MAVENCLAD
Clinical safety rating
cautionComprehensive clinical and safety monograph for MAVENCLAD (MAVENCLAD).
Comprehensive clinical and safety monograph for MAVENCLAD (MAVENCLAD).
FDA: Treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting disease and active secondary progressive disease.
Cladribine is a prodrug that is phosphorylated intracellularly to its active triphosphate form, which inhibits DNA synthesis and repair, leading to lymphocyte depletion. It selectively targets and reduces circulating T and B lymphocytes, thereby modulating the immune response in multiple sclerosis.
| Metabolism | Cladribine is primarily metabolized intracellularly by deoxycytidine kinase to its active triphosphate metabolite. It is also phosphorylated by other nucleoside kinases. The elimination half-life is approximately 1 day. Renal excretion of unchanged drug accounts for about 18% of the dose. |
| Excretion | Approximately 100% of cladribine dose is eliminated via renal excretion of unchanged drug and metabolites, with <5% recovered in feces. Renal clearance is about 2/3 of total clearance. Biliary elimination is negligible. |
| Half-life | Terminal elimination half-life of cladribine is approximately 5.7 days (range 4-10 days) following oral administration. This long half-life supports once-daily high-dose short-course dosing and is due to slow release from lymphocytes. Clinical context: Allows sustained intracellular levels of active triphosphate in lymphocytes. |
| Protein binding | 20% bound to plasma proteins, primarily albumin. No significant binding to alpha1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution is approximately 4.3 L/kg (range 1-9 L/kg). This large Vd indicates extensive extravascular distribution, including penetration into cells and tissues, particularly lymphocytes. Clinical meaning: High tissue distribution correlates with intracellular loading in target immune cells. |
| Bioavailability | Oral bioavailability of cladribine from MAVENCLAD is approximately 40% (range 30-50%). It is converted to active triphosphate intracellularly, so prodrug absorption is similar. Food reduces absorption by ~20% but does not affect clinical effect. |
| Onset of Action | Oral: Clinical effect (reduction in relapses) observed within 3-6 months after initial treatment course. Onset is delayed due to time required for depletion of lymphocyte subsets. |
| Duration of Action | Duration of therapeutic effect lasts approximately 2 years (based on 2 annual treatment courses). Lymphocyte recovery occurs over months to >1 year after last dose. Clinical note: No continuous dosing required; effects persist due to prolonged intracellular active triphosphate and lymphocyte recovery. |
| Molecular Weight | 285.69 |
3.5 mg/kg body weight administered orally as two treatment courses of 1.75 mg/kg each over two consecutive weeks (cumulative dose 3.5 mg/kg per year). Each course is given as a 14-day period: 1.75 mg/kg in divided doses daily for 4 or 5 days, depending on patient preference (e.g., 10 mg tablets daily for that period).
| Dosage form | TABLET |
| Renal impairment | Contraindicated in patients with estimated GFR <30 mL/min/1.73 m2 due to potential accumulation and increased risk of adverse reactions. No dose adjustment recommended for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m2). |
| Liver impairment | Contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh class B or C). No dose adjustment recommended for mild hepatic impairment (Child-Pugh class A). |
| Pediatric use | Not approved for use in pediatric patients less than 18 years of age. Safety and efficacy have not been established. |
| Geriatric use | No specific dose adjustment recommended based on age alone. However, renal function should be assessed and dosing should be based on eGFR as in younger adults. Experience in patients over 60 years of age is limited. |
| 1st trimester | Contraindicated due to teratogenicity (increased risk of congenital malformations). |
| 2nd trimester | Contraindicated due to potential fetal harm from continued exposure. |
| 3rd trimester | Contraindicated due to risk of hematologic toxicity in neonate following exposure near term. |
Clinical note
Comprehensive clinical and safety monograph for MAVENCLAD (MAVENCLAD).
