Mavenclad
Malignancies: Treatment with cladribine may increase the risk of malignancy. Cladribine is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks on an individual basis. Follow standard cancer screening guidelines for patients receiving cladribine.
Risk of teratogenicity: Cladribine is contraindicated for use in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception during cladribine dosing and for at least 6 months after the last dose in each treatment course because of the potential for fetal harm. Malformations and embryolethality occurred in animal reproduction studies. Stop cladribine if the patient becomes pregnant.
Indications
Cladribine is an oral, short-course immune reconstitution therapy approved for the treatment of relapsing forms of multiple sclerosis. It is a synthetic deoxyadenosine analog whose chlorination at the 2-position renders it resistant to deamination by adenosine deaminase, allowing intracellular accumulation as cytotoxic phosphorylated metabolites. These metabolites preferentially deplete dividing and resting lymphocytes — particularly memory B cells and certain T-cell subsets — that drive multiple sclerosis pathology, while sparing innate immunity and most non-lymphoid tissues. The result is a sustained reduction in adaptive immune cell trafficking to the central nervous system after only ~20 dosing days spread across two years, which produces durable disease control without continuous dosing. This pulsed treatment paradigm is referred to as immune reconstitution therapy (IRT). The parenteral formulation (Leustatin) was originally approved in 1993 for hairy cell leukemia and is a separate product from Mavenclad tablets.
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Relapsing forms of multiple sclerosis (RMS) — including relapsing-remitting MS (RRMS) and active secondary progressive disease (active SPMS) | Adults (FDA, EMA) | Monotherapy; second-line per FDA — generally for patients with inadequate response to or intolerance of an alternate MS DMT | FDA & EMA Approved |
Per FDA labelling, cladribine is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS. Cladribine is not recommended for clinically isolated syndrome (CIS) because of its safety profile — although the ORACLE-MS trial demonstrated significant reduction in conversion to clinically definite MS in patients with a first demyelinating event, the FDA did not approve a CIS indication. Cladribine is also not approved for paediatric MS (under 18 years) by either the FDA or EMA, and it is not indicated for primary progressive MS or non-active secondary progressive disease.
Clinically isolated syndrome (CIS) — the ORACLE-MS phase 3 trial demonstrated a significant reduction in conversion to clinically definite MS in patients with a first clinical demyelinating event. Evidence quality: moderate. The FDA explicitly excludes CIS from the approved labelling because of the safety profile; under modern McDonald 2017 criteria, however, many such patients now meet criteria for relapsing MS at presentation and may qualify for the on-label indication.
Highly active or aggressive MS as a first-line agent — supported by international guidelines and real-world cohorts in jurisdictions where regulators have permitted broader use; in the US, this is off-label.
Off-label use should follow shared decision-making and ideally be coordinated through neuroimmunology specialists.
Dosing
Cladribine is given as two short oral courses one year apart, after which no further cladribine should be administered for at least two more years. The cumulative dose is 3.5 mg/kg of body weight, delivered as two yearly treatment courses of 1.75 mg/kg each. Each yearly course is split into two cycles approximately one month apart. Within each cycle, the patient takes one or two 10 mg tablets once daily for 4 or 5 consecutive days, with no more than two tablets per day. The total active dosing footprint over the two years is therefore a maximum of approximately 20 days of tablet-taking. This pulsed schedule produces sustained lymphocyte depletion despite the drug’s rapid plasma clearance (terminal half-life ~24 h), because cytotoxic phosphorylated metabolites are retained intracellularly within lymphocytes for far longer.
