Cladribine-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLYADIBIN-VISTA (CLADRIBINE-VISTA)

Composition:

active substance: cladrabine;

1 tablet contains 10 mg of cladrabine;

excipients: hydroxypropylbetadex, purified water, sorbitol (E 420), magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: round, biconvex tablets of white or almost white color, with imprint «751» on one side and smooth on the other side.

Pharmacotherapeutic group. Selective immunosuppressants. Cladrabine. ATC code L04A A40.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Cladribine is a nucleoside analogue of deoxyadenosine. Substitution with a chlorine atom in the purine ring protects cladribine from degradation by adenosine deaminase, thereby increasing the intracellular residence time of cladribine prodrugs. Subsequent phosphorylation of cladribine leads to the formation of its active form, 2-chlorodeoxyadenosine triphosphate (Cd-ATP). This process occurs particularly efficiently in lymphocytes due to their constitutively high levels of deoxycytidine kinase (DCK) and relatively low levels of 5'-nucleotidase (5'-NT). The high DCK to 5'-NT ratio promotes accumulation of Cd-ATP, rendering lymphocytes especially sensitive to cell death. Other bone marrow-derived cells are less affected due to their lower DCK/5'-NT ratio. DCK is the rate-limiting enzyme in the conversion of cladribine into its active triphosphate form, leading to selective depletion of both dividing and non-dividing T- and B-cells.

The primary mechanism of Cd-ATP-induced apoptosis involves direct and indirect effects on DNA synthesis and mitochondrial function. In dividing cells, Cd-ATP interferes with DNA synthesis by inhibiting ribonucleotide reductase and competes with deoxyadenosine triphosphate for incorporation into DNA by DNA polymerases. In resting cells, cladribine causes single-strand DNA breaks, rapid depletion of nicotinamide adenine dinucleotide, ATP breakdown, and cell death. Evidence suggests that cladribine may also induce direct, caspase-dependent and caspase-independent apoptosis by releasing cytochrome C and apoptosis-inducing factor into the cytosol of non-dividing cells.

The pathogenesis of multiple sclerosis (MS) involves a complex cascade of events in which various immune cells, including autoreactive T- and B-cells, play a critical role. The therapeutic mechanism of cladribine in MS is not fully elucidated, but it is believed that its primary effect on T- and B-lymphocytes interrupts the immune cascade central to MS pathophysiology.

Differential expression levels of DCK and 5'-NT among immune cell subtypes may explain the varying sensitivity of immune cells to cladribine. Due to these expression patterns, cells of the innate immune system are less affected than those of the adaptive immune system.

Pharmacodynamic Effects

Cladribine has been shown to exert a prolonged effect, primarily targeting lymphocytes and autoimmune processes involved in the pathophysiology of MS.

In clinical studies, the highest proportion of patients with grade 3 or 4 lymphopenia (defined as < 500 to 200 cells/mm³ or < 200 cells/mm³) occurred approximately 2 months after the first dose of cladribine each year, indicating a time lag between plasma presence of cladribine and maximal hematological effect.

Data from clinical trials using the proposed cumulative dose of 3.5 mg/kg body weight indicate a gradual recovery of median lymphocyte count to the normal range by week 84 after the first cladribine dose (approximately 30 weeks after the last dose). Lymphocyte counts returned to the normal range in over 75% of patients by week 144 after the first cladribine dose (approximately 90 weeks after the last dose).

Oral cladribine treatment leads to a rapid reduction in circulating CD4+ and CD8+ T-cells. The reduction in CD8+ T-cells is less pronounced and recovers more quickly than CD4+ T-cells, resulting in a temporary decrease in the CD4 to CD8 ratio. Cladribine reduces the number of CD19+ B-cells and CD16+/CD56+ natural killer cells, both of which also recover more rapidly than CD4+ T-cells.

Clinical Efficacy and Safety

Relapsing-Remitting Multiple Sclerosis

The efficacy and safety of oral cladribine were evaluated in a randomized, double-blind, placebo-controlled clinical trial (CLARITY) involving 1326 patients with relapsing-remitting multiple sclerosis. The primary objective of the study was to assess the efficacy of cladribine versus placebo in reducing the annualized relapse rate (ARR) (primary endpoint), slowing disability progression, and reducing MRI-active lesions.

Patients received either placebo (n = 437), or cumulative cladribine doses of 3.5 mg/kg (n = 433) or 5.25 mg/kg body weight (n = 456) over a 96-week (2-year) study period consisting of two treatment courses. Patients were randomized to receive a cumulative dose of 3.5 mg/kg during the first treatment course in weeks 1 and 5 of the first year and the second treatment course in weeks 1 and 5 of the second year. Patients were randomized to receive a cumulative dose of 5.25 mg/kg during an additional treatment period in weeks 9 and 13 of the first year. The majority of patients in the placebo group (87%), and in the cladribine treatment groups at 3.5 mg/kg (91.9%) and 5.25 mg/kg (89%), completed the full 96-week study period.

