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FDA News: Issue 1, January 2019

Published on 1/4/2019 1:02:00 PM


FDA Approves ULTOMIRIS (Ravulizumab-cwvz) for Adult Patients with Paroxysmal Nocturnal Hemoglobinuria

On December 21, 2018, the US Food and Drug Administration (FDA) approved ULTOMIRIS (ravulizumab-cwvz) for the treatment of adult patients (≥ 18 years of age) with paroxysmal nocturnal hemoglobinuria (PNH). The approved recommended dosage of ULTOMIRIS is based on body weight and consists of loading and maintenance doses administered by intravenous infusion: 
  • ≥ 40 to < 60 kg: 2,400 mg loading dose and 3,000 mg maintenance dose
  • ≥ 60 to < 100 kg: 2,700 mg loading dose and 3,300 mg maintenance dose
  • ≥ 100 kg: 3,000 mg loading dose and 3,600 mg maintenance dose
Starting 2 weeks after the loading dose administration, begin maintenance doses at a once every 8-week interval.
 
ULTOMIRIS is contraindicated in patients with unresolved Neisseria Meningitidis infection. 
 
Life-threatening meningococcal infections/sepsis have occurred in patients treated with ULTOMIRIS. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. 
  • Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies. 
  • Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing a meningococcal infection. 
  • Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected. 
ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must enroll in the program.

 
Additional information regarding warnings and precautions can be found in the full prescribing information linked below. 
 
Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD) 
  • MOA: Ravulizumab-cwvz is a terminal complement inhibitor. 
  • General PK: Ravulizumab-cwvz pharmacokinetics increase proportionally over a dose range of 200 to 5400 mg.
  • Distribution: The mean (SD) volume of distribution at steady state was 5.34 (0.92) L.
  • Elimination: The mean (SD) terminal elimination half-life and clearance of ravulizumab-cwvz in patients with PNH are 49.7 (8.9) days and 0.08 (0.022) L/day, respectively.
  • PD: The extent and duration of the pharmacodynamic response (maximal intravascular hemolysis control and complete terminal complement inhibition) in patients with PNH were exposure dependent for ULTOMIRIS.
  • Immunogenicity: Treatment-emergent antibodies to ravulizumab-cwvz were detected in 1 of 206 (0.5%) patients. No apparent correlation of antibody development to altered pharmacokinetic profile, clinical response, or adverse events was observed.
 
Use in Specific Populations
No clinically significant differences in the pharmacokinetics of ravulizumab-cwvz were observed based on sex, age (18 to 83 years), race, hepatic impairment, or mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2, estimated by MDRD). The effect of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2, estimated by MDRD) on ravulizumab-cwvz pharmacokinetics is unknown.

Efficacy and Safety 
The safety and efficacy of ULTOMIRIS in patients with PNH was demonstrated in two open-label, randomized, active-controlled, non-inferiority Phase 3 studies. Additional information regarding efficacy trials can be found in the full prescribing information linked below.
 
The most frequent adverse drug reactions (> 10%) were upper respiratory infection and headache. 
 
Full prescribing information is available at https://go.usa.gov/xEYJk.

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. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at http://go.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs.

We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to ocp@fda.hhs.gov.

This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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