| Course / Cycle | Timing | Dose Per Cycle | Daily Schedule | Notes |
|---|---|---|---|---|
| First Course / First Cycle | Start any time after pre-treatment workup is complete | 1.75 mg/kg ÷ 2 = 0.875 mg/kg, given as 10 mg tablets rounded by weight | 1 or 2 tablets once daily for 4–5 consecutive days (max 2 tablets/day) | Verify lymphocyte count is within normal range before this cycle Repeat HIV, hepatitis B/C, TB and pregnancy screening before each course |
| First Course / Second Cycle | 23–27 days after the last dose of First Course / First Cycle | 0.875 mg/kg | 1 or 2 tablets once daily for 4–5 consecutive days (max 2 tablets/day) | If a dose is missed, take it on the next day; if 2 consecutive doses are missed, extend the cycle by 2 days. Do not double doses |
| Second Course / First Cycle | At least 43 weeks after the last dose of First Course / Second Cycle | 0.875 mg/kg | 1 or 2 tablets once daily for 4–5 consecutive days (max 2 tablets/day) | Verify absolute lymphocyte count (ALC) ≥800 cells/µL before this cycle. If <800, delay until recovery (up to 6 months) |
| Second Course / Second Cycle | 23–27 days after the last dose of Second Course / First Cycle | 0.875 mg/kg | 1 or 2 tablets once daily for 4–5 consecutive days (max 2 tablets/day) | This completes the cumulative 3.5 mg/kg total dose over two years |
| After Year 2 | Years 3 and 4: do not administer additional cladribine | — | — | Re-treatment within 2 years was associated with a malignancy rate of 0.91 events/100 patient-years (vs 0.27/100 PY for the standard 2-course schedule). Beyond Year 4, the risk and necessity of additional courses have not been established |
Weight-Based Tablet Distribution per Cycle
Each cycle dose (0.875 mg/kg, rounded to whole 10 mg tablets) is divided across 4 or 5 consecutive days. Patients weighing 40 to less than 50 kg receive 4 tablets per cycle (4 days × 1 tablet); 50 to less than 60 kg, 5 tablets (5 days × 1 tablet); 60 to less than 70 kg, 6 tablets (5 days, with one day of 2 tablets); 70 to less than 80 kg, 7 tablets; 80 to less than 90 kg, 8 tablets; 90 to less than 100 kg, 9 tablets; 100 to 110 kg, 10 tablets; and so on, never exceeding 2 tablets in a single day. Patients weighing <40 kg are not included in the FDA labelling table; consult the full prescribing information for individual cases. Tablets must be swallowed whole with water on dosing days, with or without food, and any other oral medication should be separated from cladribine by at least 3 hours to avoid bioavailability interactions.
Special Populations
- Mild renal impairment (CrCl 60–89 mL/min): no dose adjustment. Population PK estimates a ~25% increase in exposure at CrCl 65 mL/min, judged not clinically significant.
- Moderate–severe renal impairment (CrCl <60 mL/min): contraindicated. Limited clinical experience and risk of accumulation with cytotoxic exposure.
- Mild–moderate hepatic impairment (Child-Pugh A or B; score ≤6): no specific dose recommendation. Use with caution.
- Severe hepatic impairment (Child-Pugh score >6): contraindicated.
- Elderly (≥65 years): not specifically studied; clinical trials enrolled patients aged 18–66. Use with closer monitoring of renal function and infection risk.
- Pregnancy: contraindicated (boxed warning). Confirm a negative pregnancy test before each cycle. Effective contraception is required during dosing and for at least 6 months after the last dose of each yearly course in females of reproductive potential and male partners.
- Lactation: contraindicated during dosing days and for 10 days after the last dose. Cladribine is excreted in animal milk and the high cellular accumulation creates unacceptable infant risk.
- Paediatric patients (<18 years): not established and not approved by FDA or EMA.
- Vaccination of seronegative patients: vaccinate against varicella zoster virus prior to treatment if antibody-negative. Recombinant adjuvanted zoster vaccine (Shingrix) is recommended for VZV-seropositive patients before or during therapy.
Cladribine is among the few MS therapies in which the patient is not actively dosed at the time of clinical effect. The ~20 days of tablets across two years selectively deplete proliferating and memory lymphocytes, after which immune reconstitution proceeds in a way that appears to durably reset autoreactive immunity. CLARITY Extension data showed that most patients who received two courses then received placebo in years 3 and 4 maintained efficacy without further dosing. Re-treatment in years 3–4 increases malignancy risk substantially (0.91 vs 0.27 events/100 patient-years), so additional cladribine should not be given until at least 2 years after the second course is completed; data on later re-treatment beyond year 4 remain limited and should be specialist-led.
Pharmacology
Mechanism of Action
Cladribine (2-chloro-2′-deoxyadenosine) is a synthetic purine nucleoside analog of deoxyadenosine. The 2-chloro substitution renders the molecule resistant to deamination by adenosine deaminase, the enzyme that normally inactivates deoxyadenosine. Cladribine enters cells through equilibrative and concentrative nucleoside transporters (ENT1, CNT3) and is then phosphorylated, primarily by deoxycytidine kinase, into the mononucleotide cladribine monophosphate (Cd-AMP) and ultimately to the active triphosphate (Cd-ATP). Lymphocytes have a particularly high ratio of deoxycytidine kinase (which activates the drug) to 5′-nucleotidase (which deactivates it), so they accumulate active cladribine metabolites at intracellular concentrations roughly 30 to 40 times those measured extracellularly. Cells with lower kinase-to-nucleotidase ratios — most non-lymphoid cells — remain relatively unaffected.