Patients were required to have experienced at least one relapse in the preceding 12 months. In the overall study population, the median age was 39 years (range 18 to 65 years), with a female-to-male ratio of approximately 2:1. The mean duration of MS prior to study entry was 8.7 years, and the median baseline neurological disability score, measured by the Expanded Disability Status Scale (EDSS) across all treatment groups, was 3.0 (range 0 to 6.0). Over two-thirds of patients had not received disease-modifying therapies for MS prior to the study. The remaining patients had previously been treated with beta-1a interferon, beta-1b interferon, glatiramer acetate, or natalizumab.

In patients with relapsing-remitting MS receiving cladribine at a dose of 3.5 mg/kg, statistically significant improvements were observed compared to placebo-treated patients in annualized relapse rate, proportion of patients without relapses over 96 weeks, proportion of patients without sustained disability progression over 96 weeks, and time to 3-month EDSS progression (see Table 1).

Table 1

Clinical Results from the CLARITY Study (96 Weeks)

Parameter	Placebo (n = 437)	Cumulative cladribine dose
		3.5 mg/kg (n = 433)	5.25 mg/kg (n = 456)
Annualized relapse rate (95 % CI)	0.33 (0.29; 0.38)	0.14* (0.12; 0.17)	0.15* (0.12; 0.17)
Relative reduction (cladribine vs placebo)		57.6 %	54.5 %
Proportion of patients relapse-free over 96 weeks	60.9 %	79.7 %	78.9 %
Time to 3-month EDSS progression, 10th percentile (months)	10.8	13.6	13.6
Hazard ratio (95 % CI)		0.67 (0.48; 0.93), p = 0.018	0.69 (0.49; 0.96), p = 0.026
CI – confidence interval. *p < 0.001 vs placebo.

The results of cladribine treatment at a dose of 3.5 mg/kg were statistically significantly superior to placebo regarding the number and relative reduction of T1 Gd+ lesions, active T2 lesions, and combined unique lesions on brain MRI scans over the full 96-week study period. Patients receiving cladribine, compared to the placebo group, showed a relative reduction of 86% in the mean number of T1 Gd+ lesions (adjusted mean number was 0.12 in the 3.5 mg/kg cladribine group versus 0.91 in the placebo group), a relative reduction of 73% in the mean number of active T2 lesions (adjusted mean number was 0.38 in the 3.5 mg/kg cladribine group versus 1.43 in the placebo group), and a relative reduction of 74% in the mean number of combined unique lesions per patient MRI scan (adjusted mean number was 0.43 in the 3.5 mg/kg cladribine group versus 1.72 in the placebo group) (p < 0.001 for all three MRI outcomes). A retrospective analysis of time to 6-month confirmed disability progression showed a 47% reduction in the risk of disability progression in the group receiving cladribine 3.5 mg/kg compared to placebo (hazard ratio 0.53; 95% CI [0.36; 0.79], p < 0.05). The 10th percentile for disability progression was reached at 245 days in the placebo group, whereas it was not reached during the entire study period in the 3.5 mg/kg cladribine group.

As shown in Table 1, higher cumulative doses of cladribine provided no clinically meaningful benefits but were associated with a higher incidence of grade ≥3 lymphopenia (44.9% in the 5.25 mg/kg group versus 25.6% in the 3.5 mg/kg group).

Patients who completed participation in the CLARITY study could be enrolled in the CLARITY Extension study, whose primary objective was safety assessment. In this extension study, 806 patients received either placebo or a cumulative dose of cladribine 3.5 mg/kg (using a regimen similar to that used in CLARITY) over 96 weeks.

The treatment effect on reducing relapse frequency and slowing disability progression in patients receiving the 3.5 mg/kg dose over 2 years was maintained during years 3 and 4.

Efficacy in patients with highly active disease

A retrospective analysis of efficacy was conducted in subgroups of patients with highly active disease who received oral cladribine at the recommended cumulative dose of 3.5 mg/kg. These subgroups included:

• patients with one relapse in the prior year and at least one T1 Gd+ lesion or nine or more T2 lesions while on other disease-modifying therapies;
• patients with two or more relapses in the prior year, regardless of whether they were on disease-modifying therapies or not.

