Identification

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Name
Ravulizumab
Accession Number
DB11580
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Ravulizumab is considered a long-acting complement 5 (C5) inhibitor that has been undergoing clinical trials for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) as of 4 February, 2016. A drug similar to ravulizumab (ALXN1210), called eculizumab, is currently approved for the treatment of PNH in 46 countries under the brand name Soliris®. Ravulizumab is considered by Alexion Pharmaceuticals Inc. to be a "next-generation" eculizumab molecule. Ravulizumab was subsequently approved by the US FDA in December of 2018 for a variety of beneficial characteristics that make it an advanced, next-generation agent in comparison to eculizumab 3. In particular, ravulizumab is currently the first and only long-acting C5 complement inhibitor that can be administered every eight weeks for the treatment of adult patients with PNH whereas eculizumab is a bi-weekly treatment 3,Label. Moreover, virtually all of the phase 3 trial results for ravulizumab have demonstrated the equivalent efficacy and safety established by eculizumab and that patients transition safely and effectively from using eculizumab to ravulizumab 3. Subsequently, whereas PNH patients may have needed to previously plan their lives rather strictly around the bi-weekly infusion administrations of eculizumab, with ravulizumab such patients can find a more relaxed dosing schedule of only six or seven infusions over an entire year 3,Label.

Just as the US FDA permitted a timely and expedited approval of ravulizumab ahead of the Prescription Drug User Fee Act (PDUFA) date of February 18, 2019 following the use of a rare disease priority review voucher by Ultomiris (ravulizumab) developer Alexion for many of the aforementioned beneficial treatment reasons, regulatory authorities in the European Union (EU) and Japan have currently accepted and are reviewing applications for the approval of Ultomiris (ravulizumab) as a treatment for adults with PNH as well 3.

Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
>Light Chain
DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGATNLADGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGEILPGSGHTEY
TENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYFFGSSPNWYFDVWGQGTLVTV
SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE
GNVFSCSVLHEALHSHYTQKSLSLSLGK
References:
  1. METHOD FOR SIMULTANEOUS QUANTIFICATION OF ALXN1210 AND ECULIZUMAB IN HUMAN SERUM OR URINE: International Publication Number WO 2018/183449 A1 [File]
Download FASTA Format
Synonyms
  • Ravulizumab
  • ravulizumab-cwvz
External IDs
ALXN-1210 / ALXN1210
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
UltomirisSolution10 mgIntravenousAlexion Pharma GmbhNot applicableNot applicableCanada
UltomirisSolution, concentrate300 mg/30mLIntravenousAlexion Pharmaceuticals Inc.2018-12-21Not applicableUs
Additional Data Available
  • Application Number
    Application Number

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
C3VX249T6L
CAS number
1803171-55-2

Pharmacology

Indication

Ravulizumab is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) Label.

Associated Conditions
Pharmacodynamics

Immediate and complete inhibition of serum-free complement protein C5 (concentration of less than 0.5 mcg/mL) was observed by the end of the first ravulizumab infusion and sustained throughout the entire 26-week treatment period in all patients, both complement-inhibitor naïve and previously treated with eculizumab Label.

The extent and duration of the pharmacodynamic response in patients with PNH were exposure dependent for ravulizumab Label. Free C5 levels of <0.5 mcg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition Label.

Complete terminal complement inhibition following initiation of ravulizumab treatment led to normalization of serum LDH by week 4 in complement-inhibitor naïve patients and maintained LDH normalization in patients previously treated with eculizumab Label.

Mechanism of action

Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, debilitating and life-threatening ultra-rare blood disorder characterized by hemolysis (destruction of red blood cells) that is mediated by the uncontrolled activation of the complement system, a component of the body’s immune system 1.

Ravulizumab is subsequently a terminal complement inhibitor that specifically binds to the particular complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex [C5b-9]) and preventing the generation of the terminal complement complex C5b9 Label. Ravulizumab inhibits terminal complement-mediated intravascular hemolysis in patients with PNH Label.

TargetActionsOrganism
UComplement C5
inhibitor
Humans
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Blackbox Warnings

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Absorption

It has been demonstrated that mean ravulizumab Cmax and AUC∞ increase in a dose-proportional manner and that a single 400 mg intravenous dose of ravulizumab administered to subjects reach or exceed the threshold level of 100 µg/mL 2.

