Mavenclad - Drug Monograph

Introduction

Mavenclad® (cladribine) is an oral immunomodulatory agent approved for the treatment of relapsing forms of multiple sclerosis (MS). It represents a unique therapeutic approach with a short-course oral dosing regimen that provides sustained efficacy while minimizing treatment burden. As a purine analog, Mavenclad offers a distinctive mechanism of action that selectively targets lymphocytes involved in the autoimmune process of MS.

Mechanism of Action

Cladribine is a purine nucleoside analog that preferentially targets lymphocytes through selective incorporation into DNA during the synthesis and repair processes. The drug requires intracellular phosphorylation by deoxycytidine kinase to become active. The active metabolite, cladribine triphosphate, accumulates in lymphocytes with high deoxycytidine kinase activity and low deoxynucleotidase activity.

The mechanism involves:

• Incorporation into DNA strands during synthesis and repair
• Disruption of DNA metabolism leading to DNA strand breaks
• Preferential depletion of CD4+ and CD8+ T lymphocytes
• More modest effects on B lymphocytes
• Relative sparing of other immune cells due to differential enzyme expression

This selective lymphodepletion results in long-lasting immunomodulatory effects with subsequent immune reconstitution.

Indications

Mavenclad is indicated for the treatment of:

• Relapsing-remitting multiple sclerosis (RRMS)
• Active secondary progressive multiple sclerosis (SPMS) with clinical relapses or imaging activity

The drug is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, one or more disease-modifying therapies.

Dosage and Administration

• Total cumulative dose: 3.5 mg/kg body weight over 2 years
• Year 1: 1.75 mg/kg divided into 2 treatment cycles
• Year 2: 1.75 mg/kg divided into 2 treatment cycles
• Each treatment cycle consists of 4-5 days of daily dosing based on body weight

• Oral administration with water
• Should be taken without food (at least 3 hours after and 1 hour before meals)
• Tablets should not be divided, crushed, or chewed

• Renal impairment: Not recommended in patients with creatinine clearance <60 mL/min
• Hepatic impairment: Use with caution in patients with moderate to severe hepatic impairment
• Elderly: Limited data available; use with caution
• Pregnancy: Contraindicated (see Contraindications section)

Pharmacokinetics

• Oral bioavailability: Approximately 40%
• Tmax: 0.5-1.5 hours after administration
• Food reduces bioavailability by approximately 30%

• Protein binding: Approximately 20%
• Volume of distribution: 4.5 L/kg
• Crosses the blood-brain barrier

• Primarily phosphorylated intracellularly to active metabolites
• Minimal hepatic metabolism via cytochrome P450 system
• Not a significant substrate, inhibitor, or inducer of CYP enzymes

• Half-life: Approximately 10 hours for cladribine
• Elimination primarily renal (50-60% of dose)
• Clearance: Approximately 30 L/h

Contraindications

• Pregnancy and women of childbearing potential not using effective contraception
• Current malignancy
• Human immunodeficiency virus (HIV) infection
• Active chronic infections (tuberculosis, hepatitis)
• Hypersensitivity to cladribine or any excipient
• Moderate to severe renal impairment (CrCl <60 mL/min)
• Immunocompromised patients, including those receiving concomitant immunosuppressive or myelosuppressive therapy

Warnings and Precautions

• Increased risk of malignancies, particularly with higher cumulative doses
• Screen for malignancies before treatment initiation and during follow-up

• Severe lymphopenia (Grade 3/4) occurs in approximately 25% of patients
• Monitor lymphocyte counts before each treatment cycle
• Delay subsequent cycles if lymphocyte counts <500 cells/μL

• Increased susceptibility to infections
• Screen for tuberculosis and hepatitis B/C before initiation
• Consider herpes zoster vaccination before treatment
• Monitor for signs of infection during and after treatment

• Cases of liver injury, including elevated transaminases, reported
• Monitor liver function tests before treatment and during follow-up

• Teratogenic and embryotoxic in animals
• Women of childbearing potential must use effective contraception during and for 6 months after last dose

Drug Interactions

• Immunosuppressive/myelosuppressive agents: Increased risk of additive immunosuppression
• Live vaccines: Avoid administration during treatment
• Antiviral agents (e.g., acyclovir, ganciclovir): Potential interference with cladribine activation
• Drugs affecting renal function: May alter cladribine elimination

• CYP450 substrates, inhibitors, or inducers
• Oral contraceptives
• Commonly used MS symptomatic treatments

Adverse Effects

• Lymphopenia
• Headache
• Nausea

• Upper respiratory tract infections
• Herpes zoster
• Alopecia
• Rash
• Back pain
• Fatigue
• Increased liver enzymes

• Malignancies (including solid tumors and lymphoproliferative disorders)
• Severe infections
• Progressive multifocal leukoencephalopathy (PML) - rare
• Autoimmune disorders
• Severe hepatic injury

Monitoring Parameters

• Complete blood count with differential
• Liver function tests
• Renal function assessment
• Pregnancy test
• Screening for HIV, hepatitis B/C, tuberculosis
• Malignancy screening

• Lymphocyte counts before each treatment cycle
• Liver function tests at least every 3 months
• Regular clinical assessment for signs of infection
• Monitoring for signs/symptoms of malignancy

• Annual malignancy screening
• Continued monitoring for infections
• Lymphocyte count monitoring until recovery

Patient Education

• Understand the unique dosing schedule (short courses with long intervals)
• Importance of adherence to contraception requirements
• Recognize signs of infection and when to seek medical attention
• Awareness of potential malignancy risks and importance of regular screening
• Understand the need for regular blood test monitoring
• Report any new or worsening symptoms promptly
• Avoid live vaccines during treatment
• Inform all healthcare providers about Mavenclad treatment
• Understand that lymphopenia is expected and part of the mechanism of action

• Take tablets whole with water
• Take on an empty stomach (at least 3 hours after and 1 hour before food)
• Do not break, crush, or chew tablets
• Follow the prescribed dosing schedule exactly

References

1. 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. 2. Cook S, Vermersch P, Comi G, et al. Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the 96-week extension CLARITY study. Mult Scler. 2018;24(12):1594-1604. 3. Mavenclad® (cladribine) tablets prescribing information. EMD Serono, Inc.; 2023. 4. Leist TP, Comi G, Cree BAC, et al. Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis. Mult Scler Relat Disord. 2020;46:102572. 5. European Medicines Agency. Mavenclad assessment report. EMA/CHMP/600988/2017. 6. National Multiple Sclerosis Society. Cladribine (Mavenclad). 2023 Clinical Bulletin. 7. Wiendl H, Schmierer K, Hodgkinson S, et al. Effectiveness and safety of cladribine tablets in patients with relapsing multiple sclerosis: Final results from the 96-week CLARITY study. J Neurol. 2020;267(12):3565-3574.