Analysis of data from the CLARITY study showed a similar treatment effect on relapse rate, with the annualized relapse rate ranging from 0.16 to 0.18 in the cladribine groups and from 0.47 to 0.50 in the placebo group (p < 0.0001). Compared to the overall population, a greater treatment effect was observed on the time to 6-month confirmed disability progression, with cladribine reducing the risk of disability progression by 82% (hazard ratio 0.18; 95% CI [0.07; 0.47]). The 10th percentile for disability progression was reached between weeks 16 and 23 in the placebo group, whereas it was not reached during the entire study period in the cladribine groups.

Secondary progressive MS with relapses

An additional study of cladribine added to interferon beta versus placebo plus interferon beta also included a limited number of patients with secondary progressive MS (26 patients). In these patients, treatment with cladribine 3.5 mg/kg resulted in a reduced annualized relapse rate compared to placebo (0.03 versus 0.3; risk ratio: 0.11; p < 0.05). There was no difference in the annualized relapse rate between patients with relapsing-remitting MS and those with secondary progressive MS with relapses. No effect of cladribine on disability progression was demonstrated in either of these subgroups. Patients with secondary progressive MS were excluded from the CLARITY study. However, a retrospective analysis of pooled patient groups from the CLARITY and ONWARD studies, identified by a baseline EDSS score ≥ 3.5 as an indicator of secondary progressive MS, showed a similar reduction in the annualized relapse rate compared to patients with an EDSS score below 3.

Pharmacokinetics

Cladribine is a prodrug that must be phosphorylated intracellularly to become biologically active. The pharmacokinetics of cladribine have been studied after oral and intravenous administration in patients with MS and in patients with malignancies, as well as in in vitro systems.

Absorption

After oral administration, cladribine is rapidly absorbed. A 10 mg dose of cladribine results in a mean Cmax of cladribine in the range of 22 to 29 ng/mL and a corresponding mean AUC in the range of 80 to 101 ng ∙ h/mL.

Following oral administration on an empty stomach, the median Tmax was 0.5 hours (range 0.5 to 1.5 hours). When administered with a high-fat meal, absorption of cladribine was delayed (median Tmax was 1.5 hours, range 1 to 3 hours), and Cmax was reduced by 29%, while AUC remained unchanged. The bioavailability of a 10 mg oral dose of cladribine was approximately 40%.

Distribution

Cladribine has a large volume of distribution, indicating extensive tissue distribution and intracellular uptake. Studies have shown that the mean volume of distribution of cladribine ranges from 480 to 490 L. Plasma protein binding is 20% and independent of cladribine plasma concentration. Distribution of cladribine across biological membranes is mediated by various transporter proteins, including ENT1, CNT3, and BCRP.

In vitro studies have shown that efflux of cladribine is only minimally associated with P-glycoprotein (P-gp), so clinically significant interactions with P-gp inhibitors are not expected. In vitro studies indicated negligible transporter-mediated uptake of cladribine into human hepatocytes.

Cladribine has the potential to cross the blood-brain barrier. A small study in cancer patients showed that the ratio of its concentration in cerebrospinal fluid to plasma is approximately 0.25.

Cladribine and/or its phosphorylated metabolites substantially accumulate and are retained in human lymphocytes. In vitro, the intracellular-to-extracellular accumulation ratio was found to be approximately 30 to 40 within 1 hour of exposure.

Biotransformation

Metabolism of cladribine was studied in patients with MS after a single 10 mg tablet and a single intravenous dose of 3 mg. After both oral and intravenous administration, the parent compound cladribine was the main component detected in plasma and urine. The levels of its metabolite 2-chloroadenine in both plasma and urine were negligible. Only trace amounts of other metabolites of cladribine were detectable in plasma and urine.

In in vitro hepatic systems, metabolism of cladribine was insignificant (at least 90% remained as unchanged cladribine).

Cladribine is not a significant substrate for cytochrome P450 enzymes and does not show significant inhibitory potential against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Inhibition of these enzymes or genetic polymorphisms (e.g., CYP2D6, CYP2C9, or CYP2C19) are not expected to have a clinically significant effect on the pharmacokinetics or exposure of cladribine. Cladribine does not have a clinically significant inductive effect on CYP1A2, CYP2B6, or CYP3A4.

After entering target cells, cladribine is phosphorylated by DCK (and also by mitochondrial deoxyguanosine kinase) to cladribine monophosphate (Cd-AMP), then to cladribine diphosphate (Cd-ADP), and finally to cladribine triphosphate (Cd-ATP). Dephosphorylation and deactivation of Cd-AMP is catalyzed by cytoplasmic 5'-NTase. In an intracellular pharmacokinetic study of Cd-AMP and Cd-ATP in patients with chronic myelogenous leukemia, Cd-ATP levels were approximately half of Cd-AMP levels.