Once incorporated, Cd-ATP disrupts DNA synthesis and repair, producing single-strand DNA breaks, depleting nicotinamide adenine dinucleotide (NAD), and triggering apoptosis. The result is a selective, dose-dependent reduction in B and T lymphocytes, with B-cell counts falling earliest and most steeply and CD4 and CD8 T-cell subsets falling more slowly. Innate immune compartments (neutrophils, monocytes, NK cells) are largely spared. Lymphocyte nadirs occur approximately 2 to 3 months after the start of each treatment cycle and are deeper after the second cycle of each course; median time to recovery to absolute lymphocyte count ≥800 cells/µL is approximately 28 weeks (about 6.5 months). The clinical consequence in MS is a sustained reduction in disease activity (annualised relapse rate, MRI lesion accrual, confirmed disability progression) that persists well beyond the period of active dosing.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral bioavailability approximately 40%; rapid absorption with median Tmax 0.5 h (range 0.5–1.5 h) under fasted conditions. With a high-fat meal, Tmax is delayed to ~1.5 h and Cmax is reduced by ~29%; AUC is essentially unchanged. Pharmacokinetics are linear across the 3–20 mg dose range | Tablets may be taken with or without food. Other oral medications should be separated by at least 3 hours from cladribine to avoid potential transporter-mediated bioavailability interactions |
| Distribution | Apparent volume of distribution 480–490 L (large); plasma protein binding 20%, independent of concentration. Cladribine accumulates approximately 30–40-fold inside lymphocytes. CSF-to-plasma concentration ratio approximately 0.25 | The wide tissue distribution and high lymphocyte concentration ratio explain how short oral courses produce prolonged immunological effect, and why standard plasma assays do not reflect intracellular drug exposure |
| Metabolism | Cytochrome P450-mediated metabolism is minor and not clinically significant. Whole blood and intracellular metabolism dominate: deoxycytidine kinase phosphorylates cladribine to Cd-AMP, then to Cd-ADP and Cd-ATP. Intracellular half-lives are 15 h for Cd-AMP and 10 h for Cd-ATP | Few CYP-based drug interactions. The most clinically relevant interactions occur at the level of nucleoside transporters (ENT, CNT) and BCRP, which mediate cellular uptake and bioavailability |
| Elimination | Estimated terminal plasma half-life approximately 24 hours (~1 day); cladribine is essentially cleared from the body within ~1 week. Approximately 50% of cladribine is excreted unchanged renally and approximately 50% is eliminated through non-renal routes (intracellular sequestration and metabolism). Median apparent renal clearance is ~22.2 L/h. Renal clearance correlates with creatinine clearance: a typical patient at CrCl 65 mL/min has ~25% increased exposure | Despite the very short plasma half-life, the pharmacodynamic effect (lymphocyte depletion) lasts many months because intracellular Cd-ATP and downstream DNA damage outlast plasma drug exposure. Renal impairment beyond mild requires avoidance because of unpredictable accumulation in a cytotoxic agent |
The dramatic divergence between cladribine’s plasma half-life (~1 day) and its clinical duration of action (years) is one of the most distinctive features of its pharmacology and the basis for the immune reconstitution therapy concept.
Side Effects
The safety profile of cladribine is characterised primarily by lymphopenia and its downstream consequences (infections, particularly herpes zoster), modest haematological effects, hypersensitivity reactions, a numerical imbalance in malignancies relative to placebo, and an overall low rate of acute adverse effects given the cytotoxic mechanism. Frequencies below are drawn from FDA prescribing information Table 2 (CLARITY pivotal trial; cladribine 3.5 mg/kg, n=433 vs placebo, n=437), the EMA Summary of Product Characteristics, the long-term Monotherapy Oral cohort (923 cladribine 3.5 mg/kg vs 641 placebo over up to 8 years of follow-up), and post-marketing data through 2024.