| Placental transfer | Cladribine crosses the placenta; studies in animals show embryotoxicity and teratogenicity. In humans, placental transfer is expected based on molecular weight and pharmacokinetics. |
| Breastfeeding | Cladribine and its metabolites are excreted in human milk; potential for serious adverse reactions in nursing infants. Advise women not to breastfeed during treatment and for at least 10 days after the last dose. |
| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | MAVENCLAD (cladribine) is contraindicated in pregnancy. Based on animal studies and its mechanism of action (cytotoxicity to rapidly dividing cells), there is an increased risk of fetal harm, including teratogenicity and embryolethality. In humans, no adequate controlled studies exist; therefore, use in all trimesters is contraindicated. Women of childbearing potential must use effective contraception during treatment and for at least 6 months after the last dose. |
| Fetal Monitoring | In women of childbearing potential, pregnancy must be excluded before starting therapy. A pregnancy test is required prior to each treatment course. During therapy, monitor complete blood counts (lymphocyte counts) regularly due to lymphopenia risk. No specific fetal monitoring is indicated if pregnancy occurs, but exposure should be avoided. |
| Fertility Effects | Cladribine may impair fertility in humans. In animal studies, cladribine caused adverse effects on spermatogenesis and female fertility. Men with childbearing potential should use effective contraception during and for at least 6 months after treatment. Women may experience decreased fertility; however, reversibility is unknown. |
■ FDA Black Box Warning
WARNING: MALIGNANCIES. Cladribine can increase the risk of malignancies (including cases of cancer-related deaths). Because of this risk, MAVENCLAD should be used in patients who have had an inadequate response to, or are unable to tolerate, other drugs indicated for the treatment of MS.
| Serious Effects |
Current malignancy (except basal cell carcinoma)Pregnancy and women of childbearing potential not using effective contraceptionBreastfeedingHIV infectionActive chronic infections (e.g., tuberculosis, hepatitis)Severe hepatic impairment (Child-Pugh C)Severe renal impairment (CrCl <30 mL/min)Hypersensitivity to cladribine or any excipient
| Precautions | Risk of malignancies: including treatment-emergent malignancies (e.g., cancers of the lung, gastrointestinal tract, skin, breast, and others)., Hematologic toxicity: severe bone marrow suppression (thrombocytopenia, anemia, neutropenia); monitor CBC counts before and during treatment., Infections: increased risk of serious infections, including opportunistic infections (e.g., tuberculosis, herpes zoster, progressive multifocal leukoencephalopathy); screen for latent infections before initiation., Hepatic injury: cases of drug-induced liver injury; monitor liver enzymes., Fetal risk: can cause fetal harm; advise females of reproductive potential to use effective contraception during and for 6 months after the last dose., Vaccinations: avoid live vaccines during and after treatment., Impaired renal function: use with caution; cladribine pharmacokinetics may be altered. |
| Food/Dietary | No significant food interactions reported. Avoid grapefruit and grapefruit juice as they may alter drug metabolism. |
| Clinical Pearls | Mavenclad (cladribine) is an oral purine antimetabolite approved for relapsing multiple sclerosis. It is given as two short courses per year for two years. Monitor for lymphopenia, infections, and malignancies. Contraindicated in patients with active infections or current malignancy. Do not use in patients with HIV or hepatitis B/C. Live vaccines contraindicated during and after treatment. Pregnancy category D; effective contraception required. Monitor liver enzymes and bilirubin. Consider PCP and VZV prophylaxis if lymphopenia severe. MRI monitoring for PML is recommended. |
| Patient Advice | Mavenclad is taken in two treatment courses per year, each consisting of 4 or 5 days of tablets, for 2 years. · You need regular blood tests to monitor your white blood cell count, liver function, and for infections. · Avoid live vaccines during treatment and for at least 1 year after the last dose. · Use effective contraception during treatment and for at least 6 months after the last dose. · Report any signs of infection (fever, chills, cough), unusual bleeding, or easy bruising immediately. · Do not take Mavenclad if you have an active infection, cancer, or HIV/hepatitis B or C. · Avoid grapefruit products during treatment. · Store tablets at room temperature away from moisture. |
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