The intracellular half-life was 15 hours for Cd-AMP and 10 hours for Cd-ATP.

Elimination

Based on pooled population pharmacokinetic data collected from various studies, median values of elimination were 22.2 L/h for renal clearance and 23.4 L/h for non-renal clearance. Renal clearance exceeded the glomerular filtration rate, indicating active renal tubular secretion of cladribine. The non-renal component of cladribine elimination (approximately 50%) includes negligible hepatic metabolism and extensive intracellular distribution and uptake of the active cladribine derivative (Cd-ATP) into the target intracellular compartment (i.e., lymphocytes), followed by elimination of intracellular Cd-ATP according to the life cycle and elimination pathways of these cells. The estimated terminal half-life in a typical patient from the population used for pharmacokinetic parameter estimation is approximately 1 day. However, this does not result in any drug accumulation after daily dosing, as this half-life applies only to a small fraction of the AUC.

Dose and time dependence

After oral administration of cladribine at doses from 3 to 20 mg, Cmax and AUC increased in a dose-dependent manner, suggesting that absorption processes do not limit rate or capacity for oral doses up to 20 mg.

After repeated dosing, no significant accumulation of cladribine in plasma was observed. There is no indication that the pharmacokinetics of cladribine after repeated administration change over time.

Special patient groups

Pharmacokinetic evaluation of cladribine in elderly or pediatric MS patients, as well as in patients with renal or hepatic impairment, has not been conducted.

Population kinetic analysis showed no effect of age (range 18 to 65 years) or patient sex on the pharmacokinetics of cladribine.

Renal impairment

Renal clearance of cladribine has been shown to depend on creatinine clearance. Based on a population pharmacokinetic analysis including data from patients with normal renal function and mild renal impairment, total clearance of cladribine in patients with mild renal impairment (CLCR = 60 mL/min) is expected to be moderately reduced, resulting in a 25% increase in exposure.

Hepatic impairment

The role of hepatic function in the elimination of cladribine is considered negligible.

Pharmacokinetic interactions

Drug interaction studies in patients with MS showed that the bioavailability of 10 mg oral cladribine is not altered when co-administered with pantoprazole.

Clinical Characteristics

Indications

The medicinal product is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (MS) with highly active disease, established on the basis of clinical or imaging assessments.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• Human immunodeficiency virus (HIV) infection;
• Active chronic infections (tuberculosis or hepatitis);
• Initiating cladribine treatment in patients with weakened immunity, including patients receiving immunosuppressive or myelosuppressive therapy;
• Active malignancies;
• Moderate or severe renal impairment (creatinine clearance < 60 mL/min);
• Pregnancy and breastfeeding.

Interaction with other medicinal products and other forms of interaction

The medicinal product contains hydroxypropylbetadex, which may form complexes with other medicinal products, potentially leading to increased bioavailability of such agents (especially medicinal products with low solubility). Therefore, during the limited number of days of cladribine administration, it is recommended to take any oral medicinal products at least 3 hours before or after the administration of the medicinal product.

Immunosuppressive medicinal products

Initiating treatment with cladribine is contraindicated in patients with weakened immunity, including those undergoing immunosuppressive or myelosuppressive therapy (e.g., methotrexate, cyclophosphamide, cyclosporine, or azathioprine), or in those receiving long-term corticosteroid therapy, due to the risk of additive effects on the immune system. Short-term intensive systemic corticosteroid therapy may be prescribed during treatment with cladribine.

Other disease-modifying medicinal products

The use of cladribine together with beta-interferon increases the risk of lymphopenia. The safety and efficacy of cladribine in combination with other disease-modifying treatments for MS have not been established; therefore, such concomitant therapy is not recommended.

Hematotoxic medicinal products

Since cladribine induces a reduction in lymphocyte count, additional hematological adverse reactions may be expected when cladribine is administered before or concurrently with other agents affecting the hematological profile (such as carbamazepine). In such cases, careful monitoring of hematological parameters is recommended.

Live or live attenuated vaccines

Initiating treatment with cladribine should not be performed within 4–6 weeks after vaccination with live or live attenuated vaccines due to the risk of acute vaccine-related infection. During and after treatment with cladribine, vaccination with live or live attenuated vaccines should be avoided until the patient's lymphocyte count has returned to normal levels.

Strong inhibitors of ENT1, CNT3, and BCRP transporters

At the level of cladribine absorption, the only likely source of clinically relevant interactions is 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 that can alter the pharmacokinetics of BCRP substrates by 20% in vivo include eltrombopag.

