from various studies).

When oral cladribine was given in fasted state, median Tmax was 0.5 h (range 0.5 to 1.5 h). When administered with a high-fat meal, cladribine absorption was delayed (median Tmax 1.5 h, range 1 to 3 h) and Cmax was reduced by 29% (based on geometric mean), while AUC was unchanged. The bioavailability of 10 mg oral cladribine was approximately 40%.

Distribution

The volume of distribution is large, indicating extensive tissue distribution and intracellular uptake.
Studies revealed a mean volume of distribution of cladribine in the range of 480 to 490 L. The plasma protein binding of cladribine is 20%, and independent of plasma concentration.

The distribution of cladribine across biological membranes is facilitated by various transport proteins, including ENT1, CNT3 and BCRP.

In vitro studies indicate that cladribine efflux is only minimally P-gp related. Clinically relevant interactions with inhibitors of P-gp are not expected. The potential consequences of P-gp induction on the bioavailability of cladribine have not been formally studied.

In vitro studies showed negligible transporter-mediated uptake of cladribine into human hepatocytes.

Cladribine has the potential to penetrate the blood brain barrier. A small study in cancer patients has shown a cerebrospinal fluid/plasma concentration ratio of approximately 0.25.