| Adverse Effect | Cladribine 3.5 mg/kg vs Placebo | Clinical Note |
|---|---|---|
| Upper respiratory tract infection | 38% vs 32% | Mostly viral and self-limited. Encourage seasonal vaccination (inactivated/recombinant) before therapy and during therapy |
| Headache | 25% vs 19% | Usually mild; standard analgesics and reassurance are typically sufficient. Background MS-related and population rates are also high |
| Lymphopenia (reported as a clinical adverse reaction) | 24% vs 2% | This is the proportion reported as a clinical AE in CLARITY. As a laboratory finding, lymphopenia of any grade was observed in 87% of cladribine-treated patients (see lymphopenia detail below) |
| Hypersensitivity reactions (any grade) | 11% vs 7% | Mostly mild dermatitis and pruritus; serious or discontinuation-causing hypersensitivity occurred in 0.5% (vs 0.1%). Serious cases included rash with mucous membrane ulceration and throat swelling after the first dose |
| Mild platelet count decrease (75,000 cells/µL to <LLN; lab finding) | 11% vs 4% | Generally mild. Severe thrombocytopenia is rare at the approved dose and was reported mainly with higher cumulative doses outside the MS programme |
Lymphopenia is intrinsic to cladribine’s mechanism, not an off-target adverse event. 87% of MAVENCLAD-treated patients experienced lymphopenia of any grade in clinical studies. Of these, 73% were Grade 1–2, 26% were Grade 3 (ALC <500 cells/µL), and 1% were Grade 4 (ALC <200 cells/µL). The lymphocyte nadir occurs approximately 2–3 months after the start of each cycle and is deeper after the second cycle of each yearly course. 2% of patients still had ALC <500 cells/µL at the end of the second treatment course. Median time to recovery from ALC <500 to at least 800 cells/µL is approximately 28 weeks. The incidence of severe lymphopenia is higher in patients pre-treated with other MS DMTs (32.1%) than in DMT-naïve patients (23.8%). Anti-herpes prophylaxis is required when ALC falls below 200 cells/µL, and the second yearly course must be deferred until ALC has recovered to at least 800 cells/µL.
| Adverse Effect | Cladribine 3.5 mg/kg vs Placebo | Clinical Note |
|---|---|---|
| Oral herpes | 2.6% vs 1.2% | Generally mild and amenable to standard antiviral therapy. Counsel patients to report cold sores or genital lesions early |
| Herpes zoster (CLARITY 96-week incidence) | 2.0% vs 0.2% | All cases dermatomal; no cases of disseminated zoster attributable to cladribine. Long-term incidence in the integrated cohort 0.83 events/100 patient-years vs 0.20 with placebo. Recombinant zoster vaccine (Shingrix) recommended pre-treatment |
| Alopecia | 3% vs 1% | Usually mild and reversible. Counsel patients before initiation as cosmetic concern can affect adherence to second course |
| Other adverse reactions reported with incidence ≥5% and higher than placebo (FDA PI Table 2) | Varies | Includes nausea, back pain, arthralgia, depression, cough, neutropenia (lab finding) and decreased haemoglobin per integrated PI/Mayo Clinic and pharmacy summaries — refer to current prescribing information for full table |
| Decrease in haemoglobin (lab finding, mild) | Common (1–10%) | Usually mild and asymptomatic. Severe anaemia is rare at the approved dose |
| Neutropenia (lab finding, mild) | Common (1–10%) | Usually mild. Serious neutropenia/pancytopenia was observed mainly at doses higher than the MS-approved schedule (oncology programme) |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Malignancies (boxed warning) | CLARITY: 1.4% (cladribine 3.5 mg/kg) vs 0% placebo (3 cancers: melanoma, pancreatic, ovarian). Long-term integrated cohort: 0.27/100 PY vs 0.13/100 PY for placebo (numerical imbalance, not statistically significant). Re-treatment in years 3–4: 0.91/100 PY | Variable; including post-treatment surveillance | Contraindicated in current malignancy. Follow standard age-and-sex appropriate cancer screening before treatment and on follow-up. Do not re-treat in years 3–4. Beyond year 4, individualise the decision |
| Embryofetal toxicity (boxed warning) | Class effect based on animal data; no human gestational data adequate for direct estimation | First-trimester exposure of greatest concern; 6-month tail after each course | Discontinue immediately if pregnancy occurs. Use effective contraception during dosing and for 6 months after the last dose of each yearly course. Report exposed pregnancies to the manufacturer’s pregnancy programme |