In vitro studies indicate that cladribine is a substrate of equilibrative nucleoside (ENT1) and concentrative nucleoside (CNT3) transport proteins. Therefore, the bioavailability, intracellular distribution, and renal excretion of cladribine may theoretically be affected by strong inhibitors of ENT1, CNT3, and BCRP transporters, such as dipyridamole, nifedipine, nimodipine, cilostazol, sulindac, and reserpine. However, the net effect, expressed as a change in the potential activity of cladribine, is difficult to predict. Although the clinical significance of such interactions is unknown, concomitant administration of strong inhibitors of ENT1, CNT3, and BCRP should be avoided during the 4- or 5-day cladribine treatment period. If avoidance is not possible, consideration should be given to selecting alternative medicinal products for concomitant use that lack or have minimal inhibitory properties toward ENT1, CNT3, and BCRP transporters. If this is not feasible, it is recommended to reduce the dose of medicinal products containing such compounds to the minimum required dose, separate the administration times of the medicinal products, and closely monitor the patient.

Strong inducers of BCRP and P-gp transporters

The effect of strong inducers of efflux transporters BCRP and P-gp on the bioavailability and distribution of cladribine has not been studied in dedicated trials. When strong inducers of BCRP transporters (e.g., corticosteroids) or P-gp (e.g., rifampicin, St. John’s wort) are co-administered, a potential reduction in the efficacy of cladribine should be considered.

Hormonal contraceptives

No clinically relevant pharmacokinetic interaction with cladribine was observed when administered concomitantly with oral contraceptives (ethinylestradiol and levonorgestrel). Therefore, concomitant use with cladribine is not expected to reduce the efficacy of hormonal contraceptives (see section "Use during pregnancy or breastfeeding").

Special precautions for use

Hematological monitoring

The mechanism of action of cladribine is closely related to a reduction in lymphocyte count. The effect on lymphocyte count is dose-dependent. In clinical studies, reductions in neutrophil count, red blood cell count, hematocrit, hemoglobin, and platelet count were also observed compared to baseline values, although these parameters generally remained within normal ranges.

When cladribine is administered concomitantly with or prior to other agents affecting the hematological profile, additional adverse reactions may be expected.

Lymphocyte count should be determined:

• before initiation of treatment in year 1;
• before initiation of treatment in year 2;
• at 2 and 6 months after the start of treatment in each treatment year; if the lymphocyte count is below 500 cells/mm³, this parameter should be actively monitored until values increase again.

For information on treatment decisions based on lymphocyte count, see section "Dosage and method of administration" and subsection "Infections" below.

Infections

Cladribine may weaken the body's immune defenses, thereby increasing the risk of infections. Serious, severe, and opportunistic infections, including fatal cases, have been observed during cladribine treatment. HIV infection, active tuberculosis, and active hepatitis must be excluded prior to starting cladribine therapy (see section "Contraindications"). Latent infections, including tuberculosis or hepatitis, may be reactivated during treatment. Therefore, screening for latent infections, particularly tuberculosis and hepatitis B and C, should be performed before starting therapy in year 1 and year 2. Initiation of cladribine treatment should be delayed until infections have been adequately treated. In patients with acute infections, postponement of cladribine treatment initiation should also be considered until infections are fully controlled. Particular attention should be paid to patients without a history of varicella zoster virus exposure. Vaccination against varicella is recommended prior to starting cladribine therapy in seronegative patients. In such cases, initiation of cladribine should be delayed by 4–6 weeks to allow full vaccine effect. An increased incidence of herpes zoster has been reported in patients receiving cladribine. If lymphocyte count drops below 200 cells/mm³, consideration should be given to initiating antiviral prophylaxis against herpes according to local standard protocols during grade 4 lymphopenia. Patients with lymphocyte counts below 500 cells/mm³ should be actively monitored for signs and symptoms suggestive of infection, particularly herpes zoster. If such signs or symptoms occur, appropriate treatment for infection should be initiated based on clinical indications. Interruption or delay of cladribine treatment may be considered until the infection is adequately treated. Cases of progressive multifocal leukoencephalopathy (PML) have been reported with parenteral administration of cladribine in patients treated for hairy cell leukemia under different treatment regimens. Although PML has not been reported with oral cladribine tablets, a baseline MRI scan should be performed prior to starting oral cladribine tablets (typically within 3 months).

Malignancies

Malignancies were observed more frequently in patients receiving cladribine compared to those receiving placebo in clinical studies. The medicinal product is contraindicated in patients with MS who have active malignancies (see section "Contraindications"). For patients with prior malignancies, an individual benefit-risk assessment should be performed before initiating treatment. Patients receiving cladribine should be advised to follow standard cancer screening recommendations.

