FDA Approves OCREVUS (Ocrelizumab) for Treatment of Adult Patients with Relapsing or Primary Progressive Forms of Multiple Sclerosis
On March 28, 2017, the U.S. Food and Drug Administration (FDA) approved OCREVUS (ocrelizumab) for treatment of adult patients with relapsing or primary progressive forms of multiple sclerosis. This represents the first product approved for primary progressive multiple sclerosis. The approved recommended dosage of OCREVUS for both indications is an initial dose of 300 mg intravenous (IV) infusion, followed two weeks later by a second 300 mg IV infusion. Subsequent doses are single 600 mg IV infusions every 6 months. OCREVUS is contraindicated in patients with active Hepatitis B virus (HBV) infection or a history of life-threatening infusion reaction to OCREVUS. Screen patients for HBV prior to initiating OCREVUS. Determine whether patients have active infection prior to every infusion of OCREVUS. Administer all necessary live-attenuated or live vaccines according to immunization guidelines at least 6 weeks prior to initiation of OCREVUS. Pre-medicate patients with methylprednisolone (or an equivalent corticosteroid) and an antihistamine prior to each OCREVUS infusion to reduce the frequency and severity of infusion reactions. An antipyretic may also be considered. Dose modifications in response to infusion reactions depend on the severity and are described in the full prescribing information (link below).
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)
- MOA: The precise MOA in multiple sclerosis is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes.
- Dose Proportionality: Ocrelizumab exhibits essentially linear and dose proportional pharmacokinetics between 400 mg and 2000 mg (0.7 to 3 times the approved recommended maintenance dosage).
- Elimination: Constant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at 0.05 L/day, which declined with a half-life of 33 weeks. The terminal elimination half-life was 26 days.
- Exposure-Response: Treatment with OCREVUS reduces CD19+ B-cell counts in blood by day 14 following infusion. In a clinical study of 51 patients, the median time for B-cell counts to return to either baseline or lower limit of normal was 72 weeks (range 27-175 weeks) after the last OCREVUS infusion.
Drug Interactions
The risk of immunosuppression is expected to increase with the concomitant use of OCREVUS and other immune-modulating or immunosuppressive therapies, including immunosuppressant doses of corticosteroids. Consider the risk of additive immune system effects when giving immunosuppressive therapies and OCREVUS concomitantly.
When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, consider the duration and mode of action of these drugs because of additive immunosuppressive effects when initiating OCREVUS.
Use in Specific Populations
No significant change in the pharmacokinetics of OCREVUS was observed in patients with mild renal impairment or mild hepatic impairment.
Safety and Efficacy
The efficacy of OCREVUS in patients with relapsing forms of multiple sclerosis (RMS) was demonstrated in two randomized, double-blind, double-dummy, active comparator-controlled clinical trials with a duration of 96 weeks. OCREVUS patients received the approved recommended dosage. The relative reduction in annualized relapse rate versus active comparator was 46% (p < 0.0001) in study 1 and 47% (p < 0.0001) in study 2. The risk reduction (RR) in the proportion of patients with 12-week confirmed disability progression (prospectively pooled data from both studies) versus active comparator was 40% (p = 0.0006). In a randomized, double-blind, placebo-controlled clinical trial in patients with primary progressive multiple sclerosis (PPMS), patients received the approved recommended dosage for at least 120 weeks or placebo. The time to onset of disability progression confirmed at 12 weeks after onset was significantly longer for OCREVUS-treated patients than for placebo-treated patients (32.9% vs. 39.3% [RR: 24%, p = 0.0321]).
The most common adverse reactions (incidence ≥ 10%) in the RMS trials were upper respiratory tract infections and infusion reactions and in the PPMS trial were upper and lower respiratory tract infections, infusion reactions, and skin infections. OCREVUS can result in mild to life-threatening infusion reactions and an increased risk for respiratory tract infections, skin infections, and herpes-related infections. An increased risk of malignancy with OCREVUS might exist. Although not seen in OCREVUS clinical trials, progressive multifocal leukoencephalopathy and HBV reactivation have been observed in patients treated with other anti-CD20 antibodies. Detailed information regarding clinical monitoring guidelines and recommended management are described in the full prescribing information (link below).
Full prescribing information is available at https://go.usa.gov/xXQrR.
Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products which are often available shortly following approval.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.
FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov
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