Volume of distribution

The mean (SD) volume of distribution at steady state was 5.34 (0.92) L Label.

Protein binding

Readily accessible data regarding the protein binding of ravulizumab is not available.

Metabolism

Monoclonal antibody agents like ravulizumab are not expected to generate toxic metabolites as they generally undergo proteolysis to their constituent amino acids [F94].

Route of elimination

Monoclonal antibody agents like ravulizumab are generally not eliminated via hepatic, renal, or biliary routes [F94].

Half life

The mean (SD) terminal elimination half-life of ravulizumab in patients with PNH was recorded as 49.7 (8.9) days Label.

Clearance

The mean (SD) clearance of ravulizumab in patients with PNH was recorded as being 0.08 (0.022) L/day respectively Label.

Toxicity

Although PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes like fetal death and premature delivery, there are no available data on ravulizumab use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes Label.

Although there are currently no human reproductive studies, human immunoglobulins like ravulizumab are known to cross the human placental barrier, and thus may potentially cause terminal complement inhibition in the fetal circulation Label.

There are no data on the presence of ravulizumab in human milk, the effect on the breastfed child, or the effect on milk production Label. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in a nursing child, breastfeeding should be discontinued during treatment and for 8 months after the final dose Label.

The safety and efficacy of ravulizumab in pediatric patients and geriatric use have not yet been established Label.

Genotoxicity studies have not been conducted with ravulizumab Label.

Effects of ravulizumab upon fertility have not been studied in animals Label. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ravulizumab had no adverse effects on mating or fertility Label.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Ravulizumab.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Ravulizumab is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Ravulizumab.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Ravulizumab.
AbetimusThe risk or severity of adverse effects can be increased when Abetimus is combined with Ravulizumab.
AbituzumabThe risk or severity of adverse effects can be increased when Ravulizumab is combined with Abituzumab.
AbrilumabThe risk or severity of adverse effects can be increased when Ravulizumab is combined with Abrilumab.
ActeosideThe risk or severity of adverse effects can be increased when Ravulizumab is combined with Acteoside.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Ravulizumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Ravulizumab.
Additional Data Available
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  • Severity
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Food Interactions
Not Available

References

Synthesis Reference

Method for simultaneous quantification of alxn1210 and eculizumab in human serum or urine: WO20 8183449A1, Ryan Pelto, Meng Chen

General References
  1. Alexion Receives Early FDA Approval for ULTOMIRIS™ (Ravulizumab-cwvz) in Adults with Paroxysmal Nocturnal Hemoglobinuria (PNH) [Link]
  2. First in Human Single-Ascending Dose Study: Safety, Biomarker, Pharmacokinetics and Exposure-Response Relationships of ALXN1210, a Humanized Monoclonal Antibody to C5, with Marked Half-Life Extension and Potential for Significantly Longer Dosing Intervals / Blood 2015 125:4777 [Link]
  3. Ravulizumab FDA Approval Press Release [File]
External Links
Wikipedia
Ravulizumab
FDA label
Download (1.29 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2Active Not RecruitingTreatmentParoxysmal Nocturnal Haemoglobinuria (PNH) / PNH1
2Active Not RecruitingTreatmentParoxysmal Nocturnal Haemoglobinuria (PNH) / PNH1
3Active Not RecruitingTreatmentAdult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Are Currently Being Treated With Eculizumab / Paroxysmal Nocturnal Haemoglobinuria (PNH)1
3Active Not RecruitingTreatmentAtypical Hemolytic Uremic Syndrome (aHUS)1
3Active Not RecruitingTreatmentParoxysmal Nocturnal Haemoglobinuria (PNH)1
3RecruitingTreatmentAtypical Hemolytic Uremic Syndrome (aHUS)1
3RecruitingTreatmentGeneralized Myasthenia Gravis1
3RecruitingTreatmentParoxysmal Nocturnal Haemoglobinuria (PNH)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionIntravenous10 mg
Solution, concentrateIntravenous300 mg/30mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Receptor binding
Specific Function
Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C...
Gene Name
C5
Uniprot ID
P01031
Uniprot Name
Complement C5
Molecular Weight
188303.705 Da
References
  1. Ravulizumab FDA Label [File]

Drug created on April 17, 2016 16:44 / Updated on December 02, 2019 09:06