Cladribine

Cladribine is an analogue of the nucleoside deoxyadenosine in which a chlorine atom protects the molecule from breakdown by adenosine deaminase, so that it stays inside cells for a long time. It is a prodrug: it must be converted inside the cell into the active cladribine triphosphate (Cd-ATP), and lymphocytes do this particularly efficiently. The same lymphocyte-depleting action underlies both authorised uses, the treatment of hairy cell leukaemia (Litak) and of highly active relapsing multiple sclerosis (Mavenclad), although the doses and schedules differ.

Mechanism of Action

• Activation inside lymphocytes: cladribine enters dividing and resting lymphocytes through nucleoside transporters and is phosphorylated by deoxycytidine kinase (DCK) to cladribine monophosphate, then to the diphosphate and the active triphosphate (Cd-ATP). DCK is the rate-limiting enzyme of this conversion.
• Selectivity: lymphocytes have constitutively high DCK and relatively low 5′-nucleotidase, the enzyme that inactivates the monophosphate, so Cd-ATP accumulates in them. Other cells derived from the bone marrow have a lower DCK-to-5′-nucleotidase ratio and are less affected.
• Dividing cells: Cd-ATP interferes with DNA synthesis by inhibiting ribonucleotide reductase and by competing with deoxyadenosine triphosphate for incorporation into DNA by DNA polymerases.
• Resting cells: cladribine causes DNA single-strand breaks, rapid consumption of NAD, depletion of ATP and cell death. It can also trigger caspase-dependent and caspase-independent apoptosis by releasing cytochrome c and apoptosis-inducing factor into the cytosol.
• Result: selective, dose-dependent depletion of dividing and non-dividing T and B lymphocytes. In multiple sclerosis (MS), autoreactive T and B cells play a key role in the disease process.
• Time course in MS: after Mavenclad, lymphocyte counts are lowest about 2 months after the first dose of each treatment year, and most patients are expected to recover to normal counts or grade 1 lymphopenia within 9 months.

Pharmacokinetics

• Absorption (tablets): rapid. The oral bioavailability of the 10 mg tablet is about 40%. A 10 mg dose gives a mean peak concentration (Cmax) of 22–29 ng/mL and a mean AUC of 80–101 ng·h/mL. In the fasted state the median time to peak is 0.5 hours (range 0.5–1.5 hours); a high-fat meal delays it (median 1.5 hours, range 1–3 hours) and lowers Cmax by 29% but leaves the AUC unchanged.
• Distribution: the volume of distribution is large (mean 480–490 L), indicating extensive tissue distribution and uptake into cells. Plasma protein binding is 20% and independent of concentration. Transport proteins including ENT1, CNT3 and BCRP help cladribine cross cell membranes; efflux is only minimally P-glycoprotein related. Cladribine can cross the blood–brain barrier (a cerebrospinal fluid to plasma ratio of about 0.25 in a small study in cancer patients), and it and its phosphorylated metabolites accumulate and are retained in lymphocytes.
• Metabolism: cladribine is a prodrug that is phosphorylated inside cells to its active form. After both oral and intravenous doses, unchanged cladribine is the main component in plasma and urine, and liver metabolism is negligible in vitro.
• Elimination: after oral dosing the terminal half-life is about one day. In patients with MS, about 28.5% of an oral 10 mg dose is excreted unchanged in the urine, and renal clearance exceeds the glomerular filtration rate, indicating active renal secretion. The intracellular half-life is about 15 hours for the monophosphate and 10 hours for the active triphosphate.
• Special populations: the effects of kidney and liver impairment and of age on dosing are given for each product under Administration and Dosage.

Litak and Mavenclad are separate medicinal products with different forms, doses and schedules.

• Hairy cell leukaemia (Litak): treatment of hairy cell leukaemia.
• Highly active relapsing multiple sclerosis (Mavenclad): treatment of adult patients with highly active relapsing multiple sclerosis, as defined by clinical or imaging features.

Mavenclad (multiple sclerosis)

• Hypersensitivity to cladribine or to any of the excipients.
• Infection with human immunodeficiency virus (HIV).
• Active chronic infection (tuberculosis or hepatitis).
• Starting treatment in immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy.
• Active malignancy.
• Moderate or severe renal impairment (creatinine clearance below 60 mL/min).
• Pregnancy and breastfeeding.

