Disease-modifying therapies for sickle cell disease

Therapy	Hydroxyurea (1998) (Siklos, Hydrea)	L-glutamine (2017) (Endari)	Voxelotor (2019, 2021) (Oxbryta)	Crizanlizumab (2019) (Adakveo)
Age	All ages including infants	5 years and older*	4 years and older*	16 years and older*
Route	Oral (pill or liquid; liquid used for young children requires formulary preparation)	Oral (powder added to food or beverages)	Oral (tablet)	Intravenous
Frequency	Once daily	Twice daily	Once daily	Once every 4 weeks (after initial dose week 0, 2, and 4)
Monitoring	Frequent monitoring of CBC and dose titration, especially during drug initiation	None	None	None
Benefits	Improved life expectancy Reduced acute pain episodes (4.5 versus 2.5)^¶ Reduced vaso-occlusive complications including acute chest syndrome and stroke (selected individuals) Reduced transfusion requirement 25 years of safety and efficacy data	Reduced acute pain episodes (4 versus 3)^¶ Can be combined with hydroxyurea Good safety profile	Non-statistically significant trend towards reduced acute pain episodes (3.2 versus 2.8)^¶ Can be combined with hydroxyurea Increased hemoglobin and decreased hemolysis Improved global functioning May improve fatigue	Reduced in acute pain episodes (3 versus 1.6)^¶ Can be combined with hydroxyurea Good choice for severe and frequent pain episodes
Caveats	Hair loss Gastrointestinal symptoms Generally avoid prior to conception (males and females) and during first trimester of pregnancy	Use pharmacologic grade (not over-the-counter) L-glutamine Mild gastrointestinal symptoms Long-term efficacy data are lacking	Dose adjustments for CYP3A4 interactions Gastrointestinal symptoms Monitor hemoglobin in individuals with higher baseline hemoglobin (eg, HbSC disease)	Requires intravenous access and hospital infusions Infusion reactions (rare) Arthralgias and back pain Nausea May cause platelet clumping in samples collected in EDTA

These medications are intended to be started when the individual is well; they are not appropriate for treating acute pain. Individuals with sickle cell disease may consider the information in this table or other information along with their values and preferences when determining the best therapy to use. For each drug, the year the drug was approved by the US Food and Drug Administration (FDA) and associated brand names are listed in parentheses.

CBC: complete blood count; EDTA: ethylenediaminetetraacetic acid.
* Refers to age listed on United States product information. At times we use these drugs in selected younger patients (off-label).
¶ Expressed as annualized rates, compared with placebo.^[1-4] None of the drugs have been directly compared with each other in a randomized trial.

References:

Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995; 332:1317.
Niihara Y, Miller ST, Kanter J, et al. A Phase 3 Trial of L-glutamine in Sickle Cell Disease. N Engl J Med 2018; 379:226.
Vichinsky E, Hoppe CC, Ataga KI, et al. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med 2019; 381:509.
Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med 2017; 376:429.

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Disease-modifying therapies for sickle cell disease