| Severe lymphopenia (Grade 4, ALC <200 cells/µL) | ~1% of treated patients | Nadir 2–3 months after each cycle | Initiate anti-herpes prophylaxis (e.g., aciclovir/valaciclovir) when ALC <200 cells/µL. Defer next cycle until ALC ≥800. Investigate and treat any concurrent infection |
| Serious infections — bacterial (including TB), viral, fungal, opportunistic | CLARITY serious infections 2.3% vs 1.6% placebo. TB: 3/1,976 (0.2%) cladribine-treated patients in the clinical programme; all in TB-endemic regions, one fatal. One fatal fulminant hepatitis B reported. Post-marketing serious infections: nocardiosis, varicella zoster, histoplasmosis, cryptococcosis, toxoplasmosis | Highest risk during periods of severe lymphopenia | Screen for TB, HBV, HCV, HIV before each course. Defer treatment if active infection. Investigate and treat new infections promptly; consider antimicrobial prophylaxis when ALC falls below thresholds |
| Hepatitis B / C reactivation | Rare; 1 fatal HBV case in the clinical programme | Variable | Screen before each course. In carriers, coordinate with hepatology for antiviral prophylaxis before initiating cladribine |
| Severe haematological toxicity (thrombocytopenia, neutropenia, pancytopenia) | Rare at MS-approved dose; reported mainly at higher cumulative doses (oncology programme) | Variable; requires CBC monitoring | Hold further dosing; involve haematology. Severe pancytopenia has required transfusion and G-CSF in oncology settings |
| Serious hypersensitivity | 0.5% cladribine vs 0.1% placebo (serious or led to discontinuation) | Within hours to days of dosing | Discontinue permanently. Manage acutely with antihistamines, corticosteroids, and adrenaline as indicated |
| Liver injury (serious or led to discontinuation) | 0.3% cladribine vs 0% placebo | Variable | Investigate and discontinue if significant injury attributable to cladribine. Routine baseline and on-treatment LFTs are required |
| Acute cardiac failure with myocarditis | 1 case in MS clinical studies (improved after ~1 week); also reported with parenteral cladribine in non-MS indications | Acute | Counsel patients to seek urgent care for new dyspnoea, palpitations, irregular heartbeat, or unexplained oedema |
| Serious seizures | 0.3% cladribine vs 0% placebo (CLARITY) | Variable | Investigate and manage as clinically indicated; coordinate with neurology |
| Progressive multifocal leukoencephalopathy (PML) | No cases observed in MS patients on Mavenclad to date. Cases have been reported with parenteral cladribine for oncologic indications in the post-marketing setting | N/A in MS programme | Maintain vigilance for new neurological signs/symptoms. Investigate with brain MRI and CSF JCV PCR if PML is suspected; discontinue cladribine |
| Transfusion-associated graft-versus-host disease (rare) | Rare; reported with non-irradiated blood products in patients with severe lymphopenia from cladribine | Days to weeks after transfusion | Use only irradiated cellular blood products in patients who require transfusion during periods of severe lymphopenia |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Lymphopenia / persistent ALC <800 cells/µL preventing second course | ~2% with persistent ALC <500 at end of year 2 | Per labelling, second course must be deferred until ALC ≥800. Persistent severe lymphopenia may preclude completion of the regimen |
| Hypersensitivity | 0.4% cladribine vs 0.3% placebo (EMA SmPC) | Serious dermatitis, pruritus, rash with mucous membrane ulceration. Permanent discontinuation required |
| Serious infection | ~1–2% over 96 weeks | TB, hepatitis reactivation, opportunistic infection — generally requires withholding rather than stopping if recoverable, but completion of further courses may be reconsidered |
| Pregnancy or pregnancy planning during the regimen | Variable | Confirmed or planned pregnancy mandates discontinuation. Effective contraception must continue for 6 months after the last dose of each course |
| Patient choice / ongoing breakthrough disease activity | ~1–3% | Breakthrough disease activity may prompt switch to a higher-efficacy continuous-dosing DMT (e.g., natalizumab, anti-CD20 therapy) |
Drug Interactions
Cladribine has minimal CYP-mediated metabolism, so it is rarely a victim of CYP-based interactions. The clinically important interactions occur at three levels: (1) additive immune or marrow suppression with other immunosuppressants and haematotoxic drugs; (2) impaired intracellular activation of cladribine by competing antiviral nucleoside analogs; and (3) altered absorption and disposition by inhibitors of nucleoside transporters (ENT1, CNT3) and BCRP. Live vaccines must be avoided during therapy and until lymphocyte counts have recovered.