Litak (hairy cell leukaemia)

• Hypersensitivity to cladribine or to any of the excipients.
• Pregnancy and lactation.
• Patients under 18 years of age.
• Moderate to severe renal impairment (creatinine clearance ≤ 50 mL/min) or moderate to severe hepatic impairment (Child-Pugh score above 6).
• Concomitant use of other myelosuppressive medicinal products.

The two products have different safety profiles, so their reactions are given separately.

Mavenclad (Multiple Sclerosis)

The most clinically relevant reactions are lymphopenia (25.6% of patients) and herpes zoster (3.0%). The list below comes from pooled multiple sclerosis studies of oral cladribine as monotherapy at a cumulative dose of 3.5 mg/kg (923 patients), with reactions first identified after marketing included.

Very common (≥1/10): lymphopenia.

Common (≥1/100 to <1/10): oral herpes; dermatomal herpes zoster; decreased neutrophil count; hypersensitivity (including itching, urticaria, rash and rare cases of angio-oedema; identified after marketing); rash; hair loss (alopecia).

Uncommon (≥1/1,000 to <1/100): liver injury (identified after marketing).

Very rare (<1/10,000): tuberculosis.

• Lymphopenia: 20% to 25% of patients treated with the cumulative dose of 3.5 mg/kg over 2 years developed transient grade 3 or 4 lymphopenia, and grade 4 was seen in less than 1%. The largest share was seen 2 months after the first dose of each year (grade 3 in 4.0% of patients in year 1 and 11.3% in year 2; grade 4 in 0% and 0.4%). Most patients are expected to return to normal counts or grade 1 lymphopenia within 9 months.
• Herpes zoster: the incidence was higher during grade 3 or 4 lymphopenia than at other times.
• Malignancies: in clinical studies and long-term follow-up they were seen more often with cladribine (10 events in 3,414 patient-years, 0.29 per 100 patient-years) than with placebo (3 events in 2,022 patient-years, 0.15 per 100 patient-years).

Litak (Hairy Cell Leukaemia)

The figures below come from the three most relevant trials of cladribine, in 279 patients treated for various conditions, including 62 with hairy cell leukaemia. The SmPC contains a full frequency table.

Very common (≥1/10): myelosuppression, especially severe neutropenia (41% of all patients; 98% of those with hairy cell leukaemia), severe thrombocytopenia (21%; 50%) and severe anaemia (14%; 55%); severe immunosuppression with lymphopenia (63%; 95%); infections (39%; 58%); fever (up to 64%).

Culture-negative fever after treatment occurs in 10–40% of patients with hairy cell leukaemia and is rarely seen in other neoplastic disorders. Skin rashes (2–31%) were mainly seen in patients who were also taking other medicines known to cause rash (antibiotics and/or allopurinol). Also reported were nausea (5–28%), vomiting (1–13%), diarrhoea (3–12%), fatigue (2–48%), headache (1–23%) and decreased appetite (1–22%). Cladribine is unlikely to cause hair loss: mild, transient hair loss for a few days occurred in 4 of 523 patients but could not clearly be linked to it.

Mavenclad

• Other oral medicines: Mavenclad contains hydroxypropylbetadex, which can form complexes with other medicines and may increase their bioavailability, especially for poorly soluble medicines. Any other oral medicine should therefore be taken at least 3 hours apart from Mavenclad on the limited number of dosing days.
• Immunosuppressive or myelosuppressive medicines (for example methotrexate, cyclophosphamide, ciclosporin, azathioprine, or chronic corticosteroids): starting Mavenclad is contraindicated in patients receiving them, because of additive effects on the immune system. Acute short-term systemic corticosteroids can be given during cladribine treatment.
• Other disease-modifying MS treatments: interferon beta together with cladribine increases the risk of lymphopenia. Safety and efficacy of combinations with other disease-modifying treatments have not been established, and concomitant treatment is not recommended.
• Haematotoxic medicines (for example carbamazepine): additive haematological reactions may be expected, so blood counts are monitored closely.
• Live or live attenuated vaccines: treatment should not start within 4 to 6 weeks after such a vaccine, because of the risk of active vaccine infection. Live or live attenuated vaccines should be avoided during and after treatment for as long as white blood cell counts are not within normal limits.
• Inhibitors of the ENT1, CNT3 and BCRP transporters: they may theoretically alter the absorption, distribution and elimination of cladribine, although the net effect is hard to predict. Examples are eltrombopag (BCRP) and dilazep, nifedipine, nimodipine, cilostazol, sulindac and reserpine (ENT1 and CNT3). Combining them during the 4- to 5-day treatment should be avoided; if that is not possible, alternatives with little or no transporter inhibition are chosen, or the dose of the other medicine is reduced to the minimum needed, its timing separated and the patient monitored carefully.
• Inducers of the BCRP and P-glycoprotein transporters (for example corticosteroids for BCRP; rifampicin and St John’s wort for P-gp): a possible decrease in cladribine exposure should be considered.
• Hormonal contraceptives: oral ethinylestradiol and levonorgestrel showed no clinically relevant pharmacokinetic interaction with cladribine, so Mavenclad is not expected to reduce the efficacy of hormonal contraceptives.
• Food: the tablets can be taken with or without food; a high-fat meal lowers the peak concentration but not the total exposure. The sorbitol in the tablets can affect the bioavailability of other oral medicines taken at the same time.