Liver function

Hepatic events, including serious cases, have been infrequently reported in patients treated with cladribine.

The patient's full medical history should be considered prior to prescribing the medicinal product, particularly prior episodes of drug-induced liver injury and existing liver disorders. Prior to starting treatment in year 1 and year 2, serum levels of aminotransferases, alkaline phosphatase, and total bilirubin should be determined. Liver enzymes and bilirubin should be monitored during treatment based on clinical signs and symptoms. If clinical signs develop, unexplained increases in liver enzymes occur, or symptoms suggestive of liver dysfunction (e.g., nausea, vomiting, abdominal pain, fatigue, unexplained anorexia, jaundice, and/or dark urine) are observed, serum transaminases and total bilirubin levels should be promptly assessed. Cladribine treatment should be interrupted or discontinued as necessary.

Contraception

Prior to starting treatment in year 1 and year 2, women of childbearing potential and men who may potentially father children should be informed of the potential serious risk to the fetus and the necessity of using effective contraceptive measures. Women of childbearing potential must avoid becoming pregnant by using effective contraception during treatment with cladribine and for at least 6 months after the last dose. Male patients must use contraception to prevent pregnancy in their female partner during treatment with cladribine and for at least 6 months after the last dose.

Blood transfusion

For patients requiring blood transfusion, irradiation of cellular blood components prior to administration is recommended to prevent transfusion-associated graft-versus-host disease. Consultation with a hematologist is recommended.

Transition to and from cladribine therapy

Prior to initiating treatment in patients previously treated with immunomodulatory or immunosuppressive agents, the mechanism of action and duration of effect of these medicinal products should be considered. The potential for additive effects on the immune system should also be considered if such agents are used after cladribine treatment. When switching from another medicinal product for the treatment of MS, a baseline MRI scan is recommended (see subsection "Infections" above).

Impaired liver function

Cladribine is not recommended for patients with moderate or severe hepatic impairment (>6 points according to Child-Pugh classification).

Important information on excipients

Sorbitol. The medicinal product contains sorbitol. Patients with known intolerance to certain sugars should consult their physician before starting this medicinal product. The additional impact of concomitantly administered medicinal products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be considered. The presence of sorbitol in oral medicinal products may affect the bioavailability of other concomitantly administered oral medicinal products.

Use during pregnancy or breastfeeding

Contraception in men and women

Prior to starting treatment in year 1 and year 2, women of childbearing potential and men who may potentially father children should be informed of the potential serious risk to the fetus and the necessity of using effective contraceptive measures.

In women of childbearing potential, pregnancy must be excluded prior to starting cladribine treatment in years 1 and 2, and effective contraception must be used during treatment with cladribine and for at least 6 months after the last dose. Women who become pregnant during cladribine treatment should discontinue therapy. Since cladribine affects DNA synthesis, a negative impact on human gametogenesis should be expected. Therefore, male patients must use contraception to prevent pregnancy in their female partner during treatment with cladribine and for at least 6 months after the last dose.

Pregnancy

Based on experience with other agents that inhibit DNA synthesis in humans, cladribine may cause fetal malformations if administered during pregnancy. Reproductive toxicity of cladribine has been demonstrated in animal studies. The medicinal product is contraindicated in pregnant women (see section "Contraindications").

Breastfeeding

Limited case reports indicate that cladribine is excreted into breast milk following oral administration. Due to the potential for serious adverse reactions in breastfed infants, breastfeeding is contraindicated during treatment with cladribine and for one week after the last dose (see section "Contraindications").

Fertility

No effects of cladribine on fertility or reproductive function of offspring were observed in mice; however, effects on testicular function were observed in mice and monkeys. Since cladribine affects DNA synthesis, a negative impact on human gametogenesis should be expected. Therefore, male patients must use contraception to prevent pregnancy in their female partner during treatment with cladribine and for at least 6 months after the last dose.

Ability to affect reaction speed when driving or operating machinery

The medicinal product has no or negligible influence on the ability of patients to drive or operate machinery.

Method of Administration and Dosage

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

Dosage

The recommended cumulative dose of the medicinal product is 3.5 mg/kg body weight over 2 years, administered as a single treatment course of 1.75 mg/kg annually. Each treatment course consists of two treatment weeks: one at the beginning of the first month and another at the beginning of the second month of the respective treatment year. For medical reasons (e.g., to allow recovery of lymphocyte counts), the treatment course in Year 2 may be delayed by up to 6 months. Each treatment week consists of 4 or 5 days during which the patient takes 10 or 20 mg (one or two tablets) as a single daily dose, depending on body weight. Further detailed information is provided in Tables 2 and 3. After completion of the two treatment courses, further cladribine treatment in Years 3 and 4 is not required. Reinitiation of treatment after 4 years has not been studied.