Monitoring
Monitoring is structured around the boxed warnings (malignancies and teratogenicity), the predictable course of lymphocyte depletion and recovery, and the screening for infections that might be activated by lymphopenia. Most laboratory monitoring is concentrated around each of the four treatment cycles.
-
Complete blood count with differential, including ALC
Within 3 months before Course 1; before Course 2; and 2 and 6 months after the start of each course
Routine Cornerstone of cladribine monitoring. ALC must be normal (within institutional reference range) before Course 1 and ≥800 cells/µL before Course 2. If ALC is below 800 before Course 2, defer until recovery (up to 6 months); if recovery is delayed beyond 6 months, do not give Course 2. -
Pregnancy test
Before each treatment course in females of reproductive potential
Routine Confirm a negative pregnancy test before starting each course. Effective contraception is required during dosing and for at least 6 months after the last dose of each course in both female patients and female partners of male patients. -
HIV screening
Before each treatment course
Routine Active HIV is a contraindication. Antiretroviral nucleoside analogs interfere with cladribine activation, and uncontrolled HIV plus cladribine-induced lymphopenia would be unsafe. -
Hepatitis B and C screening
Before each treatment course
Routine Identify patients who require hepatology input and antiviral prophylaxis (HBV) before initiating cladribine. One fatal fulminant HBV reactivation has been reported in the clinical programme. -
Tuberculosis screening
Before each treatment course
Routine Tuberculin skin test or IGRA. Treat latent TB before starting cladribine. Three of 1,976 (0.2%) patients in the clinical programme developed TB, all in TB-endemic regions, with one fatal case. -
Liver function tests
Baseline; periodically during therapy
Routine Cladribine itself produced clinically significant liver injury in 0.3% of patients (vs 0% placebo). Investigate symptoms of hepatotoxicity (jaundice, dark urine, RUQ pain, nausea) urgently regardless of recent normal LFTs. -
Cancer screening
Per population guidelines (cervical, breast, colon, skin, prostate as applicable)
Routine Required by the boxed warning. Document cancer screening before initiation; encourage adherence to standard schedules during follow-up. Specifically check for skin lesions (melanoma was reported in CLARITY). -
Vaccination review
Before initiation; consider booster doses pre-treatment
Routine Vaccinate VZV-seronegative patients with varicella vaccine prior to treatment (allow ≥4 weeks before first dose). Recombinant zoster vaccine (Shingrix) is recommended in seropositive patients before or during therapy. Update inactivated vaccines (influenza, pneumococcal, COVID-19, hepatitis B) where indicated. -
Anti-herpes prophylaxis
Initiate when ALC drops below 200 cells/µL; continue until recovery
Trigger-based Aciclovir or valaciclovir prophylaxis is required during periods of severe lymphopenia. Counsel about prompt reporting of any rash that could represent zoster. -
Brain MRI
Annually or per institutional MS protocol
Routine Assess MS disease activity (new T2 or gadolinium-enhancing lesions) and use as a baseline for vigilance against PML (although no PML cases have been reported in MS patients on Mavenclad to date). -
Symptom review
Every visit; safety-net all patients between visits
Routine Specifically ask about new neurological symptoms (PML vigilance), unexplained fever, dermatomal rash (zoster), unusual breathlessness or palpitations (cardiac failure), and skin lesion changes (melanoma). -
Adverse-effect-driven CBC, LFTs, microbiology
Whenever clinically indicated by infection, fatigue, bleeding, or new symptoms
Trigger-based Investigate any unexplained cytopenia, infection, or hepatic symptoms promptly. Always check ALC alongside any infection workup.
Contraindications & Cautions
Absolute Contraindications
- Current malignancy (boxed warning).
- Pregnancy (boxed warning) — and females and males of reproductive potential not using effective contraception during cladribine dosing and for at least 6 months after the last dose of each yearly course.
- Breastfeeding during cladribine dosing days and for 10 days after the last dose.
- HIV infection — confirm a negative HIV test before each treatment course.
- Active chronic infections, including active tuberculosis and active hepatitis (B or C) — exclude before each treatment course; treat and stabilise before considering initiation.
- Hypersensitivity to cladribine.
- Moderate or severe renal impairment (creatinine clearance <60 mL/min).
- Severe hepatic impairment (Child-Pugh score >6).