Litak

• Litak must not be combined with other myelosuppressive medicinal products (contraindicated). Further interaction information is in its SmPC.

The two products are started by different specialists and dosed completely differently; the doses below must not be mixed up.

Mavenclad: Highly Active Relapsing Multiple Sclerosis

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

• Cumulative dose: 3.5 mg/kg body weight over 2 years, given as one treatment course of 1.75 mg/kg in each year.
• One treatment course: two treatment weeks, one at the beginning of the first month and one at the beginning of the second month of that treatment year. Each treatment week has 4 or 5 days on which the patient takes 10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body weight.
• Dose per treatment week by body weight (treatment week 1 / treatment week 2):
  • 40 to below 50 kg: 40 mg (4 tablets) / 40 mg (4 tablets)
  • 50 to below 60 kg: 50 mg (5 tablets) / 50 mg (5 tablets)
  • 60 to below 70 kg: 60 mg (6 tablets) / 60 mg (6 tablets)
  • 70 to below 80 kg: 70 mg (7 tablets) / 70 mg (7 tablets)
  • 80 to below 90 kg: 80 mg (8 tablets) / 70 mg (7 tablets)
  • 90 to below 100 kg: 90 mg (9 tablets) / 80 mg (8 tablets)
  • 100 to below 110 kg: 100 mg (10 tablets) / 90 mg (9 tablets)
  • 110 kg and above: 100 mg (10 tablets) / 100 mg (10 tablets)
• Timing: the daily doses in a treatment week are taken at 24-hour intervals at about the same time each day; if the daily dose is two tablets, both are taken together as a single dose. The SmPC has a table showing how the tablets are spread over the days.
• Years 3 and 4: no further cladribine treatment is required. Restarting treatment after year 4 has not been studied.
• Body weight below 40 kg: use has not been investigated.

Mavenclad: Criteria for Starting and Continuing Treatment

• Lymphocyte counts must be normal before treatment starts in year 1.
• Lymphocyte counts must be at least 800 cells/mm³ before treatment starts in year 2.
• If medically necessary (for example, to allow lymphocytes to recover), the year-2 course can be delayed by up to 6 months. If recovery takes longer than 6 months, the patient should not receive cladribine tablets any more.
• In women of childbearing potential, pregnancy must be ruled out before each yearly course (see Special Instructions).

Mavenclad: How to Take the Tablets

• Mavenclad is for oral use. The tablets are swallowed with water, without chewing, and can be taken with or without food.
• The tablets are uncoated, so they are swallowed immediately once removed from the blister and are not left exposed on surfaces or handled for longer than needed for dosing. If a tablet is left on a surface, or a broken or fragmented tablet is released from the blister, the area must be washed thoroughly.
• Any other oral medicine is taken at least 3 hours apart from Mavenclad on the dosing days.

Mavenclad: Special Populations

• Renal impairment: no dedicated studies. No dose adjustment is considered necessary in mild impairment (creatinine clearance 60 to 89 mL/min); in moderate or severe impairment Mavenclad is contraindicated.
• Hepatic impairment: no studies. No dose adjustment is needed in mild impairment, because liver function is considered of negligible importance for elimination; use is not recommended in moderate or severe impairment (Child-Pugh score above 6).
• Elderly: caution is recommended, because liver or kidney function may be decreased more often and concomitant diseases and other medicines are more common.
• Children and adolescents: safety and efficacy below 18 years of age have not been established.
• Missed dose: follow the instructions in SmPC section 4.2 and from the treating specialist.