Criteria for Initiation and Continuation of Therapy

Lymphocyte count must be:

• normal before starting treatment in Year 1;
• at least 800 cells/mm³ before starting treatment in Year 2.

If necessary, to allow recovery of lymphocyte counts, the treatment course in Year 2 may be postponed for up to 6 months. If recovery takes longer than 6 months, the patient must not receive further cladribine treatment.

Dose Distribution

The distribution of the total dose over the 2 years of treatment is shown in Table 2. For some patients, depending on body weight, the number of tablets may differ between the first and second treatment weeks. The use of oral cladribine in patients with body weight below 40 kg has not been studied.

Table 2

Cladribine dose according to patient body weight during each treatment week of each treatment year

Body weight range, kg	Dose in milligrams (number of 10 mg tablets) in the treatment week
	Week 1 of treatment	Week 2 of treatment
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 3 shows how to distribute the total number of tablets per treatment week across individual days. It is recommended that each daily dose of cladribine in each treatment week be administered at 24-hour intervals, approximately at the same time of day. If the daily dose consists of two tablets, both tablets should be taken together as a single dose.

Table 3

Distribution of tablets by days of the week

Total number of tablets per week	Day 1	Day 2	Day 3	Day 4	Day 5
4	1	1	1	1	0
5	1	1	1	1	1
6	2	1	1	1	1
7	2	2	1	1	1
8	2	2	2	1	1
9	2	2	2	2	1
10	2	2	2	2	2

A missed dose should be taken as soon as possible on the same day after realizing the omission, according to the treatment schedule.

A missed dose must not be taken together with the next scheduled dose on the following day. If a dose is missed, the patient should take it the next day and extend the number of treatment days by one day within that treatment week. If two consecutive doses are missed, the same approach should be applied, and the number of days in the treatment week should be extended by two days.

Concomitant use of other oral medicinal products

Due to the limited number of days during which cladribine is administered, it is recommended to separate the administration of any other oral medicinal products from cladribine by at least 3 hours.

Special patient groups

Patients with renal impairment

Specific studies on the treatment of patients with renal impairment have not been conducted. For patients with mild renal impairment (CLCR = 60–89 mL/min), dose adjustment is not required.

The safety and efficacy of cladribine in patients with moderate or severe renal impairment have not been studied. Therefore, cladribine is contraindicated in such patients (see section "Contraindications").

Patients with hepatic impairment

Studies on the treatment of patients with hepatic impairment have not been conducted. Dose adjustment is not required in patients with mild hepatic impairment, as the role of liver function in the elimination of cladribine is considered to be negligible. Due to the lack of data, the use of cladribine is not recommended in patients with moderate or severe hepatic impairment (>6 points according to Child–Pugh classification).

Elderly patients

Cladribine should be used with caution in elderly patients, taking into account the potentially higher incidence of impaired hepatic or renal function, concomitant diseases, and other therapies being administered.

Method of administration

The medicinal product is intended for oral use. Tablets should be taken with water and swallowed whole, without chewing. Tablets may be taken independently of food intake. Since the tablets are not coated, they should be swallowed immediately after removal from the blister, not left on any surface, and not held in the hands longer than necessary for dosing. If a tablet has been left on a surface or if a broken or crushed tablet has been removed from the blister, the contact surface should be thoroughly washed with water. The patient should handle the tablets with dry hands, and hands should be thoroughly washed afterward.

Instructions for self-administration of the medicinal product tablets by the patient

1. Prepare a glass of water and ensure your hands are dry and clean.

2. Take the medicinal product box and turn it so that the side with printed instructions faces you.

3. (1) Open the flap on the left side of the box.

(2) Simultaneously press the clips on both sides of the box with your index finger and thumb, and hold them in this position.

(3) Pull out the push-through foil packaging until it moves.

WARNING: Do not remove the push-through foil packaging from the box.

1. Remove the package leaflet from the box. Ensure you have carefully read its contents, including the instructions for self-administration of the tablets.

2. Lift the blister by pressing your fingers through the opening in the push-through foil packaging. Place your hand under the blister and push 1 or 2 tablets into your hand, as prescribed by your doctor.

3. Take the tablets with water. Tablets must be swallowed whole, without chewing or allowing them to dissolve in the mouth. Contact of the tablets with the skin should be minimized. During tablet administration, avoid touching the nose, eyes, or other body parts with your hands.

