Serious, including life-threatening or fatal, bacterial, viral, parasitic, and fungal infections have been reported in patients receiving MAVENCLAD. MAVENCLAD reduces the body's immune defense, and an increased risk of infections has been observed in patients receiving MAVENCLAD.

Infections occurred in 49% of MAVENCLAD-treated patients compared to 44% of placebo patients in clinical studies; serious or severe infections occurred in 2.4% of MAVENCLAD-treated patients and 2.0% of placebo-treated patients. The most frequent serious infections in MAVENCLAD-treated patients included herpes zoster and pyelonephritis (see Herpes Virus Infections). Fungal infections were observed, including cases of coccidioidomycosis.

In the postmarketing setting, serious infections have been reported, including nocardiosis, varicella zoster, histoplasmosis, cryptococcosis, and toxoplasmosis. The majority of patients with these infections who had an available absolute lymphocyte count at the time of the event had concurrent lymphopenia, consistent with the mechanism of action of MAVENCLAD [see Warnings and Precautions (5.3)].

HIV infection, active tuberculosis, and active hepatitis must be excluded before initiation of each treatment course of MAVENCLAD [see Contraindications (4)].

Delay initiation of MAVENCLAD in patients with an acute infection until the infection is fully resolved or controlled.

Initiation of MAVENCLAD in patients currently receiving immunosuppressive or myelosuppressive therapy is not recommended [see Drug Interactions (7.1)]. Concomitant use of MAVENCLAD with these therapies could increase the risk of immunosuppression.

Tuberculosis

Three of 1,976 (0.2%) cladribine-treated patients in the clinical program developed tuberculosis. All three cases occurred in regions where tuberculosis is endemic. One case of tuberculosis was fatal, and two cases resolved with treatment.

Perform tuberculosis screening prior to initiation of the first and second treatment course of MAVENCLAD. Latent tuberculosis infections may be activated with use of MAVENCLAD. In patients with tuberculosis infection, delay initiation of MAVENCLAD until the infection has been adequately treated.

Hepatitis

One clinical study patient died from fulminant hepatitis B infection. Perform screening for hepatitis B and C prior to initiation of the first and second treatment course of MAVENCLAD. Latent hepatitis infections may be activated with use of MAVENCLAD. Patients who are carriers of hepatitis B or C virus may be at risk of irreversible liver damage caused by virus reactivation. In patients with hepatitis infection, delay initiation of MAVENCLAD until the infection has been adequately treated.

Herpes Virus Infections

In controlled clinical studies, 6% of MAVENCLAD-treated patients developed a herpes viral infection compared to 2% of placebo patients. The most frequent types of herpes viral infections were herpes zoster infections (2.0% vs. 0.2%) and oral herpes (2.6% vs. 1.2%). Serious herpes zoster infections occurred in 0.2% of MAVENCLAD-treated patients.

Vaccination of patients who are seronegative for varicella zoster virus is recommended prior to initiation of MAVENCLAD. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD. Vaccination with zoster vaccine recombinant, adjuvanted is recommended for patients who are seropositive to VZV, either prior to or during MAVENCLAD treatment, including when their lymphocyte counts are less than or equal to 500 cells per microliter.

The incidence of herpes zoster was higher during the period of absolute lymphocyte count less than 500 cells per microliter, compared to the time when the patients were not experiencing this degree of lymphopenia. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter.

Patients with lymphocyte counts below 500 cells per microliter should be monitored for signs and symptoms suggestive of infections, including herpes infections. If such signs and symptoms occur, initiate treatment as clinically indicated. Consider interruption or delay of MAVENCLAD until resolution of the infection.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

No case of PML has been reported in clinical studies of cladribine in patients with multiple sclerosis. In patients treated with parenteral cladribine for oncologic indications, cases of PML have been reported in the postmarketing setting.

Obtain a baseline (within 3 months) magnetic resonance imaging (MRI) before initiating the first treatment course of MAVENCLAD. At the first sign or symptom suggestive of PML, withhold MAVENCLAD and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms.

Vaccinations

Administer all immunizations (except as noted for VZV) according to immunization guidelines prior to starting MAVENCLAD. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD, because of a risk of active vaccine infection (see Herpes Virus Infections). Avoid vaccination with live-attenuated or live vaccines during and after MAVENCLAD treatment while the patient's white blood cell counts are not within normal limits.