Litak: Hairy Cell Leukaemia

Therapy with Litak should be started by a qualified physician with experience in cancer chemotherapy.

• Dose: a single course of 0.14 mg/kg body weight once daily for 5 consecutive days, as a subcutaneous bolus injection. Deviations from this dose are not advised.
• Preparation: Litak is a ready-to-use solution. The dose is drawn directly into a syringe and injected without dilution. The solution is checked visually for particles and discolouration and allowed to warm to room temperature first.
• Self-administration: patients can inject Litak themselves after appropriate instruction and training; detailed instructions are in the package leaflet.
• Elderly: experience in patients older than 65 years is limited. Elderly patients are treated after individual assessment, with careful monitoring of blood counts and of kidney and liver function, and the risk is assessed case by case.
• Renal and hepatic impairment: there are no data. Litak is contraindicated in moderate to severe renal impairment (creatinine clearance ≤ 50 mL/min) and in moderate to severe hepatic impairment (Child-Pugh score above 6).
• Children and adolescents: contraindicated below 18 years of age.

Pregnancy Must Be Excluded Before Each Mavenclad Course

• In women of childbearing potential, pregnancy must be ruled out before Mavenclad is started in year 1 and again before the course in year 2, that is, before each yearly course. It must then be prevented with effective contraception during treatment and for at least 6 months after the last dose.
• Before each course, women of childbearing potential and men who could father a child are counselled about the serious risk to the foetus and the need for effective contraception.
• A woman who becomes pregnant during Mavenclad treatment should stop it. Mavenclad is contraindicated in pregnant women.
• Because cladribine interferes with DNA synthesis, effects on human gametogenesis could be expected, so male patients must take precautions to prevent pregnancy of their partner during treatment and for at least 3 months after the last dose.
• Oral hormonal contraceptives showed no clinically relevant interaction with cladribine (see Drug Interactions).
• Litak is likewise contraindicated in pregnancy and lactation.

Mavenclad: Lymphocyte and Blood Count Monitoring

Cladribine acts by lowering lymphocyte counts, and the effect depends on the dose. Lymphocyte counts must be measured before treatment in year 1, before treatment in year 2, and 2 and 6 months after the start of treatment in each treatment year. If the count is below 500 cells/mm³ it is monitored actively until it rises again. Neutrophil, red cell, haematocrit, haemoglobin and platelet values may also fall from baseline, although they usually remain within normal limits, and additive haematological reactions may be expected with other medicines that affect the blood count.

Mavenclad: Infections

• Serious, severe and opportunistic infections, including fatal ones, have been seen. HIV infection, active tuberculosis and active hepatitis must be excluded before treatment, and screening for latent infections, in particular tuberculosis and hepatitis B and C, must be done before the course in year 1 and in year 2. Starting is delayed until an infection has been adequately treated, and a delay is also considered in acute infection until it is fully controlled.
• Patients with no history of varicella zoster virus exposure need particular attention: antibody-negative patients are vaccinated before treatment, and the start of Mavenclad is postponed by 4 to 6 weeks to let the vaccine take full effect.
• Herpes zoster was more frequent with cladribine. Anti-herpes prophylaxis according to local practice should be considered while lymphocytes are below 200 cells/mm³ (grade 4 lymphopenia). Patients with counts below 500 cells/mm³ are monitored actively for signs of infection, in particular herpes zoster, and Mavenclad may be interrupted or delayed until the infection has resolved.
• Progressive multifocal leukoencephalopathy (PML) has been reported with parenteral cladribine in patients treated for hairy cell leukaemia with a different treatment regimen. No case has been reported with the tablets, but a baseline MRI is performed before treatment starts (usually within 3 months), and also when switching from another MS medicine.

Mavenclad: Malignancies

Malignancies were seen more often in cladribine-treated patients than with placebo. Mavenclad is contraindicated in patients with active malignancy, an individual benefit–risk evaluation is made before starting treatment in patients with a prior malignancy, and patients are advised to follow standard cancer screening guidelines.