4. After taking the tablets, thoroughly wash your hands with soap and water.

5. Return the push-through foil packaging to the box. Store it in the original packaging to protect from moisture.

Keep tablets in the blister until the time of the next dose. Do not push tablets out of the blister or store them in another container.

Children

For pediatric patients (under 18 years of age), the safety and efficacy of the medicinal product have not been established. Appropriate data are lacking.

Overdose

Symptoms.

There is limited experience with cladribine overdose following oral administration. It is known that lymphopenia, which develops as a result, is dose-dependent.

Treatment.

In patients with cladribine overdose, particularly careful monitoring of hematological parameters is recommended. There is no specific antidote for cladribine. Management consists of careful observation of the patient and implementation of appropriate supportive measures. Consideration should be given to the need to discontinue the medicinal product. Due to the rapid and extensive intracellular and tissue distribution, it is unlikely that hemodialysis will significantly eliminate cladribine.

Adverse reactions

Brief description of the safety profile

The most clinically significant adverse reactions are lymphopenia (25.6%) and herpes zoster (3%). The incidence of herpes zoster was higher during periods when lymphopenia grade 3 or 4 (from < 500 to 200 cells/mm³ or < 200 cells/mm³) was observed, compared to periods when patients did not have grade 3 or 4 lymphopenia.

List of adverse reactions

The information on adverse reactions described below is based on pooled data from clinical studies of oral cladribine treatment for MS, administered as monotherapy at a cumulative dose of 3.5 mg/kg. The safety database of these studies includes data from 923 patients. Adverse reactions identified during the post-marketing surveillance period are marked with an asterisk (*).

The following classification is used to define the frequency of adverse reactions: 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), frequency not known (cannot be estimated from the available data).

Infections and infestations

Common: oral herpes, herpes zoster.

Rare: tuberculosis.

Blood and lymphatic system disorders

Very common: lymphopenia.

Common: decreased neutrophil count.

Immune system disorders

Common: hypersensitivity reactions*, including pruritus, urticaria, rash, and isolated cases of angioedema.

Hepatobiliary disorders

Uncommon: liver injury*.

Skin and subcutaneous tissue disorders

Common: rash, alopecia.

Description of selected adverse reactions

Lymphopenia

In clinical studies, transient grade 3 or 4 lymphopenia developed in 20–25% of patients receiving a cumulative dose of cladribine 3.5 mg/kg over 2 years as monotherapy. Grade 4 lymphopenia was observed in less than 1% of patients. The highest proportion of patients with grade 3 or 4 lymphopenia was observed 2 months after administration of the first dose of cladribine each year (4% and 11.3% of patients with grade 3 lymphopenia in Year 1 and Year 2, respectively, and 0.4% of patients with grade 4 lymphopenia in Year 1 and Year 2). In most patients, lymphocyte counts are expected to recover to normal levels or grade 1 lymphopenia within 9 months.

To reduce the risk of severe lymphopenia, lymphocyte counts should be monitored before, during, and after treatment with cladribine, and strict criteria for initiating and continuing cladribine treatment should be followed.

Malignant neoplasms

In clinical studies and during long-term follow-up, malignant neoplasms occurred more frequently in patients treated with oral cladribine at a cumulative dose of 3.5 mg/kg (10 cases in 3414 patient-years [0.29 cases per 100 patient-years]) compared to placebo-treated patients (3 cases in 2022 patient-years [0.15 cases per 100 patient-years]).

Hypersensitivity

In clinical studies, hypersensitivity reactions occurred more frequently in patients receiving oral cladribine at a cumulative dose of 3.5 mg/kg (11.8%) compared to placebo-treated patients (8.4%). Serious hypersensitivity reactions were observed in 0.3% of cladribine-treated patients and were not observed in placebo-treated patients. Hypersensitivity reactions led to discontinuation of treatment in 0.4% of cladribine-treated patients and in 0.3% of placebo-treated patients.

Liver injury

During post-marketing surveillance, uncommon cases of liver injury, including serious cases and cases leading to treatment discontinuation, temporally associated with the use of the medicinal product have been reported. Transient increases in serum transaminase levels typically exceeded the upper limit of normal (ULN) by more than 5 times. Isolated cases of transient increases in serum transaminase levels up to 40 times above ULN and/or symptomatic hepatitis with transient increases in bilirubin and jaundice have been observed. These events occurred at various time intervals after initiation of treatment, but most cases were observed within 8 weeks after the first treatment course (see section "Dosage and administration").

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store in the original packaging to protect from moisture. Keep out of reach of children.

Packaging

1 tablet in a blister, 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Haupt Pharma Amareg GmbH.

Manufacturer's address and location of operations

Donaustraße 378, Schwabelweis, Regensburg, Bavaria, 93055, Germany.