Relative Contraindications (Specialist Input Recommended)
- History of malignancy — evaluate the benefits and risks individually; cancer screening must be up to date.
- Significant pre-existing immunodeficiency or recent treatment with potent immunosuppressants — assess immune reconstitution and lymphocyte counts before initiating.
- Significant pre-existing bone marrow disease — risk of severe cytopenia.
- History of severe or recurrent opportunistic infections, including PML risk factors — defer or choose alternative DMT.
- Chronic hepatitis B or C carriers — if treatment is necessary, coordinate with hepatology for antiviral prophylaxis.
- Older adults (≥65 years) — limited trial data; use with closer monitoring.
Use with Caution
- Patients on hematotoxic medications — additive bone marrow effects warrant more frequent CBC monitoring.
- Patients receiving non-irradiated blood products during periods of severe lymphopenia — risk of transfusion-associated graft-versus-host disease; use only irradiated cellular products.
- Patients with poor adherence to monitoring — adherence to baseline screening, before-cycle screening, and ALC recovery before Course 2 is essential to safe use.
- Patients planning pregnancy in the 6-month window after a course — counsel on contraception throughout the entire window.
Treatment with cladribine may increase the risk of malignancy. Cladribine is contraindicated in patients with current malignancy. In CLARITY, malignancy was reported in 1.4% of cladribine-treated patients (3 cancers: melanoma, pancreatic, ovarian) versus 0% of placebo patients. In the long-term integrated cohort, the malignancy rate was 0.27 events per 100 patient-years on cladribine versus 0.13 per 100 patient-years on placebo (numerical imbalance). Re-treatment within 2 years of the second course was associated with a malignancy rate of 0.91 events per 100 patient-years and is not recommended. Follow standard cancer screening guidelines.
Cladribine is contraindicated for use in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception during cladribine dosing and for at least 6 months after the last dose in each treatment course. Malformations and embryolethality have been observed in animal reproduction studies. Stop cladribine if the patient becomes pregnant.
Cladribine causes a dose-dependent reduction in lymphocyte count: 87% of treated patients experience lymphopenia, with 26% reaching nadir ALC <500 cells/µL and 1% reaching <200 cells/µL. Severe and prolonged lymphopenia (ALC <200) requires anti-herpes prophylaxis. The second yearly course must be deferred until ALC ≥800 cells/µL. Serious infections, including tuberculosis, hepatitis B reactivation (one fatal case), and post-marketing reports of nocardiosis, varicella zoster, histoplasmosis, cryptococcosis, and toxoplasmosis, have been reported. Decreases in haemoglobin, platelets, and neutrophils are usually mild but severe haematological toxicity has occurred at higher cumulative doses (oncology programme). Hypersensitivity reactions, including serious cases requiring discontinuation, have occurred. One MAVENCLAD-treated patient experienced life-threatening acute cardiac failure with myocarditis (which improved); cardiac failure has also been reported with parenteral cladribine. PML has not been reported in MS patients on cladribine but has been reported with parenteral cladribine in oncologic indications post-marketing.
Patient Counselling
Purpose of Therapy
Cladribine is an oral medicine for relapsing multiple sclerosis given as a short course of tablets — about 4 to 5 days of tablets, twice in the first year, and again twice in the second year. Although the actual time spent taking tablets is short (about 20 days total spread over two years), the medication acts on certain immune cells (lymphocytes) in a way that produces lasting MS control well beyond the dosing period. Most patients receive no further cladribine after the second year. It does not cure MS but reduces relapses and slows the development of new MRI lesions.
How to Take
Each dosing day, swallow your tablets whole with water; you may take them with or without food. Do not chew or split the tablets — they are cytotoxic and require careful handling. Wash your hands after handling tablets. Keep tablets in their original blister pack until use. If you take any other oral medication, separate it from cladribine by at least 3 hours on dosing days. If you miss a dose, take it the next day; do not double up. If you miss two doses in a row, the cycle will be extended by 2 days (your prescriber will guide you).
Sources
- EMD Serono, Inc. MAVENCLAD (cladribine) tablets — Full Prescribing Information. https://www.mavenclad.com/content/dam/web/healthcare/neurology/united-states/pdfs/Prescribing%20Information.pdf Primary US labelling; authoritative source for indications, dosing schedule, boxed warnings, contraindications, drug interactions, monitoring, and adverse reaction tables (Table 2).