Mavenclad: Liver Function

Liver injury, including serious cases, has been reported uncommonly. Before treatment a full history is taken of previous liver injury with other medicines or of underlying liver disorders, and serum aminotransferase, alkaline phosphatase and total bilirubin are measured before the course in year 1 and in year 2. During treatment, liver enzymes and bilirubin are checked according to clinical signs and symptoms. If signs, unexplained enzyme elevations or symptoms of liver dysfunction appear (unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine), aminotransferases and total bilirubin are measured promptly, and Mavenclad is interrupted or stopped as appropriate. Use is not recommended in moderate or severe hepatic impairment.

Mavenclad: Blood Transfusions and Switching Treatments

• Patients who need a blood transfusion should receive irradiated cellular blood components, to prevent transfusion-related graft-versus-host disease; consulting a haematologist is advised.
• When switching from or to other immunomodulatory or immunosuppressive medicines, their mode of action and duration of effect are considered, as is a possible additive effect on the immune system.

Litak: Safety Points

• Litak is started by a qualified physician with experience in cancer chemotherapy.
• Myelosuppression (neutropenia, thrombocytopenia, anaemia), immunosuppression with lymphopenia, infections and fever are very common (see Side Effects). In elderly patients, blood counts and kidney and liver function are monitored carefully.
• Litak must not be used with other myelosuppressive medicinal products, and it is contraindicated in moderate to severe renal or hepatic impairment, in patients under 18 and in pregnancy and lactation.
• PML has been reported with parenteral cladribine in patients treated for hairy cell leukaemia with a different treatment regimen.
• The Litak SmPC contains further warnings in section 4.4 that should be read before use.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: based on experience with other substances that inhibit DNA synthesis, cladribine could cause congenital malformations if given during pregnancy, and animal studies have shown reproductive toxicity.
• Breastfeeding: limited case reports show that cladribine is excreted in human milk, in amounts not yet well established. Breastfeeding is contraindicated during Mavenclad treatment and for 1 week after the last dose, and Litak is contraindicated in lactation.
• Fertility: in mice there were no effects on fertility or on the reproductive function of offspring, but testicular effects were seen in mice and monkeys.

Sorbitol and Hydroxypropylbetadex

Each Mavenclad tablet contains 64 mg of sorbitol. The additive effect of other products containing sorbitol (or fructose) and of dietary sorbitol (or fructose) should be taken into account, and the sorbitol in the tablets may affect the bioavailability of other oral medicines taken at the same time. The hydroxypropylbetadex in the tablets can form complexes with other medicines (see Drug Interactions).

Effect on Driving

Mavenclad has no or negligible influence on the ability to drive and use machines. For Litak, see section 4.7 of its SmPC.

• Mavenclad tablets: keep in the original package to protect them from moisture. The tablets are uncoated and are swallowed immediately once removed from the blister. They are supplied in blisters sealed in a cardboard wallet inside a child-resistant outer carton, in packs of 1, 4, 5, 6, 7 or 8 tablets; not all pack sizes may be marketed.
• Litak solution for injection: store in a refrigerator at 2–8 °C and do not freeze. As a refrigerated product it is kept in the cold chain (2–8 °C) during transport and storage until use, and it is allowed to warm to room temperature before injection. For microbiological reasons it is used immediately after opening; if not, in-use storage times and conditions are the responsibility of the user.

• Mavenclad tablets: 4 years.
• Litak solution for injection: 4 years. From a microbiological point of view, unless opening rules out the risk of microbial contamination, the product should be used immediately; if it is not, in-use storage times and conditions are the responsibility of the user.

Prescription only (Rx). The two cladribine products have different conditions of supply.

• Mavenclad (multiple sclerosis): restricted medical prescription (Annex II B). Treatment is started and supervised by a physician experienced in the treatment of MS. The tablets are taken by the patient at home in short yearly courses, so they are supplied to the patient or the treating clinic on prescription. As a condition of supply, pregnancy must be ruled out in women of childbearing potential before each yearly course (year 1 and year 2), and the lymphocyte-count and infection-screening checks of the SmPC are completed before each course starts.
• Litak (hairy cell leukaemia): started by a qualified physician with experience in cancer chemotherapy. The patient can inject it after training, so it is supplied to the patient or the treating clinic on prescription, with cold-chain delivery at 2–8 °C.