- European Medicines Agency. Mavenclad: EPAR — Product Information. https://www.ema.europa.eu/en/documents/product-information/mavenclad-epar-product-information_en.pdf European Summary of Product Characteristics; provides additional EU-specific safety data, including contraceptive guidance and frequency tables.
- National Library of Medicine. MAVENCLAD — DailyMed Drug Label. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9c75e30a-a410-40f1-b653-04d532bd9144 Continuously updated repository of the latest FDA-approved labelling text for clinician reference.
- US Food and Drug Administration. Cladribine (Mavenclad) Clinical Pharmacology Review, NDA 022561. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/022561Orig1s000ClinPharmR.pdf FDA review document detailing pharmacokinetics, drug interaction studies, and renal/hepatic impairment analysis used in approval.
- Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416–426. https://doi.org/10.1056/NEJMoa0902533 CLARITY pivotal phase 3 trial (n=1,326) establishing efficacy of cladribine 3.5 mg/kg vs placebo over 96 weeks; ARR 0.14 vs 0.33, 79.7% relapse-free vs 60.9%, HR 0.67 for 3-month sustained disability progression.
- Giovannoni G, Sorensen PS, Cook S, et al. Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: results from the randomized extension trial of the CLARITY study. Mult Scler J. 2018;24(12):1594–1604. https://doi.org/10.1177/1352458517727603 CLARITY Extension; demonstrated that efficacy is maintained in years 3–4 without further dosing, supporting the immune reconstitution therapy paradigm.
- Leist TP, Comi G, Cree BAC, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014;13(3):257–267. https://doi.org/10.1016/S1474-4422(14)70005-5 Phase 3 trial in patients with a first clinical demyelinating event; demonstrated reduction in conversion to clinically definite MS, although the FDA did not approve a CIS indication.
- Cook S, Leist T, Comi G, et al. Safety of cladribine tablets in the treatment of patients with multiple sclerosis: an integrated analysis. Mult Scler Relat Disord. 2019;29:157–167. https://doi.org/10.1016/j.msard.2018.11.021 Integrated safety analysis from CLARITY, CLARITY Extension, ORACLE-MS, and PREMIERE registry; showed no overall increase in infection risk except for herpes zoster.
- Giovannoni G, Leist T, Aydemir A, et al. Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis. Mult Scler Relat Disord. 2021;48:102776. https://doi.org/10.1016/j.msard.2020.102776 Long-term integrated safety from the Monotherapy Oral cohort (923 cladribine 3.5 mg/kg vs 641 placebo); reports SAE incidence (14.4% vs 10.6%), herpes zoster Adj-AE 0.83/100 PY, lymphopenia Adj-AE 7.94/100 PY, malignancy 0.26/100 PY.
- Hermann R, Karlsson MO, Novakovic AM, Terranova N, Fluck M, Munafo A. The clinical pharmacokinetics of cladribine tablets for the treatment of relapsing multiple sclerosis. Clin Pharmacokinet. 2019;58(3):283–297. https://doi.org/10.1007/s40262-018-0695-9 Comprehensive PK review covering bioavailability (~40%), Vd (480–490 L), 20% protein binding, intracellular accumulation in lymphocytes (30–40-fold), terminal half-life ~24 h, and equal renal and non-renal elimination.
- Leist TP, Weissert R. Cladribine: mode of action and implications for treatment of multiple sclerosis. Clin Neuropharmacol. 2011;34(1):28–35. https://doi.org/10.1097/WNF.0b013e318204cd90 Mechanistic review of cladribine’s selective lymphocyte depletion through deoxycytidine kinase activation and intracellular Cd-ATP accumulation.
- Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis. Neurology. 2018;90(17):777–788. https://doi.org/10.1212/WNL.0000000000005347 American Academy of Neurology guideline (reaffirmed 2024) positioning cladribine among DMT options for active relapsing MS in patients with breakthrough disease activity.
- Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Eur J Neurol. 2018;25(2):215–237. https://doi.org/10.1111/ene.13536 European treatment guideline informing positioning of cladribine as a high-efficacy option for highly active relapsing MS.
- Vukusic S, Carra-Dalliere C, Ciron J, et al. Pregnancy and multiple sclerosis: 2022 recommendations from the French multiple sclerosis society. Mult Scler J. 2023;29(1):11–36. https://doi.org/10.1177/13524585221129472 Practical guidance on managing DMTs around conception and lactation; informs the contraception and pregnancy windows in this monograph.